The Crucial Role of Diet and the Gut Microbiome in Colorectal Cancer Risk

Colorectal cancer (CRC) is a major global health burden as its ranks third in terms of incidence and second in mortality worldwide. It has increased steadily in recent years, including in younger age groups. As with many chronic diseases, it is the interaction between genetic and environmental factors (also referred to as “exposome”) that determines the risk for CRC development and outcome. Environmental risk factors include western dietary habits, smoking, obesity, diabetes, and heavy alcohol consumption, with the gut microbiome playing an important role of mediating between environmental factors, in particular our diet and the development (“carcinogenesis”), formation and progression of CRC.

“Scientific evidence has demonstrated associations between CRC prevalence, and the composition and function of the gut microbiota…”

The gut microbiome plays an important role in energy homeostasis, keeping the intestinal epithelium intact, protecting against pathogenic organisms, and maintaining a healthy immune system. Emerging evidence has demonstrated associations between CRC prevalence, and the composition and function of the gut microbiota, suggesting a role of the gut microbiome in colorectal carcinogenesis. Much of the focus on microbiome research in CRC has been on microbes as pathogenic drivers of CRC, in the hope that these efforts can be leveraged for preventive, diagnostic, and therapeutic purposes. Human data and data from mechanistic studies in cell culture and animal models support a role of specific microbes as potentiators of tumor development — including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, colibactin-producing Escherichia coli and Peptostreptococcus anaerobius. Chronic low grade immune system activation of the colon also plays an important role the development of dysplasia and CRC. For example, in patients with inflammatory bowel disease, chronic, severe inflammation of the colon increases the likelihood of developing CRC. More subtle inflammation, such as the changes occurring in individuals with metabolic endotoxemia in otherwise healthy colonic tissues plays an important role in the conversion of a healthy colon to one with dysplastic, precancerous lesions. Disruption of the intestinal barrier by inflammatory mediators facilitates bacterial translocation from the intestinal lumen into the gut-associated immune system and into the systemic circulation and, ultimately, exposure of immunogenic microbial compounds to both epithelial cells and antigen-presenting cells. Activation of immune signaling pathways by bacterial stimuli results in a loss of homeostasis that drives an inflammatory environment conducive to the development of colon cancer. The presence of colorectal adenoma, the early stage of CRC, has also been found to be associated with changes in the gut microbiome, raising the possibility of future use of such microbiome changes as biomarkers enabling screening tests and early diagnosis.

The changes in the gut microbial ecosystem have been attributed to key dietary factors in the Standard American Diet (SAD), such as low intake of fruits and vegetables, high consumption of animal-based products, and ultra-processed foods. There are multiple mechanisms and pathways through which the gut microbiota can affect CRC formation and progression, including inflammation, tumor-inducing metabolites, genotoxins, and oxidative stress.

“Emerging evidence confirms that colorectal cancer and gut microbiome composition and diversity alterations are directly correlated, suggesting a role of the intestinal microbiota in colorectal carcinogenesis”.

Based on a number of large epidemiological studies, largely plant-based and vegetarian-style diets such as the traditional Mediterranean diet, with consumption of an abundance and variety of fruits, vegetables, nuts and whole grains, low in red meat, and especially processed meat have been associated with a low risk for developing CRC, and have been recommended as an important component of CRC prevention measures. Even though it remains to be determined, which individual component of the Standard American Diet (SAD) is the main factor underlying the increased prevalence of colon cancer, the high consumption of red meat and dairy products has been implicated as potential risk factor in a number of studies. However, a recent meta-analysis published in the prestigious journal Nature Medicine of epidemiological studies on the association of unprocessed red meat consumption and several health outcomes, including CRC, failed to show a significant correlation. Regardless of the causative role of red meat in colon carcinogenesis, the more colorful the meals, the better, as the plant compounds responsible for the various colors of vegetables and fruit which often belong to the polyphenol group have been shown to have beneficial effects on the gut microbiome, and may reduce the risk for the development of colon cancer. Altogether, diets made up to 75% of fruits and vegetables and low in animal products are the most recommended for protection from CRC.

“…one would expect that dietary assessment and nutrition counseling would be an integral part of CRC prevention programs.”

In view of the close relationship between diet, the gut microbiome and CRC risk, one would expect that dietary assessment and nutrition counseling would be an integral part of CRC prevention programs. This relationship may be one of the drivers of increasing CRC risk in younger age groups, which has resulted in lowering of the recommended age for colon cancer screening, but not in increased efforts in dietary counseling. Such efforts are nearly absent in gastroenterology practices with large numbers of colon cancer screening, and the topic of diet has largely been absent in the recent discussions about the most cost-effective approaches to colon cancer screening.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Jill Horn is a recent UCLA graduate with a Neuroscience. She is deeply interested in the interconnectedness of body, mind, and spirit takes an integrative approach to health and well-being.

The Exciting New Science Underlying IBS Treatments

In the absence of satisfactory medical therapies for irritable bowel syndrome (IBS) and other disorders of brain gut interactions, clinical guidelines identify self-management as a first line treatment. Its goal is for patients to acquire skills to help reduce the impact of their condition, optimize function, and, in the absence of curative therapy, gain optimal control of symptoms. Behavioral self-management modalities typically emphasize a strategy called cognitive behavioral therapy (CBT). CBT is a learning-based treatment that teaches practical skills for unlearning symptom-aggravating processes such as symptom related worry and avoidance, substituting more adaptive self-management skills.

In a collaborative study with Dr. Jeff Lackner from the University of Buffalo, NY, we aimed to test the hypothesis that CBT-treated patients with IBS who learn to self-manage painful gut symptoms show improvement in cognitive flexibility, abdominal pain, and quality of life. Participants included 130 patients with a mean age of 40 years and with moderate-to-severe symptoms who were randomly assigned to either CBT (N = 86) or a nonspecific education/support (EDU) intervention (N = 44).

CBT but not EDU patients showed significant symptom improvement from baseline to post-treatment in cognitive flexibility. For CBT patients, changes in cognitive flexibility were significantly associated with changes in IBS symptom severity, abdominal pain, and IBS QOL. IBS subjects whose symptoms improved on CBT, also showed distinct changes in brain network connectivity and in the gut microbiome.The ability to self-manage painful IBS symptoms refractory to conventional medical and dietary treatments is related to the ability to respond flexibly across shifting contexts using cognitive change procedures featured in CBT for IBS.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Yvon Chouinard, the Ultimate Climate Philanthropist

For the majority of people that read the news last week that the iconic founder and owner of the world-famous company Patagonia had given his company away, it came as a shock, unparalleled in its scope and details in the business world.

According to the New York Times, Mr. Chouinard, his wife and two adult children have transferred their ownership of Patagonia, valued at about $3 billion, to a specially designed trust and a nonprofit organization. They were created to preserve the company’s independence and ensure that all of its profits — some $100 million a year — are used to combat climate change and protect undeveloped land around the globe.

However, for anybody who has known this self-declared reluctant billionaire, this decision wasn’t amazing at all. It was simply the realization of a lifelong dream.

I first met Chouinard in 2018. Together with my wife and son, and a small film crew I had the privilege to do an interview with him about his company Patagonia Provisions, at his modest but beautifully located home in Jackson Hole, Wyoming. We sat in the meadow in front of his house with a breathtaking view of the snow-covered Teton mountain range, and Chouinard spoke both plainly and eloquently about his beliefs and about the state of food production in the US.

“There’s nothing wrong with this planet, it’s perfect, but we’re destroying it of course,” he said. “Still, all of the answers are in nature. I think I’ve always believed that.”

Looking back at the 3 hourlong interview, it seemed Mr. Chouinard had plans for quite some time to find a solution that would reconcile seemingly incompatible aspects of his life: his unconditional love for nature and the outdoors, his serious and growing concerns about climate change, his self-identification as a socialist and his phenomenal success as a businessman.

For many afficionados of Patagonia, it may be news that Chouinard has been passionate about transforming the current model of industrial agriculture to a regenerative organic one, helping to tap the solutions already held in nature. “Regenerative organic farming practices yield large crops while building healthier soil, which can draw down and store more greenhouse gases,” he set forth in a recent essay on the subject. “Free-roaming buffalo restore prairie grasslands, one of Earth’s great carbon storage systems. Rope-cultivated mussels produce delicious protein while cleaning the water where they’re grown. Place-based and selective-harvest fishing techniques allow us to target truly sustainable fish populations without harming less abundant species. As these examples illustrate, the more we roll up our sleeves and dig into the world of food, the more we discover that the best ways are often the old ways.”

Chouinard was as fluent—and adamant—about his mission in our discussion as well, articulating his vision for pioneering a new way of addressing our health and our environment by changing the way that we grow our food. “That’s the revolution I want to be a part of,” he said decisively.

It may sound unusual to hear the word “revolution” from someone who is a giant in the business world and listed as a billionaire in the Forbes ranking (a listing he apparently is not happy about). But then Chouinard is an unusual leader and, in his own words, a “reluctant businessman”—the title of his most recent book: Let My People Go Surfing: The Education of a Reluctant Businessman — who is not afraid to blaze a path all his own. (Among other enlightened company policies, he has instituted at Patagonia, Chouinard has decreed that when the surf is up, employees should drop their work and go surfing. “I don’t care when you work,” he clarified, “as long as you get the job done.”) Indeed, he sees himself more as a socialist than a capitalist, and has always pursued what seems morally right and important to him as opposed to what made the most profit for his company. One of his favorite quotes is: “If you want to understand entrepreneurs, study the juvenile delinquent.” Because “the juvenile is saying with his actions, ‘This sucks, I am going to do my own thing,’” he explained, “That’s what the entrepreneur does. They just say, ‘This is wrong, I am going to do it this other way’ . . . I love breaking the rules.”

Here are a few more of Yvon’s remarkable statements from the 2018 interview. In response to my question about the basis of his business, he responded:

“My business is based on having a wild nature, you know, free flowing rivers and snow in the mountains … and public lands. … I feel like I have more responsibility to protect those places than your average business”

“I’m basically a socialist and my company is a socialistic organization. .. ”

And in response to my question about the mission of his business:

“If you were going to ask me today why I’m in business, in fact I’m going to change my mission statement. My mission statement is going to be we’re in business to protect our home planet.”

For Yvon in his early 80s, this is not just a dream, and he has done a lot to make this vision become a reality and reverse the destructive course of our current food system. He has a natural talent for building a team of people and followers that devotedly believe in Patagonia’s core principles and who will bring his vision forward into the future. Chouinard has also ensured that his mission will be widely carried out by, in 1985, creating a program at Patagonia that has since offered more than $100 million in grants to grass roots organizations and innovative startups that are forging new methods of food production in a responsible, regenerative organic way. Among many other projects, Chouinard has also supported the development of the perennial long root grain Kernza and turned it into several specialty beers, such as Patagonia Long Root Ale; he promotes the consumption of sustainably and humanely harvested salmon and bison meat; and he leads many educational and marketing campaigns, including producing impactful documentaries about environmental issues such as “Dam Nation” and “Artifishal.”

The encounter with this unique human being 4 years ago, which I documented in detail in my book, The Gut Immune Connection and which I plan to incorporate in the upcoming documentary, Interconnected Planet, had a long-lasting influence on my own world view and career trajectory. Even though other billionaires, including Jeff Bezos, Laurene Powell Jobs, the widow of the Apple co-founder Steve Jobs, Mike Bloomberg, Mark Zuckerberg, and Bill Gates have joined the exclusive club of climate philanthropists, Chouinard has set the gold standard of what needs to be done to save the planet from pending climate doom. Let’s hope other companies will follow his lead.

Parts of this post have been taken from my book, The Gut Immune Connection.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Is A Healthy Diet Good For The Planet?

While there has been an explosion of public interest in the topics of gut health, gut healthy foods and supplements in the past couple of years, the intricate link between food, human health, and the health of the planet, the so called One Health concept has received considerably less attention.

In 2019, one of the most comprehensive reports based on the One Health concept—exploring the intricate connections among a healthy diet, sustainable food systems, and planetary health—was published in the Lancet by the EAT-Lancet Commission, a group of thirty-seven leading scientists from various disciplines and sixteen countries, co-chaired by Johan Rockstroem, from the Potsdam Institute for Climate Impact Research, and Walter C. Willett from the Harvard T. H. Chan School of Public Health. When I interviewed Willett for my book, The Gut Immune Connection, he explained “This commission was put together . . . to look at the issue of whether and how we would be able to feed a diet that is both healthy and sustainable to about ten billion people by 2050.” The findings, according to its authors, “provide the first ever scientific target” for reaching this goal.

The commission reported that the production and consumption of food in the Anthropocene—our current age, in which human activity has been the primary influence on climate and the environment—represents one of the greatest health and environmental challenges of the twenty-first century. This is not only because the world is dealing with an epidemic of chronic noncommunicable diseases related to obesity, metabolic disorders, cardiovascular diseases, and chronic brain disorder, but also because many environmental systems and processes have been pushed beyond safe boundaries.

Disturbances in food supply and consumption have resulted in 2.1 billion adults being overweight or obese and in a doubling of the global prevalence of diabetes in the past thirty years—while at the same time more than 820 million people are undernourished, 151 million children are stunted, 51 million children suffer acute malnutrition, and more than 2 billion people are micronutrient deficient.

Meanwhile, food production is the largest cause of global environmental change. Agriculture occupies about 40 percent of land around the world, and food production is responsible for up to 30 percent of greenhouse-gas emissions. It also absorbs 70 percent of our freshwater use. Experiencing the historic drought conditions in California combined with continuously rising temperatures in real time, turns these statistical numbers into daily experiences for millions of people.

To eat both healthily and sustainably, the EAT-Lancet Commission recommended a “win-win” diet, meaning there must be a safe “operating space” for food systems, defined by how much we need of specific food groups daily in order to both maintain human health and the environment—for example, one hundred to three hundred grams (three and a half to seven ounces) of fruit per day. Willett explained: “We have a lot of evidence for what a healthy diet is. If we look just at health, it points us in the direction of being largely plant-based— not necessarily all vegetarian or vegan but predominantly plant-based. Remarkably, the convergence of scientific advances in a wide range of disciplines, ranging from epidemiology, the microbiome field, metabolism, neuroscience, all the way to plant and soil science, all support the benefits of [this] diet as well.”

A recent study, published in the prestigious journal Proceedings of the National Academcy of Sciences (PNAS) a group of investigators from the University of Oxford, UK, under the leadership of Michael Clark aimed to increase the understanding of the environmental impacts of commercially available food products in order to support transitions to environmentally sustainable food systems. Using ingredient lists to infer the composition of each ingredient in commercially available foods and pairing them with environmental databases containing information about environmental impact they derived estimates of a food product’s environmental impact across four indicators: greenhouse gas emissions, land use, water stress, and eutrophication potential (harmful algal blooms, dead zones, and fish kills secondary to agricultural run off into rivers and coastal waters).

Using this approach on 57,000 (!) food products commercially available online from eight online stores, including the UK based company called Tesco showed that certain food categories can be identified that have low (e.g., sugary beverages, fruits, breads), to intermediate (e.g., many desserts, pastries), to high environmental impacts (e.g., red meat, fish, cheese). They could also show that more nutritious products are often but not always more environmentally sustainable. They identified exceptions to this trend, with foods consumers may view as substitutable can have markedly different impacts.

The authors reported that “…many Aisles at Tesco were win-wins (good for the environment and good for human health) and were more nutritious and sustainable than most other Aisles (e.g., an estimated environmental and nutritional impact below the median of all of the Aisles examined). These Aisles included, for instance, fruits, vegetables, salad, breakfast cereals, some breads, and meat alternatives (e.g., tofu, vegan sausages). Conversely, there were numerous lose-lose foods (bad for the environment and bad for human health) with nutrition and environmental impacts above the median. These foods included cheese, chocolate, savory pies, and quiches. Win-lose foods (good nutrition composition but above median estimated environmental impact) included fish and seafood, (threatened by overfishing) nuts (excessive water use), and some ready meals. Interestingly, beef and lamb also fell into the win-lose category. According to the authors (not necessarily shared by myself), “…evidence suggests that the health and nutrition impacts of beef can range from detrimental to beneficial, depending on the context in which it is consumed: studies in high-income and high-consuming contexts indicate that increasing consumption of red meat would negatively affect health outcomes, whereas red meat consumption (and, more broadly, animal-based foods) in food-insecure contexts can be integral to nutrition security. Lose-win categories (poor nutrition quality but below median environmental impacts) included sweet cakes and pies, sugary drinks (colas, squash, cordials, fruit juices), frozen desserts, and table sauces. Many of these lose-win categories included processed food products that contain ingredients with low environmental impacts but that are also
known to contribute to poor health outcomes (e.g., sugar, salt, added fats, refined grain flours).

In summary, the Clark study using a more granular analysis supported many of the conclusions reached by the EAT Lancet commission 3 years ago, pointing out the complexity of dietary recommendations. By estimating the environmental impacts of food products in a standardized way, the authors aimed to enable informed decision making by end users such as consumers and policy makers. For the average consumer, the message is clear for the win-win category of foods, which corresponds with the general recommendations of a largely plant-based diet, and for the win-lose category which highlights the negative environmental impact of several healthy foods. The question remains if the findings of these amazing research efforts will be able to transform dietary habits of consumers in industrialized countries, in particular in the US soon enough to slow or prevent the detrimental effects on the health of humans and the planet.

Parts of this post were taken from chapter 9, The One Health Concept of The Gut Immune Connection.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Chronic Stress

For most people chronic stress has become a regular aspect of modern life, amplified by a bombardment with negative news from the internet: the pandemic, catastrophic climate events, political polarization, and a raging war in the middle of Europe are just the most recent examples. As I will explain, our biology is poorly equipped to deal with this type of constant and repeated exposure to stress 24 hours a day. The mismatch between our ancient biological acute stress response systems and this new form of chronic perturbation of the body’s homeostasis is likely to negatively affect our health.

Acute, often life-threatening stress has been part of human life for millions of years and there has been enough time in our evolutionary history to perfect our biological stress response systems in a way that has kept our species alive through natural disasters, wars, famines, and pandemics. There are two such systems in our body: the older immune stress response system and the brain’s stress response system, and both are often engaged together.

Our organism responds to any situation – in the presence or the future – that is perceived as a threat to our integrity and homeostasis by engaging one or both of these stress response systems. While they have evolved and are optimized to respond to infrequent, but life-threatening stresses – the poisonous snake, the wild tiger, the severe injury, or the infection, for most people in developed countries, these are no longer the kind of stresses we encounter on a regular basis. Unfortunately, the worry about being shot remains a persistent stress for a significant segment of the population as highlighted by the series of recent high profile police shootings.

Today’s perturbation of our body’s balance most often comes in form of chronic stressors associated with modern life: The chronic psychological stress on our minds generated by the relentless daily bombardment with negative news, worries about the future, increasing competition, and number of challenges associated with a lower socioeconomic status (in plain language, poverty, food insecurity, health conditions). And at the same time, the dietary stress on our metabolism in form of the unhealthy Standard American Diet (SAD).

Unfortunately, these two types of stressors often occur together, and the relentless engagement of our stress systems comes at an increasing cost to the health of our bodies and minds. Evolution had not foreseen these kinds of stressors which we have never experienced as a species. While our stress response systems (the sympathetic nervous system and the HPA axis) keep responding in the same way that has been so adaptive for human life, chronic hyperproduction of the stress mediator’s cortisol and noradrenaline, and chronic systemic engagement of the immune system are responsible for many aspects of our current chronic non-infectious disease epidemic as I have described in detail in The Gut Immune Connection.

Not everybody responds to these challenges in the same way: the responsiveness of our neurological and immunological stress system is influenced by genetic factors and is programmed during the first 18 years of life, starting in utero, and will determine our lifetime risks for developing these common chronic diseases. This will result in a situation where two people exposed to the same kind and severity of stress will respond in very different ways: one will remain healthy, the other one developing a chronic disease.

In this short videoclip, I provide a brief explanation of the relentless transition that has been occurring in the US and increasingly in developing countries from a state of optimal health and the associated subjective feeling of wellness to the current epidemic of chronic non-infectious diseases and provide an understanding of how both psychosocial and dietary stresses interact to result in a maladaptive engagement of the stress systems ultimately leading to organ dysfunction and disease.

If you want to learn more about this topic, you might also be interested in my book, The Gut Immune Connection, which is available now.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Does a Diet High in a Variety of Fermented Foods Protect You Against Cognitive Decline and Colon Cancer?

When I spent time in Seoul, South Korea, I had the pleasure of experiencing traditional Korean meals with a wide variety of different fermented vegetables and seafood. I have always wondered if this unique eating habit of Koreans is reflected in different health outcomes when compared to the Standard American Diet (SAD).

A recent study has shown that consumption of a large variety of fermented foods is associated with an increased diversity of the microbial ecosystem in our gut, even more so than the diversity associated with a diet rich in fiber. Even more surprising was the observation that a lot of the new microbial taxa that appeared in the fermented food consuming group were not contained in these fermented foods, but were recruited from another source.

Does this observation obtained under controlled conditions in a small group of healthy people translate into health benefits in a larger population? Dietary habits and health outcomes in South Korea may hold an answer to this question. Since Koreans have a high consumption of fermented food from early on in life, do adult Koreans have a more diverse microbiome than people living in the US? And if they do, is this diversity associated with measurable health benefits such as lower rates of cancer and cognitive decline?

Dramatic dietary changes associated with the adoption of the SAD in Korea (increased consumption of animal products, reduced consumption of plant based and fermented foods), which were associated with the migration of people from rural areas to big cities, makes this question difficult to answer.

The scientific numbers from the Korean natural experiment don’t support such a connection between a diet high in fermented food and the prevalence of cognitive decline.

In a 2021 study published in the Journal of Clinical Neurology, researchers found that the prevalence of dementia per 100,000 increased from 178.11 in 2003 to 5,319.01 in 2015 – a dramatic increase! In addition, the standardized prevalence of dementia was higher in other areas than in Seoul metropolitan area, arguing against the rural to metropolitan change in diet hypothesis.

Similarly, South Korea has experienced a rapid increase in colorectal cancer incidence rates, making it the country with the second highest incidence rate of colon cancer in 2018, worldwide.

Are other factors in the modern Korean lifestyle and eating habits such strong risk factors for neurodegenerative disease and cancer that the consumption of high amounts of fermented foods are unable to compensate for the increased risks? Is the current enthusiasm for the consumption of fermented foods following the Sonnenburg study overblown and not supported by large epidemiological data? Are there particular fermented food items, like fermented dairy products that provide greater health benefits, while most of the fermented foods in the Korean diet (largely plant based and seafood) have less significant effect on these outcomes? Future studies will have to address these questions.

So, while eating a variety of fermented food is delicious, the epidemiological studies in the Korean population suggest that they do not necessarily translate into dramatic health benefits, or protection against serious noninfectious diseases, in particular chronic diseases related to low grade immune activation.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

The Myth of Multivitamins and Other Supplements

“In 2021, people in the US spent an estimated $50 billion on dietary supplements and the dietary supplement industry spent about $900 million on marketing”

Billions of dollars are being spent by consumers each year on products marketed as health promoting without solid evidence supporting such claims. In contrast to pharmacological treatments which have to be FDA approved before they can be sold to patients (even if they bit the placebo by less than 10%), these unregulated products only have to be safe and can’t make any claims about effectiveness in the treatment of a particular disease. Some of the best-known examples are gluten-free products (annual 8 billion US $ market), probiotics (62 billion), and an incredible array of supplements, including vitamins. More than half of adults take dietary supplements, and use of supplements in the US is projected to increase. In 2021, people in the US spent an estimated $50 billion on dietary supplements and the dietary supplement industry spent about $900 million on marketing. These marketing messages (and messengers) have flourished in the social media, and even the medical establishment has adopted some of the largely unfounded recommendations. Cleverly disguised promotions by internet influencers have become one of the most popular ways of fueling the supplement market and selling supplements has become a lucrative income stream for both physicians and allopathic healthcare providers.

“In theory, vitamins, minerals and phytochemicals have antioxidative and anti-inflammatory effects that should translate into a reduction of cardiovascular disease and cancer…”

As pointed out by Dr F. Perry Wilson of the Yale School of Medicine in a commentary in the online publication Medscape, the appeal of supplements is obvious. In theory (at least in the test tubes and animal models), vitamins, minerals and phytochemicals have antioxidative and anti-inflammatory effects that should translate into a reduction of cardiovascular disease and cancer, which has remained an elusive goal to reach. However, arguments can be made about the benefits of taking supplementary vitamins in otherwise healthy people. For example, it is well established in the literature that individuals with vitamin deficiencies are at higher risk for bad health outcomes. Even people with lower levels of certain vitamins, not in the deficiency range, are at higher risk for cancer and cardiovascular disease.

On the other hand, as I have discussed extensively in The Gut Immune Connection, eating a largely plant based diet, like the traditional Mediterranean, the MIND, and the DASH diets, with lots of fruits and vegetables has repeatedly shown to be associated with decreased cardiovascular disease and cancer risk in large epidemiological studies and in some clinical trials.

In order to generate a profit over and above selling these healthy food items, it is reasonable to think that key vitamins, botanicals, and minerals could be extracted from fruits and vegetables, packaged into a pill, and people could avoid the difficulty and expense of maintaining a balanced diet. This is the logic of a large number of health-conscious people who are not willing to abandon the traditional Standard American Diet (SAD) devoid of sufficient amounts of plant-based foods, and rather pop their supplement pills every morning.

“Micronutrients in isolation may act in a combinatorial manner and affect the body differently than when naturally packaged with a host of other dietary components”

As pointed out by Dr. Jenny Jia in an editorial published in the Journal of the American Medical Association (JAMA) entitled Multivitamins and Supplements—Benign Prevention or Potentially Harmful Distraction, the most common reason people report taking supplements is to improve or maintain overall health. However, in contrast to a single ingredient supplement pill, whole fruits and vegetables contain a mixture of vitamins, phytochemicals, fiber, and other nutrients that probably act synergistically to deliver health benefits. There are thousands of phytochemicals contained in different combinations in fruits and vegetables, and the same concept applies to fiber. Micronutrients in isolation may act in a combinatorial manner and affect the body differently than when naturally packaged with a host of other dietary components.

“…current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamin supplements, single supplements, or most paired supplements for the prevention of cardiovascular disease or cancer..”

In a rare event, two recent large-scale studies have provided evidence-based information related to health benefits of regular vitamin intake. For otherwise healthy, nonpregnant adults, the US Preventive Services Task Force (USPSTF) has updated its recommendation about the use of supplements to prevent cardiovascular disease or cancer. The USPSTF is an independent panel of experts involved in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services
This updated recommendation is based on a new evidence report and systematic review of 84 studies, including 52 new studies since the last USPSTF recommendation on this topic in 2014. It is worth mentioning that these were general-population studies, not studies of people with known vitamin deficiencies. The USPSTF concluded that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamin supplements, single supplements, or most paired supplements for the prevention of cardiovascular disease or cancer. No analyses of individual vitamins — beta-carotene, vitamin A, vitamin E, vitamin D (with a whopping 32 randomized trials), and calcium supplements — showed significant benefit in terms of either cardiovascular disease or cancer. Notable findings for the harm analysis included evidence that vitamin A use might increase the risk for hip fracture, that vitamin E use might increase the risk for hemorrhagic stroke, and that vitamin C or calcium use might increase the risk for kidney stones.

As correctly commented by Dr Wilson in the Medscape article, “why are the observational data that show lower vitamin levels linked to worse healthy outcomes so powerful, and the randomized trial data of vitamin supplementation so weak? This is classic confounding. Basically, healthier people have higher vitamin levels, and healthier people have less cardiovascular disease and cancer. Vitamin levels are a marker of overall health, not a driver of overall health.”

“…the results of the Harvard study failed to show a significant effect of a daily MVM on breast or colorectal cancer, prostate cancer or melanoma …”

Howard D Sesso and collaborators from the COSMOS Research Group at the Division of Preventive Medicine, Brigham and Women’s Hospital and Department of Epidemiology, and the Harvard T.H. Chan School of Public Health, both at the Harvard Medical School published results from another, large randomized, double-blind, placebo controlled clinical trial, evaluating the benefits of daily consumption of multivitamins for the prevention of cancer and cardiovascular disease. The study population included 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major cardiovascular disease at the time of study begin and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020.

Participants were randomly assigned to daily multivitamin multimineral (MVM) supplement or placebo. The primary outcome was total invasive cancer, (excluding non-melanoma skin cancer). Secondary outcomes included major site-specific cancers, total cardiovascular disease, all-cause mortality, and total cancer risk among those with a baseline history of cancer.

Consistent with the results of the USPSTF analysis of a large number of published studies, the results of the Harvard study failed to show a significant effect of a daily MVM on breast or colorectal cancer, prostate cancer or melanoma but showed a protective effect on lung cancer. The study did not show a significant association between MVM use and all-cause mortality or mortality from cardiovascular disease. Based on their results, the authors concluded that a daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer or cardiovascular disease among older men and women.

The take home message from these two studies is that unless you have a proven vitamin deficiency, or don’t have access to a variety of fresh fruit and vegetables for financial or geographical reasons, you should not expect a health benefit from taking your daily vitamin cocktail for common forms of cancer and for cardiovascular disease. If you get non-specific benefits from the regular MVM, such as higher energy, less brain fog or improved immune function, these benefits may be attributed to the placebo effect, so masterfully orchestrated by your brain.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Have We Made Progress in Fecal Microbial Transplantation?

Fecal Microbiota Transplantation (FMT) is a therapy in which fecal material from a single (or multiple) healthy donor(s) is transferred to a diseased individual to restore health. The technique was first described in the 4th Century in China, practiced since the 1950’s and re-discovered relatively recently. Different delivery techniques of the fecal material have been used using enemas and oral applications in capsule form. In a recent article in the Microbiome Times, Luis Gosalbez discussed the current status of this intriguing therapeutic modality.

FMT was the therapeutic strategy that sparked considerable interest in microbiome drug development back in 2013, with the publication of the results of a human trial in which FMT was shown to be highly efficacious in the treatment of recurrent Clostridium difficile (C. difficile) colitis, a serious condition affecting the large intestine.

C. difficile colitis results when the normal microbial ecosystem in the colon is severely disrupted, a situation generally induced by the intake of antibiotics in vulnerable individuals. Characteristic symptoms include diarrhea, belly pain, and fever. The disease can cause severe damage to the colon and can even be fatal. Its prevalence has been increasing and affects about 200,000 individuals per year. Paradoxically, even though antibiotics are the most common cause of the disease, the most common treatment includes antibiotics, even though recurrence rates with this approach are high, and scientists have tried to find a more effective and long-lasting therapeutic modality.

Multiple research groups and companies have been involved in the development and evaluation of FMT treatments for different conditions, including C. difficile infection, irritable bowel syndrome, inflammatory bowel diseases, autism spectrum disorder and metabolic syndrome. Despite some promising results in some studies, results have been conflicting and largely disappointing, and the dramatic benefits seen in the treatment of C. difficile could not be demonstrated in other disease areas, raising fundamental questions about the usefulness of this approach for disorders other than C. difficile.

Initially, FMT was performed after little processing of the original fecal material. However, advances in microbiome science have allowed to identify the key microbial species or activities thought to be responsible for its efficacy. At the same time, safety concerns, such as transmission of enteric infections, or induction of metabolic and psychiatric disorders (as has been observed in animal models) have also made it necessary to design processes which eliminate or rule out the presence of infectious agents, donors with psychiatric disorders, or microbial metabolites with potential systemic effects. Whereas some current FMTs are still the result of simple processing (e.g., filtration, centrifugation), some companies have designed sophisticated procedures to further refine the original material, creating products composed of defined consortia of microorganisms.

A logical step in the search to develop gut microbiome-based therapeutics was to replace the actual stool transplantation with transfer of gut microbial communities (or consortia), or by the metabolites produced by these consortia. Drugs based on FMT-derived defined consortia of microorganisms are amongst the most advanced clinical programs of the entire microbiome drug development industry.

In 2021, two leading companies, namely Seres Therapeutics and Rebiotix-Ferring Pharmaceuticals, reported positive results from their respective Phase 3 clinical trials in recurrent C. difficile infection using microbial consortia, and this month, Seres announced further confirmatory results from an additional study with their lead candidate for this indication. Both companies are now involved in the process of approval to become the first FDA-authorized microbiome therapeutic for C. difficile.

Whereas infectious diseases (primarily recurrent C. difficile) have classically been the main application of FMT, oncology indications have been gaining significant traction over the last years. The exploration of the therapeutic benefit of FMT in cancer patients started with applications in supportive care as a means to preserve or restore the gut microbial ecosystem damaged or impoverished after cancer treatments, for instance aiming at preventing colitis and chemotherapy-induced diarrhea. These applications have followed a mechanistic rationale somehow similar to the one of FMT in C. difficile.

However, after it became clear that the gut microbiome plays an important role in mediating and predicting the benefits of some cancer treatments, in particular immunotherapy-based approaches, efforts have started to explore FMT as an adjuvant therapy to immunotherapy in the treatment of melanoma, leukemia and other malignancies. Given its potential immune-modulatory capacity, also a large share of FMT research programs have focused on immune-mediated diseases, mostly Inflammatory Bowel Disease.

In summary, based on available clinical data from high quality clinical trials, several questions about the clinical benefits of FMT and its more commercial variants can be addressed:

  1. Has the initial excitement about the possibility to treat a range of serious and common disorders with FMT from a healthy individual to a patient turned into tangible benefits for diseases other than C. difficile colitis? Despite multiple clinical trials and research studies, the answer to date is negative. The reason that FMT works in C. difficile patients and in germfree (gnotobiotic) animals (which don’t have any microbes in their gut) but not in other conditions may be due to several reasons: one has to do with the resilience and stability of microbial ecosystems. Even though many of the disorders in which FMT has been tried have been found to have altered gut microbial communities (so called dysbiosis), these altered microbial ecosystems still provide a high degree of resilience and stability which prevents the transplanted microbiome to colonize the gut with the transplanted bacteria, a phenomenon called colonization resistance. Alternatively, in many of these conditions, the observed state of dysbiosis may not play a causative role in the pathophysiology of a disease but may be an epiphenomenon.
  2. Has there been progress towards replacing the somewhat archaic technique of transferring actual fecal material from one person to another with a more scientific approach? Based on the recent positive studies with such microbial consortia in patients with C. difficile colitis, the answer is a definitely yes.
  3. Will FMT become an important strategy in the prevention and treatment of medical, psychiatric, and neurological conditions in which an altered gut microbiome has been identified, including metabolic syndrome, some forms of depression and Alzheimer’s disease? the answer is a careful yes. Barriers to overcome in this approach include a better understanding of the role of dysbiosis, including the virome in these disorders, identification of consortia of microbes that are effective, and ways to temporarily overcome colonization resistance of the gut microbiome to allow the transplanted microbes to “take roots” in the gut of the patient. Until these barriers have been overcome and objective effectiveness of FMT has been demonstrated, this approach should not be used.

Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Olive Oil – Medicine Produced by Nature and Refined by Human Expertise and Traditions

Extra-virgin olive oil (EVOO) has become a popular component of gut and brain healthy recipes. EVOO not only adds a delicious flavor to your salad and vegetables, but its health benefits have been reported from preclinical and clinical studies. EVOO is one of the key health-promoting ingredients of the Mediterranean diet. These benefits are applicable to a wide range of metabolic disorders and cardiovascular diseases.

“…current evidence suggests benefits are largely related to polyphenols and vitamin antioxidants—vitamins A and E—found in the oil.”

There are at least two major components that mediate the oil’s health benefit—the high concentration of monounsaturated fatty acids (primarily oleic acid) and the high content of polyphenols (primarily oleuropein and hydroxytyrosol). As explained many times in this newsletter, polyphenols exert their health benefit with the help of the gut microbiome, and research suggests this may be true for oleic acids, too. Oleic acid is the predominant fatty acid in olive oil—73 percent of its total oil content—while 11 percent is polyunsaturated, such as omega-6 and omega-3 fatty acids. Monounsaturated fatty acids (MUFAs) are quite resistant to high heat, making EVOO a healthy choice for cooking. Traditionally, the high content of MUFAs was considered to be responsible for the protective effects of EVOO, but current evidence suggests benefits are largely related to polyphenols and vitamin antioxidants—vitamins A and E—found in the oil.

“…the concentration of polyphenols in EVOO ranges from 50 to 800 milligrams per kilogram…”

As many as thirty different polyphenol molecules have been identified in different olives. Furthermore, the concentration of polyphenols in EVOO ranges from 50 to 800 milligrams per kilogram, and the amount of polyphenols in EVOO depends on the region where the olives were grown, corresponding differences in climate, soil composition, degree of ripeness when harvested, and the oil-extraction process. In addition, the phenolic fraction of olive oil can vary greatly among different types of olives. As a result, it can be a challenge to figure out which olive oil to buy in order to get the full benefit in terms of both flavor and polyphenols.

“…olive trees started to grow in the southeastern Mediterranean basin more than six thousand years ago…”

I learned more about olive oil a couple of years ago, when I visited my friend Marco Cavalieri, the owner of Le Corti Dei Farfensi in Fermo, on the picturesque Adriatic coast of Italy. In addition to his wines, Marco produces EVOO from eight-hundred- year- old olive trees, using a wide variety of olives, including the Sargano, Carboncella, Ascolana, Coratina, Frantoio, and Moraiolo varieties. An eight-hundred- year- old tree may sound ancient, but it’s practically a sapling in olive oil–making years: olive trees started to grow in the southeastern Mediterranean basin more than six thousand years ago, and they were a major item of trade for the ancient Greeks, Romans, Persians, and Phoenicians throughout the Mediterranean region. These varieties contain the polyphenol molecules oleuropein, demetiloleuropein, andquercetin, with an average polyphenol concentration of around 800 milligrams per kilogram.

In addition to harvesting the olives from the ancient trees, Marco uses several strategies to ensure the highest possible polyphenol content in his product. The olives are harvested when they have not fully ripened, when their polyphenol production is at its highest. Harvested olives are stored in airtight steel containers to protect them from oxygen and light. Those made into oil are taken to the local facility where they are cold-pressed just hours after they’re harvested. The fresh oil has a uniquely pungent flavor and fragrance, with an initial almost burning sensation and taste. In addition to its flavor and health benefits, the polyphenols contribute to its superior oxidative stability compared to other edible oils.

“…the high polyphenol content of EVOO makes it a medicine produced by nature and refined by human expertise and traditions.”

In seeking out the health benefits of the Mediterranean diet, it became clear to me that the high polyphenol content of EVOO makes it a medicine produced by nature and refined by human expertise and traditions. Like any medicine, the precise amount of active ingredients and the quality of processing play major roles in its effectiveness. So rather than being misled by the dark appearance of many expensive olive oils marketed as EVOOs produced in Italy or Greece, it is worth investigating where and how they were harvested and processed, as well as their average polyphenol content. This may take a bit of investigating, as most producers don’t include information about polyphenol content on their labels. Given the difficulty of tracking down the polyphenol content, the best way for a consumer to determine it is by taste—a pungent flavor is generally a sign of high polyphenol content.

Like many healthy things (and all medications), EVOO should be consumed in moderation. It is obviously a calorie dense food, so adding just the right amount to your salads and dishes without adding excess calories is important to get the most health benefits.

Taken from The Gut Immune Connection with minor edits


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Are Bioactives the New Magic Treatment for Cardiovascular Disease?

What is responsible for the multiple benefits of a largely plant based diet?

The benefits of a largely plant-based diet have been implicated in primary disease prevention, disease-risk reduction, as well as healthy aging. The most well known example of a largely plant-based diet is the traditional Mediterranean diet. A series of observational and epidemiological studies have concluded that higher adherence to this type of diet is positively associated with better cognitive function and reduced risk of several chronic often comorbid diseases, including cardiovascular disease, depression, Parkinson’s, and Alzheimer’s disease.

The regular consumption of a Mediterranean diet has also been shown to be associated with reduced microvascular brain damage. This suggests a possible role of diet-related impairments in cerebral blood flow to brain regions involved in different aspects of memory such as the hippocampus and the prefrontal cortex. Several variants of the Mediterranean diet such as the DASH diet (Dietary Approaches to Stop Hypertension) and the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) have been shown to reduce several cardiovascular risk factors, and are associated with better cognitive function, slower cognitive decline, lower depressive symptoms, decreased risk of dementia and larger total brain volumes. In summary, these epidemiological studies strongly suggest benefits of these largely plant-based dietary patterns both on brain and cardiovascular health, with considerable evidence for a mediating role of improvements in cerebral vascular function.

The unique family of polyphenol molecules.

Polyphenols are bioactive compounds (referred to as “bioactives”, “phytochemicals” or “botanicals) found in plants, consisting of a large, diverse group of molecules, serving two major beneficial roles in plants: One, as defense mechanisms to respond to perturbations of homeostasis, such as drought, UV light, pests, and diseases and two as part of a signaling code between soil microbes living in close proximity of the root system and the plant. While many polyphenols are natural antioxidants when evaluated in a test tube, able to scavenge harmful free radicals that would otherwise damage the cell, only a very small proportion of their beneficial effects when ingested by humans is related to their antioxidant effects.

Polyphenols are found in fruits and vegetables, with tea, pome fruits and some berries being among the foods richest in polyphenols. More than 8,000 polyphenol compounds have been discovered in various plant species, which can be classified into four subclasses: phenolic acids (~30% of all polyphenols), stilbenes, lignans, and flavonoids (~60% of all polyphenols). Flavonoids, the largest family of polyphenols, can be broken down into 6 further subclasses: flavanols (also known as flavan-3-ols), flavonols, flavanones, flavones, anthocyanins, and isoflavones.

Bioavailability studies in humans indicate that due to their large size, flavonoid polyphenols are poorly absorbed in the small intestine (5-10%), reaching very low, transient plasma levels after consumption. This lack of bioavailability has led the FDA several years ago to remove a comprehensive website listing polyphenols based on their antioxidant capacity. (Antioxidant capacity is the ability for a compound or compounds to reduce the concentration of free radicals in a given system, a test almost exclusively determined in an in vitro system). This assessment is very different from what happens to these molecules when consumed by a person. Most of polyphenols will reach the ileum and colon intact where they interact with the gut microbiota resulting in an extensive chemical modification of the ingested compound into small phenolic, absorbable metabolites

“…beneficial effects of polyphenol consumption on brain and cardiovascular health have been supported by a growing number of randomized controlled trials…”

Even though epidemiological studies demonstrating a beneficial effect of polyphenol consumption on brain and cardiovascular health have been supported by a growing number of randomized controlled trials, conflicting results have been reported, with considerable divergence in study designs and poor characterization of the tested products (e.g., whole fruit powders, polyphenol-rich berry extract, fruit juices, effect of extensive processing of the original compound), impeding the progress to conclusively demonstrate a causative role of polyphenol containing foods on brain health.

The idea that dietary bioactives, food constituents not essential to human life, may play an important role in disease risk reduction, primary disease prevention, and healthy aging, has had significant developments in the last decade. For example, there are a considerable number of dietary intervention studies which found that the flavanol epicatechin (contained in green tea, red wine, and cocoa beans) plays a role in the prevention of cardiovascular disease, as well as the secondary prevention of diabetes.

Dietary flavonoids are a structurally diverse set of naturally occurring polyphenolic compounds in plant-based foods, and flavan-3-ols are derivatives of flavanols, a major subclass of flavonoids, that include complex, bioactive molecules found in cocoa beans, tea leaves, grapes, red wine, and other foods.

The rediscovered healing power of the cocoa bean.

Cocoa is made from the bean of the cacao tree, Theobroma cacao, and has a long history of medicinal use and potential health benefits based upon its flavanol and procyanidin content. Cocoa extract also contains methylxanthines such as theobromine and caffeine, which may enhance the vascular and central nervous system effects of cocoa flavanols.

Numerous short term, small-scale dietary intervention studies have examined the cardiovascular effects of flavanols and procyanidins, which have included well-characterized cocoa and cocoa product test materials linked to cardiovascular benefits. These trials have provided broader insights on the absorption, metabolism, and excretion of flavanols in humans with those focused on cocoa flavanol intake (as beverages, supplements, or chocolate) at up to 2000 mg/d and up to 1 y of treatment. Data have shown improvements in several biological mechanisms involved in cardiovascular disease, such as the ability of blood vessels to widen (“endothelium-dependent vasodilation”), blood pressure, inflammation, and platelet activation and provide insight into cocoa’s potential vascular effects due to intake of the flavanol (−)- epicatechin. Even though meta-analyses of such studies support benefits for flavanols on cardiometabolic biomarkers, prospective studies examining cocoa products restricted to chocolate intake or to usual levels of dietary flavanol intake with risk of cardiovascular disease (CVD) have been inconsistent, likely due to uncertainty of cocoa flavanol content and measurement error.

“COSMOS is the first trial testing how these individual or combined cardiovascular mechanisms may translate into longer-term reductions in clinical cardiovascular events.”

However, until recently, no large-scale trials have evaluated flavanol-rich cocoa extract containing all potential bioactive components of the cocoa bean on clinical cardiovascular outcomes. To address this question, Howard Sesso and a team of investigators from the Brigham and Women’s Hospital and Harvard Medical School, Boston, MA initiated the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a large-scale randomized double blind, placebo controlled trial supported by the company Mars Edge and the National Institutes of Health. The COSMOS study aimed to test a supplement prepared from cocoa bean extract and a typical multivitamin in the prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major cardiovascular disease and recently diagnosed cancer. Participants were randomly assigned to the cocoa bean extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction, stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.

After a median of 3.6 years of treatment, the investigators found that among older women and men with high compliance, flavanol supplementation significantly reduced cardiovascular death by 27%, whereas the risk for individual cardiovascular outcomes (such as myocardial infarction, stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina), or for the number of total cardiovascular events were not significantly reduced compared to the placebo arm. Finally, cocoa extract had no effect on the secondary outcomes of total invasive cancer and major site-specific cancers.

Does a piece of chocolate a day keep the doctor away?

As discussed in a recent podcast with Hagen Schroeter, Chief Science Officer of Mars Edge, the cosponsor of the COSMOS study, the answer is a definite no. Even though this large-scale study was originally designed to demonstrate the health benefit of eating chocolate, the main commercial product of the parent company Mars, any such claim had to be publicly withdrawn for several reasons. Any health benefits from consuming flavanols from commercial, tasty chocolate products would be negated by the simultaneous consumption of excessive calories in the form of sugar, fat and emulsifiers contained in these products. Moreover, while the raw material from which chocolate is made is the flavonoid rich cocoa bean, the extensive processing of the bean extract results in a depletion of the end product of any health promoting flavanols. Finally, the metabolism of the ingested flavonoid is highly dependent on the composition of the gut microbiome, breaking the nonabsorbable parent compound into the smaller metabolites, including the compound gamma valerolactone which can be detected in the blood.

Not every individual has the right composition of such microbes to effectively generate the absorbable compound, a situation that was reflected in significant interindividual variation of clinical benefits. Based on these caveats and the impressive findings of the COSMOS study, is it beneficial to take a daily supplement of 1,000 mg of Cocoa flavanols? The evidence for such a recommendation is definitely a lot stronger than for most other supplements or multivitamins on the market, and may be worth the cost associated with the chronic intake of this supplement. If the primary mechanism underlying the flavanols’ benefit on the heart and on the brain (evidence not discussed in this post) is indeed the combination of beneficial effects on the blood vessels supplying these organs, it is a prudent investment in overall health when combined with other health promoting lifestyle changes such as exercise and healthy diet. And for the chocolate lovers out there: Continue to indulge in a piece of delicious chocolate after a healthy dinner, but don’t expect it will protect your heart!


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Do Millions of People Need a Gluten Free Diet?

Going gluten-free is a popular trend fueled by the media, the internet, and a sizable group of medical practitioners. This trend is based on the claim that a gluten free diet (GFD) has vast benefits for a number of disorders affecting mind and body.
Empiric gluten avoidance likely is not without negative health consequences. Avoidance of gluten from whole grains may affect the risk for type 2 diabetes mellitus, cardiovascular disease, and mortality. In addition, indiscriminate exclusion diets have even been linked to malnutrition and disordered eating behaviors.

A National Health and Nutrition Examination survey estimated that by 2014, 2.7 million US adults without celiac disease adhered to a GFD, increasing by more than 3-fold since 2009. This may be owing to gastrointestinal symptoms erroneously attributed to gluten intake, as in nonceliac gluten sensitivity. Alternatively, the GFD, popularized by the media and consumer-directed marketing, may be used by patients because of various perceived health benefits.

The economic impact of this trend is remarkable. The gluten-free products market size was valued at $4.3 billion in 2019 and is estimated to reach $7.5 billion by 2027. Gluten-free labels can now be found on almost every food product, even on water bottles and pill box labels.
While a GFD is essential for people with gluten allergies and celiac disease – a serious autoimmune disorder of the small intestine – the existence of non-celiac gluten sensitivity and its involvement in many gut and brain disorders has been challenged by a number of epidemiological studies and controlled clinical trials.

A series of large, well designed epidemiological studies from the Harvard T.H. Chan School of Public Health under the leadership of Andrew Chan has provided strong evidence refuting a role of gluten in common brain and gut disorders, or a benefit of a GFD for any serious health problem.

In a study looking at the long-term intake of gluten and cognitive function among a cohort of 13,494 women at midlife without a celiac disease diagnosis, there was no statistical evidence of any association of long- or short-term consumption of wheat, barley or rye – the major sources of gluten – and “brain fog”, a condition reflecting compromised cognitive ability. According to the study authors, the only individuals who benefitted from avoiding gluten were the small number of patients with celiac disease.

In similar studies, no evidence between gluten intake and cancers of the gastrointestinal tract or cardiovascular risk were identified. However, the authors emphasized that avoidance of gluten may result in reduced consumption of beneficial whole grains, which may affect cardiovascular risk. They recommended that the promotion of gluten-free diets among people without celiac disease should not be encouraged.

In the most recent study, the Harvard investigators aimed to examine the relationship between dietary gluten and the risk of inflammatory bowel diseases (IBD) in adults without celiac disease.

Inflammatory bowel diseases, including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the gastrointestinal tract that are thought to result from a dysregulated immune response to environmental and microbial stimuli in a genetically susceptible host. Although several hundred gene polymorphisms have been identified, the total variance of IBD risk explained by known genetic factors is less than 14%, highlighting the significance of environmental factors in disease development. One important environmental factor is diet, likely owing to its influence on gut microbiota composition, mucosal barrier function, and mucosal inflammation.

IBD is associated with an increased risk for celiac disease, although nonceliac gluten sensitivity also is commonly reported by patients with IBD, and some patients report improvements in gastrointestinal symptoms following dietary gluten restriction. There are several possible reasons to explain such a benefit.

It may be due to the fact that these patients were suffering from undiagnosed celiac disease or by an effect of gluten on IBD disease activity. To answer these questions, the Harvard investigators explored the relationship between dietary gluten intake and the risk of IBD in 3 large prospective US cohorts of men and women. These cohorts were made up by 208,280 US participants from the Nurses’ Health Study (1986–2016), Nurses’ Health Study II (1991–2017), and by the Health Professionals Follow-up Study (1986–2016). None of the participants had a diagnosis of IBD or celiac disease at baseline, and all of whom had completed semiquantitative food frequency questionnaires.

The study identified 337 CD cases and 447 UC cases over 5,115,265 person-years of follow-up evaluation. (“Person-years” is a statistic for expressing incidence rates which is determined by the summing of the results of events divided by time).

The results showed that dietary gluten intake was not associated with an increased risk of IBD. Adjusting their results for primary sources of gluten intake did not significantly change their estimates.

When viewed together, the large, well-designed studies from the Harvard School of Public Health do not support commonly held beliefs about the detrimental effects of gluten consumption on cognitive function and gut health. Despite the impressive numbers of participants in the mentioned studies, there are limitations such as their epidemiological nature and the reliance on food frequency questionnaires to assess gluten intake. However, they point out the dangers of avoiding gluten in the diet and emphasize the considerable economic cost and lifestyle limitations that are associated with a restricted diet, that is often not based on scientific evidence but rather on food related fears.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

How Mom’s Gut Microbes Can Influence the Health of the Offspring

By Emeran Mayer, MD

One of the puzzling aspects of our current epidemic of chronic non-communicable diseases is the continued increase in allergic and autoimmune disorders. While many factors may play a role in this phenomenon, recent research strongly implicates changes in interactions between the gut microbiota and the gut-associated immune system.

“… host-microbe interactions during the first three years of life starting in utero (the “first thousand days”) are particularly important for the development of the immune system.”

It has been known for some time, that host-microbe interactions during the first three years of life starting in utero (the “first thousand days”) are particularly important for the development of the immune system. Perturbations of the developing gut microbiota during this critical time (including C-section delivery, formula feedings, antibiotic exposure) can have long-lasting and often irreversible detrimental effects on health, including increasing the risk for allergic and autoimmune disorders. Until very recently, this microbe-mediated immune programming was thought to be initiated at birth when a newborn baby leaves the relatively sterile environment of the uterus and is exposed in the birth canal to the mother’s vaginal/rectal microbiota which begin to colonize the newborn’s gut.

“… it seems increasingly possible that our mothers’ microbiomes may, to some extent, shape our health and well-being long before we are born. One such mechanism is the transfer of maternal antibodies to the fetus.”

As discussed in an excellent review article by Drs. Carolyn Thomson and Kathy McCoy from the University of Calgary in The Scientist the maternal microbiome can exert its influence much earlier—on the developing fetus. Based on the accumulating science, it seems increasingly possible that our mothers’ microbiomes may, to some extent, shape our health and well-being long before we are born. One such mechanism is the transfer of maternal antibodies to the fetus. Antibodies generated by the pregnant mom’s immune system against her own microbiota as well as pathogenic microbes can cross the placenta to protect the fetus from infection. This remote control of the fetal microbiome via both bacteria-produced molecules and maternally derived antibodies appear to drive immune development in utero.

“… mouse studies have shown that perturbing the microbiota of pregnant mice, either with antibiotics or dietary intervention, can lead to a variety of physiological alterations in the offspring with implications not only for diabetes, but for susceptibility to asthma, obesity, and colitis, as well as the progression of autism-like behaviors.”

Less than a decade ago, as researchers began to question the role of the maternal microbiota during pregnancy several research groups performed epidemiological and preclinical studies to examine whether exposure of the fetus to antibiotics taken by the pregnant mother poses a risk to a child’s health. As fetuses don’t have their own microbiota, any microbe-mediated immune system modulation that may happen in the womb must be related to the gut microbes of the pregnant mother, and antibiotic exposure of the mother during pregnancy would disrupt this. As shown in mouse studies, prenatal antibiotic exposure influenced the development of type 1 diabetes, an autoimmune disease in the offspring. Subsequent mouse studies have shown that perturbing the microbiota of pregnant mice, either with antibiotics or dietary intervention, can lead to a variety of physiological alterations with implications not only for diabetes, but for susceptibility to asthma, obesity, and colitis, as well as the progression of autism-like behaviors.

In most circumstances, manipulating the maternal microbiota by chronic stress, antibiotics or diet are vertically passed from mother to offspring at birth, and subsequently alters both the infant’s microbiome and immune development. It has therefore proven challenging to attribute the immune system changes described in most of these studies to the maternal microbiota directly, as opposed to those mediated by the newly seeded microbiota of the neonate. However, recent research is beginning to demonstrate that the maternal microbiota can shape both the immune and nervous system development of the offspring remotely, via different communication channels.

“… the intestinal immune system must quickly learn to differentiate between innocuous and beneficial food components and benign microbes, and harmful molecules and pathogens which require the triggering of a successful defense against them.”

By adulthood, the intestine is home to the body’s largest collection of immune cells, about 70% of the entire immune system. Being located in such close connection to the intestinal contents transporting an enormous number of foreign antigens derived from both the microbiota our diet and ingested chemicals, the intestinal immune system must quickly learn to differentiate between innocuous and beneficial food components and harmful molecules, between benign microbes and pathogens which require the triggering of a successful defense against them. Moreover, even beneficial microbes can quickly become harmful if they come into contact with specific receptors (so called toll like receptors or TLRs) on gut-associated immune cells like dendritic cells, which extend into the intestinal mucus layer, or translocate into the bloodstream through a “leaky gut”. Such translocation of gut microbes from the gut into the bloodstream has been reported under conditions of chronic stress and when consuming a Western diet.

The immune system of a newborn infant is inexperienced. Despite some early reports to the contrary, the fetus is not thought to be colonized with its own microbial communities before birth. Traditionally, researchers thought that maternal antibodies transferred across the placenta were specific to infectious microbes that might infect the baby while its own immune system was still developing. We now know that maternally derived antibodies can also bind commensal bacteria—and that this helps to keep these nonpathogenic bacteria from crossing the epithelial barrier as a newborn’s gut is rapidly colonized by a vast array of unfamiliar microbes.

“Different components of breast milk also play an important role in mediating the maternal influence on the developing infant microbiome…”

According to the American Academy of Pediatrics, babies should be breastfed until they are 1 or older, and the Centers for Disease Control and Prevention states that breast milk is the best source of nutrition in those early months. In addition to providing optimal nutrition for the baby, different components of breast milk play an important role in mediating the maternal influence on the developing infant microbiome, including the Human Milk Oligosaccharides (HMOs) and maternal antibodies which can interact directly with the microbial inhabitants of the infant’s gastrointestinal tract.

The medical and economic realities of new parenthood in America can make that one-year finish line an impossible goal for many mothers. By six months, the majority of new mothers give their babies some formula, for reasons ranging from problems with latching and milk supply to the demands of work outside the home. Aggravating this problem, there is now a nationwide formula shortage, driven by supply chain problems and exacerbated by the closure of a major production plant in February and the recall of select infant formulas.

Both HMOs and antibodies are unique to human breast milk, and not provided by baby formula. While the HMOs, which are influenced both by maternal genes and diet, are large, non-absorbable molecules essential for the initial organization and development of the microbial ecosystem, the antibodies contained in breast milk keep populations of beneficial microbes in check and ensure that they stay in the gut lumen, preventing the inappropriate activation of the gut-associated immune system.

The role of the maternal diet

Another important component of the maternal influence on the infant’s microbiome and immune system are short-chain fatty acids (SCFAs), derived from the fermentation of dietary fiber by the mother’s intestinal microbes. The amounts and types of SCFAs that are produced in the mother’s gut and transferred to her baby depend on the maternal microbiome, which is in turn shaped by her diet. As discussed in detail in The Gut Immune Connection, when pregnant women eat a largely plant-based diet rich in fiber (Microbe Accessible Carbohydrates, or MACs), SCFA-producing microbes thrive, and increased amounts of SCFAs not only have an anti-inflammatory effect on the mother’s gut and body but are transferred to the developing fetus as well. Recent research suggests that SCFAs not only exert their anti-inflammatory effects but influence the maturation of the fetal immune system. Specifically, they stimulate the development of a population of immune cells (regulatory T cells, or Tregs), which produce anti-inflammatory molecules (in particular the cytokine IL-10) crucial for the prevention of immune activation in the gut.

“Considering the extent of inflammatory diseases that can be controlled and suppressed by these anti-inflammatory immune cells simply through maternal dietary changes, these findings are likely to have far-reaching effects on a better understanding of developmental diseases…”

These IL-10 producing cells are crucial for protecting our bodies from attacking our own tissues in the form of autoimmune diseases, as well as from allergies and asthma. They also teach our immune systems to tolerate food and friendly bacteria. These abilities make these cells a key factor in differential immune response to what is good or bad for our bodies. These immune cells are long-lived, and their “offspring” is assumed to be present throughout the life of the host. It is easy to see, how the influence of maternal microbiome, shaped by the mother’s diet can influence the development or maturation of these cells, could have far-reaching implications for the health of the offspring. This crucial effect of maternal diet on the anti-inflammatory ability of the offspring’s microbiome was demonstrated in a study from the Juntendo University in Tokyo which showed that pregnant dams that ate more fiber not only had increased amounts of several SCFAs in their feces, as well as increased butyrate in their blood, but that their pups had increased SCFAs in their blood at day 11 of life as well. Considering the extent of inflammatory diseases that can be controlled and suppressed by these anti-inflammatory immune cells simply through maternal dietary changes, these findings are likely to have far-reaching effects on a better understanding of developmental diseases like autism spectrum disorders. For example, a recent mouse study reported that a high fat diet in pregnant mothers induced a shift in the gut microbiome that negatively impacted social behavior in the offspring.

As pointed out by the authors of this The Scientist article, implications of these new insights into the role of maternal diet, and its influence on the microbiome and immune system are extensive. For one, they could provide evidence for guidance about maintaining a healthy microbiota throughout gestation—for example, by eating a microbiome targeted diet (largely plant-based diet without ultra-processed foods and high amounts of sugar), avoiding unnecessary antibiotic use, and practicing simple stress reduction techniques.

In addition, as the current baby formula crisis has brought to public attention, greater public health efforts should be made to enable mothers to nurse their babies during the first year, and not become fully or partially dependent on alternatives that lack some crucial components necessary for the development of a healthy gut microbiome.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

An Apple a Day Keeps the Doctor Away

There are numerous benefits we have derived from our microbial co-inhabitants on planet Earth over millions of years. It starts with the realization that we humans wouldn’t be here if microbes living in the planet’s oceans had not developed the sophisticated language that ultimately was adopted by our nervous system and made our brains the most powerful computational devices in the universe. Equally important was the fact that microbes developed and continue to synergize with our metabolic machinery that keeps all of our cells alive.

This body of wisdom has been stored in hundreds of millions of genes and handed down during evolution over several billion years. Even though only partially understood, this microbe-based wisdom still helps us to adapt to the many challenges we are faced in a rapidly evolving world.

“The majority of our adult gut microbiome develops early on in life through vertical transmission from our mothers.”

Fast forwarding to the arrival of humans some 1 million years ago, and particularly to the present, the best-known benefits of living in harmony with our gut microbes come from the interactions of these trillions of microbes, and the rest of our body, including the brain. Research has shown that lifelong diversity and richness of this largely stable gut microbiome is associated with a lower prevalence of many if not most chronic non-transmissible diseases.

The majority of our adult gut microbiome develops early on in life through vertical transmission from our mothers. However, there are several environmental influences on our gut microbial ecosystem, including our diet, and microbes transmitted from household members, pets, and exposure to greenspaces.

Another influence comes from a group of microbes that we add to our stable gut microbiota when we regularly consume a variety of naturally fermented foods. As shown in a recent study published by the Sonnenburg Lab at Stanford University, the consumption of a diet rich in a number of naturally fermented foods, is able to increase the diversity of the gut microbiome, even more than eating a fiber rich diet.

And interestingly, this food-related transfer of microbes into our gut is not limited to fermented foods. Professor Gabriele Berg from Graz University of Technology in Austria has studied this question in great detail and has published some little-known aspects about the health benefits of consuming organically grown apples. In 2019, her group published a research article in the journal Frontiers in Microbiology, in which they compared the bacteria in conventional store-bought apples with those in visually matched organic ones. Stem, peel, flesh, seeds, and calyx – the straggly bit at the bottom where the flower used to be – were analyzed separately.

“…the data showed that freshly harvested, organically managed apples harbored a significantly more diverse, and distinct bacterial community, compared to conventional ones.”

Overall, the organic and conventional apples were occupied by similar numbers of bacteria. According to Berg, “Putting together the averages for each apple component, it has been estimated that a typical 240g apple contains roughly 100 million bacteria.” Organically managed apples harbored a significantly more diverse, and distinct bacterial community, compared to conventional ones.

There are some major caveats to this study, including the fact that the conventionally grown apples were packaged and refrigerated for days before analysis. In contrast, the organic apples were analyzed immediately following harvest, and were grown on a different farm in Austria.

Despite these methodological limitations, the study confirms previous results, showing that the majority of the bacteria found in apples were located in the seeds, with the flesh and skin accounting for most of the remainder. So, if you discard the core, as most apple consumers do – your intake falls to closer to 10 million!

“Considering that 83 million tons of apples were grown in 2018, this source of ingested microbes is quite substantial.”

Matthew Prior, science writer for the Frontiers journals stated wisely: “To the heroes among you who eat the whole apple: besides extra fiber, flavonoids and flavor, you’re also quaffing 10 times as many bacteria per fruit as your core-discarding counterparts.” Considering that 83 million tons of apples were grown in 2018, this source of ingested microbes is quite substantial.

There is general evidence that the more diverse microbial ecosystem protects the apple against harmful bacteria and fungi, just like a diverse gut microbiome protects us against enteric infections. But does eating these apple-associated microbes provide any health benefits for us? Do the treatments that some apples go through before coming to your market, like spraying with insecticides, irradiating them to destroy harmful bacteria and covering them with a thin layer of wax to make them look more attractive have a negative effect on the apple’s microbial ecosystem? Certainly, the absence of these treatments could be one reason for the observed differences of the organically grown apples.

While the final answers to these questions have not been shown in well controlled studies, based on Berg’s exciting research and studies looking into other health benefits of apples, one can make some well-informed speculations:

  1. Organically grown and treated apples are likely to contain a more diverse and health promoting microbiome, and when consumed on a regular basis – ideally including the apple core, seeds, and skin – will add to the health and diversity of our gut microbiome, just like the consumption of naturally fermented foods do.
  2. In addition to being an excellent source of beneficial microbes, apples contain the highest amounts of flavanols, the same compound contained in cocoa beans. Flavonoids are not only metabolized into absorbable small molecules by our gut microbes, but they also have a beneficial effect on the diversity and relative abundance of beneficial gut microbes. A recent study in a large, placebo controlled clinical trial has shown that regular consumption of 1000 mg of flavanols reduces cardiovascular morbidity and improves cognitive function.
  3. As the polyphenol content of plants grown in regenerative organic soil seems to be higher than of plants grown conventionally, the greatest health benefits both from ingested apple-associated microbes and flavanol content would be expected to come from apples grown in regenerative organic agriculture.

Birgit Wasserman, Berg protégé and co-author of the study, suggested that “The microbiome and antioxidant profiles of fresh produce may one day become standard nutritional information, displayed alongside macronutrients, vitamins, and minerals to guide consumers … another key step will be to confirm to what extent diversity in the food microbiome [and flavanol content] translates to gut microbial diversity and improved health outcomes.”


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

The Role of Diet in Inflammatory Bowel Diseases – Facts and Myths

The topic of gut health and the role of diet and the gut microbiome in maintaining and improving gut health has been receiving a tremendous amount of attention. Catchwords like leaky gut, gut inflammation, and anti-inflammatory diets fill social media and have entered the general conversation where influencers make endless recommendations about what healthy people can or cannot eat to fight the symptoms thought to arise from these gut problems.

On the scientific level, increased permeability of the gut and resulting systemic immune activation as a consequence of the unhealthy Standard American Diet (SAD) has been recognized as a potential risk factor underlying the epidemic of chronic non-communicable diseases plaguing the developed world, including a wide range of common diseases including cardiovascular disease, Alzheimer’s and Parkinson’s disease, chronic liver disease, colon cancer and inflammatory bowel diseases. Considerable epidemiological evidence supports the benefits of a largely plant-based diet, like the traditional Mediterranean diet in improving gut health, reducing systemic inflammation, and reducing the risk of common chronic non communicable diseases.

But how good is the evidence for a role of such a diet in the development and in the treatment of inflammatory bowel diseases ulcerative colitis and Crohn’s disease?

Although the cause of inflammatory bowel diseases (IBD with its two major diagnosis ulcerative colitis, UC, and Crohn’s disease, CD) remains incompletely understood, diet has been suggested to play a pivotal role in their pathogenesis and in the course of the disease. Various dietary components may impact on the disease course due to their regulatory effects on the intestinal microbiota, mucosal barrier function, nutritional status, and intestinal immunity.

A large body of preclinical and clinical evidence has implicated the SAD, which is high in sugar, ultra-processed foods, animal-derived protein, saturated fats, altered omega-6 to omega-3 ratio, and diets low in fruits and vegetables as an important factor underlying to intestinal and systemic inflammation.

The SAD is likely to contribute to intestinal inflammation through alterations in the intestinal microbiota, decreased production of anti-inflammatory metabolites such as short-chain fatty acids (SCFAs) and an increased production of microbial protein fermentation metabolites. Together, these factors may compromise the intestinal barrier function leading to inappropriate activation of the gut associated immune system. Although the nutrient content and composition of plant foods vary greatly, the consumption of largely plant-based diets often result in a reduced intake of saturated fatty acids (SFAs) and animal-derived dietary protein and a concomitant higher intake of dietary fiber and phytochemicals due to intakes of fruits and vegetables.

“The Mediterranean diet had a beneficial effect on gut inflammation in CD patients with mild to moderate disease activity”

Several studies have identified a lower risk of Crohn’s disease (CD) among populations consuming a diet consistent with the traditional Mediterranean diet, a diet high in fresh fruits, vegetables, nuts, fish, and whole grains and use of olive oil as the predominant fat source. Consumption of such a diet has also been associated with reduced symptoms and improved quality of life after diagnosis of CD. A recent study by Lewis et al, published in Gastroenterology in 2021 showed that the Mediterranean diet had a beneficial effect on gut inflammation in CD patients with mild to moderate disease activity, even though the benefit was not different from another often-prescribed diet in IBD, the so-called Specific Carbohydrate Diet (SCD).

The SCD was popularized by Elaine Gottschall in the book Breaking the Vicious Cycle. It is characterized by a number of allowed and excluded foods, the former category containing the majority of fresh fruits and vegetables which are universally acceptable, with the exception of certain starchy vegetables. The second category includes grains and several animal products including processed, canned, and most smoked meats, and milk. In the Lewis study, both diets were equally effective in achieving symptomatic and biological remission. Based on these results, the authors suggested that “ the greater ease of following the Mediterranean diet and other health benefits associated with it, the Mediterranean diet may be preferred to the SCD for most patients with CD with mild to moderate symptoms.”

Even though we now know about the effectiveness of a diet high in fresh fruits and vegetables and low in animal products, how much do we know about the mechanisms underlying these clinical benefits?

Fatty Acids

It remains to be elucidated if dietary plant-derived fatty acids are beneficial in relation to disease activity in UC and CD patients. It seems most likely that reducing the saturated fatty acids content and the level of n-6 fatty acids (relatively to n- 3 fatty acids) in the diet by the reduction of animal products and by an increased consumption of plant-based foods and seafoods high in omega-3 fatty acids (mussels, sardines, salmon) could potentially minimize disease activity via the incorporation of n-3 acids into the host membrane phospholipids or due to their influence on the intestinal microbiota.

Carbohydrates

Carbohydrates can be classified as simple sugars (glucose, sucrose, fructose) and digestible starch, which are all rapidly absorbed in the small intestine, and in complex carbohydrates which require the gut microbes to break them down into absorbable molecules such as fiber molecules, or so-called microbiota accessible carbohydrates (MACs).

Plant-based foods provide large amounts of MACs that have been suggested to play a significant regulatory effect on the gut and provide the major source of energy for the gut microbes. Microbial metabolism of MACs is the major source for short chain fatty acids like butyrate (different from the saturated fatty acids coming from animal products), which has a local and systemic anti-inflammatory effect, as well as being an important nutrient for the cells lining the gut. Although the consumption of a diet high in MACs has been linked to reduced disease activity in IBD patients, there seems to be only limited evidence available on the impact of a high fiber diet on disease activity from high quality clinical trials.

Polyphenols

The consumption of various plant foods provides many phytochemicals or so-called bio-actives that may significantly impact intestinal and gut microbial health. Several fruits and vegetables contribute considerable amounts of polyphenols (there are up to 8000 different polyphenol molecules), with spices and herbs as one of the richest sources. Several well-designed clinical studies of curcumin in UC patients with mild to moderate disease have shown promising results, even though the number of studies is limited. A substantial number of factors influence the actual intake of polyphenols, such as environmental factors (e.g., time of harvest, organic vs. conventional agriculture) and food processing methods such as cooking and boiling. Thus, the actual intake of polyphenols with the diet may vary considerably according to these factors and may not reflect the actual amount of polyphenols reaching the gut. As only a limited number of studies have investigated the efficacy of polyphenols in IBD patients, the optimal safe dose and efficacy of these bioactive substances still need to be determined based on adequate powered clinical studies.

Protein

Many IBD patients have an increased protein requirement depending on their disease status (active vs. remission). At present, little is known about the role of proteins originating from plants in regard to actual measures of disease activity and nutritional status of IBD patients, as most of the research has been conducted in other populations or using animal protein. One large epidemiological study clearly demonstrated that the much demonized gluten, a structural protein naturally found in certain cereal grains, in particular in wheat, does not play a role in IBD pathophysiology. Thus, the role of other plant-derived protein on IBD-related outcomes (i.e., measure of disease activity and nutritional status) remains to be determined.

In summary, there is strong evidence that plant-based dietary components may impact various physiological mechanisms of intestinal inflammation, and that a diet optimized for these components, like the Mediterranean diet (and to a certain degree the Specific Carbohydrate Diet) may be beneficial in reducing the number of disease flares and reducing disease severity. A key question is whether it is possible to support and maintain clinical remission of IBD by adopting a largely plant-based eating pattern, and/or by adding supplements to the diet like the flavonoid curcumin. Plant-based foods are major sources of complex carbohydrates and phytochemicals that have bidirectional effects with the gut microbiota and exert a direct anti-inflammatory effect on the gut. Awaiting further corroborative evidence from well-designed clinical trials in subpopulations of IBD patients, I strongly recommend a personalized, traditional Mediterranean type diet as an important component in the treatment of IBD patients with mild to moderate disease activity.

Suggested Further Reading

The Gut Microbiome and Inflammatory Bowel Diseases

A Randomized Trial Comparing the Specific Carbohydrate Diet to a Mediterranean Diet in Adults With Crohn’s Disease

Diet in the pathogenesis and treatment of inflammatory bowel diseases

Reducing Disease Activity of Inflammatory Bowel Disease by Consumption of Plant-Based Foods and Nutrients

Dietary Inflammatory Potential and Risk of Crohn’s Disease and Ulcerative Colitis

Dietary Gluten Intake Is Not Associated With Risk of Inflammatory Bowel Disease in US Adults Without Celiac Disease


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

The Relationship Between FODMAPs and IBS Symptoms

A diet low in Fermentable Oligo-, Di- and Monosaccharides And Polyols (FODMAPs) has been shown to significantly improve IBS symptoms, in particular bloating and diarrhea-type symptoms, even though the health benefits of such a diet when consumed over a prolonged period of time are highly questionable.

FODMAPs are poorly absorbed short-chain carbohydrates including fructose, fructans, lactose, polyols, as well as large complex sugar molecules, so-called galacto-oligosaccharides. They are found in a wide variety of foods, and in certain patients with IBS, may trigger lower gastrointestinal symptoms, in particular bloating, abdominal distension, cramping and a sensation of gas. It has been suggested that these symptoms are triggered by distention of the small bowel as a consequence of the osmotic effects of these foods via fermentation in the colon by the gut microbiota, resulting in increased gas production.

As FODMAPs have been implicated as a major source of certain IBS symptoms, the low FODMAP diet is often recommended by physicians and dietitians as a therapy for IBS. It is worth noticing that increased consumption of many of these foods (except those contained in unprocessed fruits and vegetables) is a hallmark of the Standard American Diet (SAD) and moving to a personalized largely plant-based diet, such as a modified Mediterranean diet, may accomplish the same effect without the negative consequences. So, what is behind this FODMAP frenzy?

Before going into the mechanisms by which FODMAPs worsen IBS symptoms, lets go through a brief FODMAP-101 course, to become aware which components in our diet make up this maligned group of largely plant-based molecules.

Number I. Fructose

Fructose, or “fruit sugar,” is a simple sugar molecule like glucose. It’s naturally found in fruits, most root vegetables, honey, and agave. Importantly, fructose is commonly added to many processed foods in the form of high-fructose corn syrup, which has been identified as an important factor of obesity and metabolic syndrome. Fructose is sourced from sugar cane, sugar beets and corn.

The most significant sources of fructose in the SAD include:

  • High fructose corn syrup added to a large number of foods, including fruit juices and ketchup.
  • Table sugar

Other high-fructose foods include:

  • Most fruits, especially dried fruits and fruits canned in juice or high fructose corn syrup.
  • Vegetables including artichoke, asparagus, broccoli, leeks, mushrooms, okra, onions, peas, red pepper, shallots, and tomato products.
  • Foods with wheat as the main ingredient, such as wheat bread and pasta.

Number II. Fructans

Fructans are large, poorly absorbable complexes (or polymers) of fructose molecules. The human gut is unable digest and absorb fructans, so they are instead fermented by the bacteria in the gut.

The most significant sources of fructans in the SAD include

  • Wheat and onions.

Other fructan containing foods include:

  • Many fruits including watermelon, grapefruit, nectarine, persimmon, plums, pomegranate, ripe bananas, dates, prunes, and raisins.
  • Many vegetables, including onions, shallots, leeks, asparagus, artichoke, beets, Brussels sprouts, savoy cabbage, fennel, and snow peas.

Number III. Lactose

Lactose is a large sugar molecule contained in milk and non-fermented dairy products, which requires the gut-based enzyme lactase to be broken down into absorbable components one molecule of glucose and one of galactose linked together. If lactase is absent or deficient, as it is in the majority of healthy and symptom-free adult humans, unabsorbed lactose travels down the intestine and is fermented by the gut microbes into its constituent molecules.

While human breast milk and cow’s milk is an essential source of nutrients for infants, consumption of large amounts of unfermented dairy products by adults is an unnatural way to improve nutrition and can lead to abdominal discomfort.

Number IV. Polyols

Polyols are a specific group of sugar alcohols that are formed via the enzymatic alterations of certain sugar molecules. They are naturally contained in certain fruits, vegetables, and mushrooms.

However, the most significant sources of polyols in the SAD are sugar-free sweeteners in products such as chewing gum, candies, and sweetened beverages and food items. These products have become a popular replacement for sugar in the SAD, despite the conflicting evidence for their health benefits.

Number V. Galacto-oligosaccharides

Galacto-oligosaccharides are large complex carbohydrates which cannot be absorbed by the human small intestine, but are essential nutrients for our gut microbes, playing a crucial role in assuring a diversity and richness of the gut microbiome.

At first glance it would seem that eating a personalized healthy, diet containing a large variety of fruits and vegetables, without added sugar and sweeteners, the avoidance of high amounts of non-fermented dairy products and ultra-processed food components should have the same beneficial effect as sticking to an unhealthy and unsustainable diet like the low FODMAP diet. At the same time, such a personalized largely plant-based diet would have the additional benefit of nurturing our gut microbes, a generally accepted goal in human health.

A recent study by an international group of investigators under the leadership of Lukas van Oudenhove at the Catholic University Leuven in Belgium provides some interesting answers why the avoidance of fructans is associated with fewer symptoms in IBS patient. In order to unravel the mechanisms within the brain gut microbiome (BGM) system that are responsible for fructan-induced IBS symptoms they randomly assigned 13 IBS patients and 13 healthy, asymptomatic control subjects to 3 conditions in a double-blind, cross-over study. During 3 visits, fructans (40 g/500 mL saline), glucose (40 g/500 mL saline) or saline (500 mL) were infused into the stomach of subjects, while abdominal symptoms were assessed with a rating scale, intestinal distension and gas measured with an abdominal imaging technique and brain activity was assessed using functional magnetic resonance imaging (fMRI) at baseline at 1 h, and 2 h post administration of the fructan solution.

As expected, IBS patients, but not healthy control subjects reported significantly more cramps, pain, flatulence, and nausea compared to glucose infusion. However, fructans increased small bowel contractions as well as gas and volume in the first part of the colon equally in IBS and control subjects. In other words, the microbially increased gas production in response to fructan was identical in IBS and control subjects. However, the difference in colonic gas between fructans and saline was correlated with differences in bloating and cramps in IBS, but not in control subjects. Brain images during the study revealed that IBS patients had greater activation in pain processing regions compared to control subjects and these brain responses were correlated covaried with symptom responses in IBS.

Based on their findings, the authors concluded that fructans increase small bowel motility and colon gas and volume similarly in IBS patients and HC. However, the increased symptom responses to fructans in IBS but not control subjects were correlated with altered brain responses in pain-related regions. Hence, increased sensitivity to normal FODMAP-induced gas production and/or osmotic activity, rather than excessive gas production and water content (which has never been identified as a cause of IBS symptoms), is the most plausible cause for FODMAP-induced symptoms in IBS.

Even though collected in a small sample of patients, the new findings are consistent with a large body of earlier evidence supporting a crucial role of visceral hypersensitivity in IBS symptomatology. While increased sensitivity and subjective responses to signals arising from the gut, related to contractions and distension has been demonstrated in many previous studies, the identification of this mechanism underlying fructan-induced symptoms leads to an important question: Is it more important to focus on therapies which reduce the enhanced perception of food-related gut signals by the brain, OR recommend a diet that is difficult to follow and sustain, and has negative long term effects on gut microbial diversity and richness?


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

How to Overcome Burnout

I recently read an article in the New York Times by Melinda Wenner Moyer entitled, Your Body Knows You’re Burned Out. Having studied and written about the effect of chronic stress on the body, and particularly the digestive system, I normally wouldn’t have taken the time to read about this topic in the lay press.

But this time it was different. Several weeks ago, I started experiencing strange and unaccustomed symptoms, which were very unfamiliar to me. I found myself waking up between 2 and 4 AM every morning in a state of sympathetic arousal, including a pounding heartbeat, feeling hot and not being able to return to sleep for hours. My mind was racing in circles obsessed with loops of thoughts that I couldn’t stop thinking about. The thoughts were around unfinished projects and self-imposed challenges and deadlines. Sometimes, I found myself going to the kitchen and snacking on something in the fridge. In the morning I woke up, feeling fatigued and non-refreshed, a feeling that recurred several times during the day, sometimes so severe that it forced me to walk away from my desk to take a nap, which often lasted up to an hour.

My physical energy level was greatly reduced, preventing me from pursuing my daily 4-mile hike or going to the gym. Furthermore, my mood state fluctuated between low grade depression alternating with moments of feeling normal and energized. I became easily irritated, short-tempered and angry from minor irritations. In many ways it was the opposite body and mind experience that I have been enjoying all my life and that I have been promoting in my writings and talks.

The term burnout is a topic that I had dealt with, written, lectured about, and researched for many years, and that I remember from conversations with collaborators in Sweden many years ago. In the Swedish literature, a very similar constellation of symptoms is called exhaustion disorder which at the time was a major cause of absenteeism in Sweden. In addition to the symptoms I described above, one study of people in Sweden suffering from this syndrome found that 67% reported experiencing nausea, gas or indigestion, and that 65% had headaches. While the syndrome had already reached epidemic proportions in Sweden in the 90s, it was not perceived as a significant health problem in the US at the time. But things have changed. Especially after millions of people dealing with the constant stress caused by the pandemic and the associated worries, there have been dramatic changes in lifestyles and work habits.

According to the NYT article, the phenomenon has practically become ubiquitous in our culture as reflected by some worrisome statistics. “In a 2021 survey of 1,500 U.S. workers, more than half said they were feeling burned out as a result of their job demands, and a whopping 4.3 million Americans quit their jobs in December in what has come to be known as the “great resignation.” Similar prevalence numbers could probably identified amongst frontline healthcare workers during the pandemic, and even amongst medical students and young physicians. The World Health Organization describes burnout as a workplace phenomenon characterized by feelings of exhaustion, cynicism and reduced efficacy. But while the close bidirectional connections to the workplace experience are important, the causes for the symptoms are certainly not limited to the workplace but can arise from all aspects of life, as I’ve experienced myself.

Allostatic Load

Burnout has a lot to do with the way our brains and bodies react to different types of stress, or perturbations of normal functioning. While the acute stress response, orchestrated by an elaborate system of signaling molecules in the brain, including the molecule corticotropin releasing factor (CRF) released from the hypothalamus, synchronizes all mental and body functions to optimally respond to the stress event (like to a threatening event), evolution hasn’t really prepared us for a world of chronic, relentless, or recurrent stress exposure. The hormonal and neural responses to an acute stressor, such as transient increase in the stress hormones cortisol or epinephrine, or the transient activation of the sympathetic nervous system, quickly return to their normal levels by powerful regulatory mechanisms in the brain. However, if faced with chronic or recurring severe stress, or if the brain system determining the amount of perceived stress becomes more sensitive, stress can have wear and tear effects on the body, especially when it doesn’t ease up after a while.

The reason for this wear and tear is the fact that the brain tries to respond by putting the same ancient, and highly effective acute stress response systems into overdrive, resulting in negative consequences for the body and brain, a situation called allostatic load. One of the biological hallmarks of allostatic load is the presence of low-grade activation of the immune system throughout the body with negative health consequences for all organs, including the brain. The clinical consequences are impaired sleep, fatigue, anxiety, depression, weight changes and all the symptoms I had experienced myself.

According to the NYT article, when researchers in Italy surveyed frontline health care workers with burnout during the first peak of the pandemic, they found that 55% reported having difficulty falling asleep, while nearly 40% had nightmares. A complicating factor of insomnia can be the common habit of midnight snacking in an attempt to calm down the mind before going back to bed. In the study of Italian health care workers, 56% reported changes in food habits with both increases and decreases in food intake. Extensive research suggests that hormones released during chronic stress can affect appetite in both directions; overeating in an attempt to attenuate the stress, or feeling less hungry than usual when they’re under a lot of stress.

What Can You Do to Overcome Burnout?

When trying to get out of the hole I found myself in, one thing that became clear to me quickly was that advice from others to do mindfulness exercises, and to put less projects on my plate wasn’t enough. Here are some effective steps that I have learned in this process, which are based on a view of an interconnected system of mind and body, and which are aimed at reducing systemic immune activation:

  1. Make sure you had a recent normal medical checkup and that there are no new alarm signs and symptoms. Unintentional weight loss, loss of appetite and loss of energy can also be symptoms of other physical conditions.
  2. Identify all the projects that you are currently engaged in and occupied with –including but not limited to work-related deadlines, unresolved financial issues, taking care of aging parents, the realization of getting older, finding enough time for regular exercise, planned travel, socializing etc. Put all these projects into a spreadsheet or on a whiteboard, and assign numbers of priority to each, including deadlines.
  3. Once you have generated such a priority list, focus on the most important one or two at a time, and try to accomplish this particular task, before embarking on another one. This will free up the memory banks in your brain and you won’t have to go through all of them every night when you can’t sleep.
  4. Put your mind and body for at least 15 min once or twice a day into a meditative state by practicing abdominal breathing, progressive muscle relaxation, autogenic training, or mindful based stress reduction. Simple versions of such programs are available online and you should be able to fit them into even the busiest schedule.
  5. When you awaken in the middle of the night with thoughts racing through your mind preventing you from falling asleep again, get up, read an entertaining book totally unrelated to your work and go back to sleep after an hour or so. This strategy can stop the recurring worrying thoughts and will help you to fall asleep again.
  6. Sustain a reduced but daily physical exercise program, including both aerobic and weightbearing exercises. Change your daily runs to walks and your resistance training to stretching exercises. This is not the time to push yourself to your limits, but to keep your body and muscles in a healthy state of activity.
  7. Now more than ever, eat a diet that is healthy for your gut, your gut microbes, and your brain. As explained many times in this newsletter and in my books, such a diet is largely plant-based, with a high variety of fruits and vegetables, with added fermented products. It will increase the microbial production of anti-inflammatory short chain fatty acids and will take advantage of the countless health promoting molecules contained in such foods. And don’t forget to avoid caffeinated drinks and minimize your alcohol intake. This will give your brain time for a reset without external stimulants and calming influences.

Did this program work for me? To be honest, things didn’t get better overnight. But by conscientiously sticking to this self-help program, I was able to regain my usual vitality, refreshing uninterrupted sleep and my usual excitement about life.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Managing IBS

In the late 70s, irritable bowel syndrome (IBS) became the quintessential disorder of brain gut interactions, almost 50 years before a major professional IBS organization, the ROME foundation, came to the same conclusion. Around 10% of the US population suffers from chronically recurring symptoms of abdominal pain, discomfort and altered bowel habits which make up the symptom criteria defining the syndrome.

What I experienced during these 50 years could fill a whole book with entertaining anecdotes, hard to believe statements by leading authorities, dramatic changes in hypothesized underlying biological mechanisms, and often conflicting dietary and other treatment recommendations.

For example, at an international meeting in the 80s, one prominent thought leader referred to IBS as “a disorder of neurotic housewives”, while another stated that it isn’t “a real disorder” in the first place. Then came the long-lasting period of attributing symptoms to disorders of gastrointestinal motility, e.g., altered contractile activity and intestinal transit, followed by a period obsessed with “excessive intestinal gas production”. In between came periods when some experts postulated a smooth muscle disorder and an inflammatory disorder, and most recently a microbiome-related disorder. What has always fascinated me was the fact that research studies performed in experimental animal models of IBS, and sometimes in human patients, actually reported findings supporting these various different disease mechanisms. And the pharmaceutical industry often spent millions of $$ developing medications aimed at these elusive mechanisms, none of which has ever been confirmed. Treatment recommendations over the decades have ranged from drugs aimed at slowing or speeding up transit through the gut (so called motility drugs), from high fiber diets to today’s promotion of the “low FODMAP diet”, a diet devoid of many fiber containing foods. And most recently, treatments have been proposed which are aimed at the microbiome from non-absorbable antibiotics to cocktails of pre- and probiotics.

While the new theories about IBS that appeared every few years captured the imaginations of clinicians and investigators in the field, my early conceptualization of IBS as a brain-gut disorder was rejected by the majority of IBS experts. While the ROME Foundation aimed to provide a systematic approach to the functional GI disorders by splitting them into some 40 different separate entities, each of them with their own postulated mechanism and treatment recommendation, we suggested from early on that alterations in the bidirectional brain gut interactions, including increased perception of visceral signals (“visceral hypersensitivity”) and aberrant autonomic nervous system responses, provided a unifying framework for all the different clinical manifestations affecting every part of the GI tract from the esophagus to the end of the large intestine.

It is ironic that while these various concepts promoted over the years have primarily benefited the careers of up-and-coming investigators, the pharmaceutical industry, and supplement companies, they have not provided consistent and lasting relief for the millions of patients suffering from symptoms of chronic abdominal pain and discomfort, often accompanied by anxiety, depression and other chronic pain conditions. With exceptions, the great majority of treatments have not been much more successful than a placebo pill (usually about 10% better in controlled studies).

In order to empower IBS patients to manage their own symptoms effectively, without worries about the latest IBS-focused diet and without having to go through trials of unsatisfactory medications often with unpleasant side effects, I have developed an online educational program for IBS patients titled, Intuitive IBS: A Personalized Approach to Healing Your Gut. The class has three elements which I feel are essential for an effective therapy:

  1. Understanding the mechanisms that cause symptoms.
  2. Empowering you to become your own IBS expert.
  3. Providing you with simple tools to manage your symptoms.

The contents of this class are based on 40 years of clinical experience working with some of the most severe IBS patients, and research performed in our center at UCLA, as well as a few outstanding investigators around the world. While I have often been told by colleagues that this information is too complicated for patients to understand, I still have yet to meet a patient who didn’t embrace this information, and who has not experienced significant symptom improvement.

Don’t miss the opportunity to sign up for the Intuitive IBS class which will become available in the coming weeks!


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Flavonoids and Forgetfulness

It is widely understood that a healthy diet consists not only of sufficient amount of high-quality fruits and vegetables, but the variety of these plant based foods in your diet is equally important. Not only are they good for us because of their various fiber content, but also because of their high concentration of flavonoids. Flavonoids, otherwise known as phytochemicals or polyphenols are large, unabsorbable molecules, which require microbes in the distal small intestine and large intestine to break them down into smaller, absorbable metabolites. Flavonoids feed our microbes, increasing the relative abundance of health-promoting microbes, and decreasing the abundance of microorganisms less advantageous for our gut health, and after metabolism contribute to the health of many organs, including the brain.

A study done by investigators at the Harvard School of Public Health, under the leadership of Dr. Walter Willet, and published in the journal Neurology in July 2021 followed more than 77,000 healthy middle-aged men and women over the course of 20 years. Based on responses of the subjects to food frequency questionnaire, the researchers estimated how often participants ate various flavonoid-rich foods and whether they experienced changes in their cognitive function in their 70s. Cognitive function was assessed in terms of remembering recent events or a short list of items, remembering things from one second to the next, understanding instructions, following a group conversation or TV plot, and finding their way around familiar streets.

The researchers calculated the participants’ intake of six classes of flavonoids from the questionnaire information: flavanols (such as quercetin in onions and kale), flavones (such as luteolin in green chile peppers and celery), flavanones (such as naringenin in grapefruit and oranges), flavan-3-ol monomers (such as catechins in red wine and strawberries), anthocyanins (such as cyanidin in blackberries and red cabbage), and polymers (such as theaflavins in black tea).

The study found that study participants that reported the highest daily intake of flavonoids from fruits and vegetables were 19% less likely to report difficulties with memory and thinking, compared to those with the lowest daily intake. These results were found after accounting for other factors that may have affected cognition, such as age, overweight, lack of physical activity, alcohol intake, depression, and non-flavonoid nutrient intake.

Some flavonoids which stood out in the study were flavones, which were associated with a 38% lower risk for self-reported cognitive decline, flavanones, which had a 36% lower risk for self-reported cognitive decline, and anthocyanins, which had a 24% lower risk for self-reported cognitive decline.

It’s important to note that this study was observational and only showed correlations between flavonoid intake and cognitive function and not causality. Furthermore, the estimation of actual flavonoids reaching our brain via the circulation based on self-reports on a food frequency questionnaire is unreliable. In other words, despite the impressive numbers and longitudinal design of the study, the results don’t prove that flavonoid intake keeps people sharp in older age. However, supporting the observed associations, a growing number of smaller studies have also found a link between flavonoid intake and cognitive health benefits.

Most people may think these flavonoids protect against cognitive decline solely because they are powerful antioxidants – fighting brain inflammation. However, we now know that only a very small fraction of the ingested flavonoids exert antioxidant effects in our body, negligible in comparison to the body’s own production of powerful antioxidants such as glutathione. What really happens is that while the intact molecules which can exert antioxidant effects in a test tube, are too large to be absorbed in the small intestine, and require the actions of our gut microbes to break them down into small, absorbable health-promoting metabolites. It is some of these metabolites that can exert powerful anti-inflammatory, antioxidant and antiaging effects.

Ironically, these healthy plant molecules are not acknowledged by the FDA and therefore the amount one should consume is not standardized. In the study, low flavonoid consumption was approximately 150 mg per day whereas high was 620 mg per day. To put that into perspective, half a cup of blueberries contains about 165mg of anthocyanins, and half a cup of peppers contains approximately 5mg of flavones.
In summary, the study found that flavonoid-rich foods such as strawberries, oranges, grapefruits, citrus juices, apples/pears, celery, peppers, and bananas were significantly associated with lower odds of subjective cognitive decline. The authors concluded that their findings support a benefit of higher flavonoid intake for maintaining cognitive function in both men and women.

A word of caution for people that justify their love of chocolate with the presumed high flavonoid content of chocolate, and the presumed health benefit of regular chocolate consumption for cognitive function. However, the evidence supporting a health benefit of chocolate, due to it containing flavonoids, is inconclusive at best. One thing that is known though, is the downside of chocolate! The tasty chocolate we all love is high in saturated and monounsaturated fats. It also often contains a lot of sugar, making it an energy dense food, containing about 550 calories per 100g. And so obviously eating high quantities of it is going to be bad for your metabolic health!

If you’ve followed our blog posts for a while, you know that we highlight the importance of a fiber- and polyphenol-rich diet. The best advice I can give you is to not worry so much about the quantity of specific polyphenols you’re consuming, but rather to eat a wide range of fruits and vegetables to give your gut microbes an adequate amount of each type. Recent evidence suggests that the consumption of 30 different fruits and vegetables a week will boost your gut microbiome and support both gut and overall health. As shown in this study, there are many types of flavonoids, each of which are metabolizes by microbes into different absorbable molecules and while we may never know what each one’s role is specifically, we know that a combination of these unique molecules, together with plant-derived fiber are all important for the health of gut and brain, and for disease free longevity.

This post was previously published on Nov 11, 2021 and has been modified slightly by Dr. Emeran Mayer.


E. Dylan Mayer is a graduate from the University of Colorado at Boulder with both a major in Neuroscience and minor in Business. He is fascinated by the interactions of brain, gut and microbiome, and the role of nutrition in influencing the health of our microbiome, as well as our own well-being.

Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

What I Tell My Patients About Probiotics

As a longtime investigator in brain gut microbiome interactions, practicing gastroenterologist and frequent host on gut health related podcasts, I am confronted with questions about probiotics on an almost daily basis.

Patients who are concerned about their gut health, want to know which probiotic is best for them, and how they can identify the right product from hundreds of such products on the internet, all claiming scientifically proven effectiveness. Are billions of colony forming units (CPUs) and a large number of different strains necessary to have beneficial effects?

Colleagues want to know if there is any credible evidence for health benefits of any probiotic on gut disorders like IBS, IBD, “SIBO” or antibiotic-induced diarrhea. Can probiotics reduce anxiety? Improve symptoms in autism spectrum disorder?

Research collaborators want to know which probiotic to best select for research studies in IBS patients, or for studies on brain function in patients with anxiety or depression.

“…my scientific interest in probiotics didn’t start until about 10 years ago, when my research group embarked on the first human study to evaluate the effect of the regular consumption of a fermented milk product…”

Even though the consumption of beneficial microbes with fermented foods, in particular different fermented dairy products, sauerkraut and brewer’s yeast (picked up at the local brewery) for stomach troubles was a traditional folk remedy when I grew up in Bavaria (it actually worked most of the time!), my scientific interest in probiotics didn’t start until about 10 years ago, when my research group embarked on the first human study to evaluate the effect of the regular consumption of a fermented milk product with a group of different microbes on the brain.

While a number of earlier studies in laboratory mice had clearly demonstrated an effect of the gut microbiome (and the lack of a normal microbiome) on behavior and brain function, our study was the first to demonstrate that ingested microbes could actually signal to the brain and change networks concerned with emotion regulation.

As the study subjects were all healthy young women, we weren’t able to demonstrate an associated psychobiotic effect, e.g., a microbially induced change in anxiety or abdominal pain. No human study has clearly demonstrated such a psychobiotic effect in patients with psychological problems to date in an unequivocal way.

Probiotics have been defined by an international expert panel as “Live microorganisms that when administered in adequate amounts confer a health benefit on the host”. Driven by the high popularity of concepts like gut health, leaky gut and immunity, there has been an intense and rapidly growing scientific and commercial interest in probiotics. More than 12,000 papers on the topic have been published in the last 7 years, and probiotic sales have been estimated to amount to $40 billion and to reach $64 billion by 2023.

“…despite these impressive numbers, many questions remain…”

However, despite these impressive numbers, many questions remain about best strains, number and combination of strains, personalization of treatments based on individual gut microbial composition and function, and clinical effectiveness in specific target populations.

While superb study results obtained in experimental mouse models continue to be published in high profile scientific journals, human studies have largely failed to reproduce the same dramatic outcomes. There are many reasons for this discrepancy, the major ones being the high interindividual variation between human subjects (compared to the genetic homogeneity of inbred mice), the challenge of controlling dietary intake in humans, lack of attention being paid to sex-related differences, sample size of study populations, and in terms of psychobiotics, poorly selected candidate probiotic strains that are either chosen for their cost to manufacture at scale, legacy research, or single mechanism of action, or the vast differences between the mouse and human brains.

Along the same lines, there is only a handful of probiotics that have gone through the rigorous approval process by federal agencies like FDA. Until these questions have been answered, consumers, not being aware of the above problems, are more influenced by the prominence and reach of social media influencers and clever marketing campaigns than by objective evidence.

Considering this state of the field, how do I answer the questions I am being asked by my audiences?

My initial answer is always that microbiome science is a very young field, that our understanding of the complexities of our gut microbial partners remains very limited and that we underestimate the power of placebo, but that we know enough to realize the phenomenal implications of the field for many aspects of our health.

As an integrative gastroenterologist, I am guided by a large body of empirical evidence that the consumption of naturally fermented foods (which humans have consumed for thousands of years, but which don’t necessarily fulfill the criteria required for the marketing as a probiotic) is associated with health benefits and is good for gut microbial diversity and health as recently demonstrated in a high quality clinical trial evaluating the effects of a diet high in naturally fermented foods and a fiber rich diet.

As a scientist, I am guided by the rapidly evolving science and by evidence derived from a few high quality clinical studies (1, 2, 3), which have demonstrated a clinically meaningful effect of certain probiotic strains and of naturally fermented foods on objective outcomes in human subjects, such as shape and consistency of bowel movements, gut microbial diversity and on functional brain changes.

While there does seem to be a role for specific probiotics to improve health, many of the commercially available probiotic strains are generic, understudied, or selected for industrial purposes like ease of manufacture or a high potency yield. Very few commercial products have sequenced the strains or generated data demonstrating the formulation effectively survives the gastrointestinal system and delivers live probiotic cells inside the body.

“There are companies and researchers pushing the field forward with scientific rigor and novel approaches…”

In this regard, I wanted share that there are companies and researchers pushing the field forward with scientific rigor and novel approaches to formulation, testing and validation. Seed Health, a microbial sciences company I have known and recently became a Scientific Advisor to, has developed a complex, multi-strain probiotic and prebiotic formulation (DS-01TM) with data to support the formulation, strains, gastrointestinal transit, and biological effects.

Seed has assembled a strong scientific team and Scientific Board, including pioneers in the field of probiotics, to work on data generation (Hill et al 2014, Gibson et al 2017, Reid et al, 2019). Seed’s approach has been to validate candidate probiotic strains based on their clinically validated success in improvement in different health outcomes and/or molecular upregulation of markers of gut barrier integrity.

The probiotic consortium they assembled was combined with a novel prebiotic, a pomegranate polyphenol which demonstrably increases beneficial Bifidobacterium and Akkermansia, which directly stimulate a favorable gut microbial balance. The polyphenol and its microbial breakdown products are also associated with anti-inflammatory and anti-oxidizing benefits that afford protection against poor immunity, metabolic upsets, and aging.

In summary, there is no question that probiotic consumption in the US will continue to grow, driven to a large extent by online marketing campaigns, unsubstantiated claims, and poor stewardship of the scientific use of the term, ‘probiotic’. The powerful placebo effect will assure that many people will perceive and report health benefits from their daily probiotic cocktail. However, encouraged by a handful of innovative companies willing and able to invest in rigorous scientific evaluation (including but not limited to Seed, Danone, and Pendulum), I believe that the Golden Age of scientifically proven pre-, pro- and syn-biotics for improving gut and brain health, is still ahead of us.

NOTE: I’ve partnered with Seed because I strongly believe in their transparent and evidence-based approach to develop a symbiotic with benefits your gut health. This post contains affiliate links, and if you make a purchase through these links I may receive a referral credit for your order.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

What Is All the Hype About SIBO?

As the COVID-19 pandemic has engulfed the world, there has never been a time in which topics like Gut Health, Immune Support, Gut Cleansing, and Improvement of Gut Health have been more popular. Suddenly self-declared experts from different fields of medicine, nutrition and wellness have all jumped on this new trend to explain old symptoms and to promote novel treatments. Podcast, master classes, social media posts and advertisements, bestselling books have all driven the frenzy around these topics, while scientific evidence from well controlled human studies have been lagging behind. In the last Gut Health Insights post, I have discussed the flawed concepts about the need for “Immune Support” to make it through the pandemic.

“There are few concepts and syndromes in Medicine and particularly in Gastroenterology which have gone through a similarly remarkable historical transformation as SIBO”.

Another one of these highly popular, yet controversial topics is Small Intestinal Bacterial Overgrowth, better known by its acronym SIBO (other references: 1, 2). There are few concepts and syndromes in Medicine and particularly in Gastroenterology which have gone through a similarly remarkable historical transformation as SIBO. The term first emerged in the literature more than 80 years ago and was a relatively rare diagnosis. However, the concept was adopted more recently by functional and integrative medicine practitioners, by the lay media and even the medical establishment and the pharmaceutical industry and has been promoted in social media as a diagnosis explaining some of the most common symptoms of abdominal discomfort. Unfortunately, it has led to the widespread and in my opinion unnecessary use of antibiotic treatments for symptoms most likely unrelated to gut microbes.

“…the diagnosis and overall conception of SIBO has become mired in uncertainty and controversy…”

SIBO is a clinical disorder that was first described in the 1930s in patients with serious symptoms of malabsorption, bloating, abdominal pain, and diarrhea, following surgical alterations of the gastrointestinal tract. However, since these early descriptions, the concept of SIBO has undergone significant change and challenges in light of emerging insights and speculations from studies into the gut microbiome. The diagnosis of SIBO which originally was limited to a small number of individuals with a specific medical history, has all of a sudden been given to a large number of patients complaining of such common, non-specific symptoms of abdominal bloating, sensations of gas and irregular bowel movements, and is now widely used as a seemingly plausible explanation for many IBS symptoms. However, as well summarized in a recent review article by Bushyhead and Quigley, the diagnosis and overall conception of SIBO has become mired in uncertainty and controversy, as there remains a lack of consensus or “gold standard” for diagnosis, an absence of causality to clearly link clinical symptoms to alterations in the gut microbiota (“dysbiosis”). In addition, the often-prescribed treatment with antibiotics is highly controversial.

To better understand the controversy, it is good to briefly review the role of our gut microbes residing in different parts of the intestinal tract. In a healthy individual, the number of microorganisms increases about tenfold from the beginning of the small intestine down to the large intestine. The majority of small intestinal microbes are thought to originate from the oral microbiome, and a small number migrating there from the large intestine. It has been suggested that such small bacterial counts ensure that the small bowel, our major site of digestion and absorption of nutrients and calories does not face competition for nutrients by the microbes following the ingestion of a meal. In contrast, in the more densely populated colon, typical the large number of bacteria accomplish many essential tasks, including the breakdown of large, unabsorbable molecules from ingested fiber and polyphenols (both contained in plant-based foods), and the transformation of these molecules into absorbable health promoting, anti-inflammatory and neuroactive substances, such as the short chain fatty acid butyrate and various phenolic compounds (reviewed extensively in The Gut Immune Connection).

“A healthy small bowel uses several different protective mechanisms … to prevent microbes from migrating from the mouth throughout the small intestine”

A healthy small bowel uses several different protective mechanisms – including concentrated hydrochloric acid produced by the stomach to kill many microbes entering from the mouth, as well as bile and pancreatic secretions- to prevent microbes from migrating from the mouth throughout the small intestine, colonize and to keep relatively low bacterial numbers. Importantly, several patterns of contractions of the small intestine, in particular the so-called migrating motor complex, a powerful wave of contractions that moves through the entire gut every 90 minutes when it is empty, make it difficult for large number of microbes to set foot in the small intestine, and greatly limit their growth. In addition, a particular valve between the end of the small intestine and the beginning of the colon prevents backward movement of colonic bacteria into the small intestine. However, under rare circumstances when pathologic microbial colonization of the small intestine does occur, it can result in a number of pathologic disturbances, including injury of the intestinal lining or malabsorption of carbohydrates. Given the variety of multiple, synergistic mechanisms preventing small bowel colonization with microbes summarized above, SIBO would be expected to be a rare condition, primarily appearing as a complication of chronic digestive disorders such as chronic pancreatitis, cirrhosis and rare disorders of intestinal motility and anatomic abnormalities.

“…there is currently no universally acknowledged or validated “gold standard” for diagnosis, and no FD-approved medications.”

Although there is no specific symptom of SIBO, patients given this diagnosis generally present with abdominal pain and distension, bloating, flatulence, and diarrhea, a nearly identical symptom complex as reported by IBS patients. Because these symptoms are neither exclusive to, nor predictive of SIBO, and SIBO is often treated with antibiotics, one would expect that such a diagnosis should only be made based on objective, generally accepted, and validated biological tests. However, despite recent advances in the scientific community’s understanding of the microbiome, there is currently no universally acknowledged or validated “gold standard” for diagnosis, and no FD-approved medications. Even though several tests are available and commonly used, including the direct analysis and quantification of small bowel microbiota and various breath tests measuring the production of hydrogen and methane by intestinal microbes, the validity of all these tests has been questioned and has generated substantial controversy. According to a North American Consensus Statement, such test results should be interpreted with caution.

Surprisingly, although there are no Food and Drug Administration–approved medications to treat SIBO, the mainstay of treatment has been oral antibiotics. Given the well-known risks of antibiotic therapy – in particular when administered repeatedly- such as reduction of gut microbial diversity, the promotion of drug-resistant bacteria and the development of Clostridium difficile colitis, one would expect that data on the efficacy of antibiotics for SIBO should be unambiguous. Unfortunately, antibiotic regimens for SIBO have, in general, been poorly studied, largely in trials involving small numbers of patients and lack of placebo controls. For example, a systematic review and meta-analysis of rifaximin, a popular, nonabsorbable antibiotic, demonstrated that the overall eradication rate (based on the controversial breath tests mentioned above) was only about 70%. Importantly, the authors of the study noted that the quality of included studies was generally poor, as only a single study was placebo- controlled.

Other treatment modalities that may have a theoretic benefit in restoring healthy GI microbiota such as changes in diet, pro- and prebiotics and even fecal microbiota transplantation (FMT) have not been adequately studied for the treatment of SIBO. I will come back to the question of treatment at the end of this post.

“…the most problematic claim relating to the diagnosis of IBS has been its implication in the pathogenesis of IBS.”

As if the topic of SIBO is not controversial enough, the most problematic claim relating to this diagnosis has been its implication in the pathogenesis of IBS. An early study demonstrating both a higher prevalence of positive lactulose breath tests in patients with IBS (thought to reflect abnormal numbers of gut microbes in the small intestine) in comparison to healthy control subjects and significant improvement in IBS symptoms following normalization of breath tests with antibiotic therapy suggested a strong association between IBS and
SIBO. However, a systematic review and meta-analysis of SIBO in IBS challenged the validity of this association. Although the pooled prevalence of a positive lactulose breath test in this review was 54%, the stricter criteria of a greater number of microbes (more than the 105 colony forming units/mL) found in a jejunal aspirate from IBS patients and culture was only 4% and not higher than controls, putting both the validity of the breath test as well as the diagnosis of SIBO into question. Significant problems in study design and reporting, as well as the possibility that a positive lactulose breath test may simply signify an abnormally fast transit time through the small intestine.

As there is some suggestion that the pathophysiology of IBS entails abnormal colonic rather than small bowel fermentation of complex carbohydrates, it is possible that the efficacy of antibiotic treatments in some IBS patients is due to an impact on colonic rather than small bowel bacterial populations (it is worth noting that a subgroup of IBS patients actually reports a worsening of their symptoms after antibiotic treatment). In view of the well demonstrated hypersensitivity of the colon to distension, even a small reduction of normal intestinal gas production could lead to some reduction in symptoms of bloating and gas. As the involvement and precise mode of action of rifaximin in SIBO remains poorly understood, it has been suggested that the effect of the drug on bacterial numbers may be minimal and effects may be related more to perturbations of bacterial metabolism. However, to date this remains a speculative hypothesis.

“…it is not possible to make any valid conclusions about a putative role of intestinal microbiota, SIBO and IBS”.

In summary, both the relationship between SIBO and altered intestinal gut microbial density, and the association between SIBO and IBS remains controversial. Whether current testing methods accurately reflect SIBO, and whether abnormal breath test results are causally related with IBS or IBS-like symptoms remains open to question. Because SIBO lacks a gold standard for diagnosis, and IBS is a diagnosis based on symptom criteria (the so-called Rome criteria) and of exclusion that lacks a validated biomarker, it is not possible to make any valid conclusions about a putative role of intestinal microbiota, SIBO and IBS. Future research focused on defining the normal small bowel microbiome with novel genomic and metabolomic technologies, and on the clinical utility of breath tests.

It shouldn’t come as a surprise to the readers of this post, that I have never made a diagnosis of SIBO in any of my patients, who did not have any of the established risk factors mentioned above, nor have I treated any IBS or IBS-like symptoms with antibiotics. My approach to patients is to take advantage of the gut’s own regulatory mechanisms, including a high fiber diet to assure normal transit of food through the small intestine, and the unique gut cleansing motility patterns (“migrating motor complex”) to keep a normal gradient of microbial density throughout the gut.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Olive Oil – A Medicine Produced by Nature and Refined by Human Expertise and Traditions

Long before becoming aware of the unique qualities of extra-virgin olive oil (EVOO), we have always used the oil in our salad dressings and preparation of Italian meals. However, in addition to its delicious flavor, various health benefits of EVOO have been reported from preclinical and clinical studies and are applicable to a wide range of metabolic disorders and cardiovascular diseases. EVOO is considered to be one of the key health-promoting ingredients of the Mediterranean diet. There are at least two major components that mediate the oil’s health benefit—the high concentration of monounsaturated fatty acids (primarily oleic acid) and the high content of polyphenols (primarily oleuropein and hydroxytyrosol). As I have discussed in previous posts, polyphenols exert their health benefit with the help of the gut microbiome. Research suggests this may be true for oleic acids, too. Oleic acid is the predominant fatty acid in olive oil—73 percent of its total oil content—while 11 percent is polyunsaturated, such as omega-6 and omega-3 fatty acids. Monounsaturated fatty acids (MUFAs) are quite resistant to high heat, making EVOO a healthy choice for cooking. Some sources put the smoke point of olive oil somewhere around 374–405°F (190–207°C) (17). This makes it a safe choice for most cooking methods, including most pan frying. Extra virgin olive oil’s smoke point is somewhere around 374–405°F (190–207°C).

“Polyphenols, unlike the vitamins found in the oil, are largely unabsorbable in the human gut, and have to travel to the end of the small intestine and colon to be broken up into absorbable molecules by specialized communities of gut microbes.”

Traditionally, the high content of MUFAs was considered to be responsible for the protective effects of EVOO, but current evidence suggests benefits are largely related to polyphenols and vitamins A and E found in the oil. While both polyphenols and these vitamins have antioxidant effects when studied in a test tube, only the vitamins which are rapidly absorbed in the small intestine have such an effect when consumed. In contrast, polyphenols are largely unabsorbable in the human gut, and have to travel to the end of the small intestine and colon to be broken up into absorbable molecules by specialized communities of gut microbes. Contrary to common belief and advertisements, the majority of these molecules are believed to exert their beneficial effects by mechanisms other than antioxidation. Amongst the thousands of polyphenols contained in different fruits and vegetables, as many as thirty different polyphenol molecules have been identified in different olives.

The phenolic concentration of EVOO ranges from 50 to 800 milligrams per kilogram, and the amount of polyphenols in EVOO depends on the region where the olives were grown, corresponding differences in climate including average rain fall, drought conditions, degree of ripeness when harvested, and the oil-extraction process. In addition, the phenolic fraction of olive oil can vary greatly among different types of olives. As a result, it can be a challenge to figure out which olive oil to buy in order to get the full benefit in terms of both flavor and polyphenols.

“In addition to his wines, Marco produces EVOO from eight-hundred- year- old olive trees, using a wide variety of olives…”

I learned more about olive oil a couple of years ago when I visited my friend Marco Cavalieri, the owner of the Le Corti Dei Farfensi winery in Fermo, on the picturesque Adriatic coast of Italy. In addition to his wines, Marco produces EVOO from eight-hundred- year- old olive trees, using a wide variety of olives, including the Sargano, Carboncella, Ascolana, Coratina, Frantoio, and Moraiolo varieties (An eight-hundred- year- old tree may sound ancient, but it’s practically a sapling in olive oil–making years: olive trees started to grow in the southeastern Mediterranean basin more than six thousand years ago, and they were a major item of trade for the ancient Greeks, Romans, Persians, and Phoenicians throughout the Mediterranean region. These varieties contain the polyphenols oleuropein, demetiloleuropein, and quercetin, with an average polyphenol concentration of around 800 milligrams per kilogram. As polyphenols are a crucial part of the plants’ pharmacy – they protect against diseases, pests, drought, and UV light – it is easy to imagine that they play a key role in the longevity of these ancient trees!

In addition to harvesting the olives from the ancient trees, Marco uses several strategies to ensure the highest possible polyphenol content in his product. The olives are harvested when they have not fully ripened, when their polyphenol production is at its highest. Harvested olives are stored in airtight steel containers to protect them from oxygen and light. Those made into oil are taken to the local facility where they are cold pressed just hours after they’re harvested. The fresh oil has a uniquely pungent flavor and fragrance, with an initial almost burning sensation and taste. In addition to its flavor and health benefits, the polyphenols contribute to its superior oxidative stability compared to other edible oils.

In seeking out the health benefits of the Mediterranean diet, it became clear to me that the high polyphenol content of EVOO makes it a medicine produced by nature and refined by human expertise and traditions. Like any medicine, the precise amount of active ingredients and the quality of processing play major roles in its effectiveness. So rather than being misled by the dark appearance of many expensive olive oils marketed as EVOOs, it is worth investigating where and how they were harvested and processed, as well as their average polyphenol content. This may take a bit of investigating, as most producers don’t include information about polyphenol content on their labels. Given the difficulty of tracking down the polyphenol content, the best way for a consumer to determine it is by taste—a pungent flavor is generally a sign of high polyphenol content.

This post was taken from my book, The Gut Immune Connection, which has a lot more information about the topic of gut friendly and anti-inflammatory foods and 40 gut friendly recipes.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

How to Be Happy During These Uncertain Times

The solstice in December, the day I am writing this, marks the first day of winter. In the Northern hemisphere, it is the shortest day and the longest night of the year. Ever since ancient times, this day has been celebrated across the world as a time of renewal, a kindling of hope, in the depths of darkness. It is something deeply embedded in the human mind that has been adopted by different religions and cultures for thousands of years. Lights on the Christmas tree and all the magical Christmas decorations tempting us to visit the local mall to buy a last-minute present are only one of the most popular versions of this ritual, co-opted by commercial interests which have made Christmas shopping one of, if not the most profitable time of the year. The ancient rituals of happiness have been replaced by a frenzy of pleasure-seeking activities.

Photograph of a nativity scene carved into a wooden mold in 1571. This mold was used by my father to make gingerbread cookies for the local Christmas market.
If we only judge by the daily flood of negative information in the media, there is little to be happy about moving towards the end of this unusual year. The beginning of the third year of the pandemic, with a new variant leading to the unexpected return of lockdowns and an overwhelmed healthcare system, extreme weather patterns around the world, with predictions of things to get much worse, millions threatened by starvation, heartbreaking stories of desperate refugees drowning in the freezing waters of the English Channel, out of control autocrats with return to cold war scenarios and continued paralysis of the political system here in the US, preventing any meaningful solutions to our most pressing problems. Unsurprisingly, in addition to the 800,000 COVID-related deaths in the US so far, and a continued death toll of about 2,000, we are witnessing an epidemic of mental illness in the form of anxiety, depression and PTSD that is overwhelming mental healthcare providers.

Is this the right time to be happy?

Instead of frantically engaging in last minute shopping sprees and focus on the transient pleasures we obtain from getting beautifully wrapped gifts, enjoying Christmas dinner and indulging on delicious sweets, we should reflect for a moment what a mental state of happiness really means, and how it is fundamentally different from the transient experience of pleasure.

In his inspiring book, Happiness, Tibetan monk Matthieu Ricard states … “We look for happiness outside ourselves when it is basically an inner state of being.” And he goes on to explain, “…by happiness, I mean here a deep sense of flourishing that arises from an exceptionally healthy mind. This is not a mere pleasurable feeling, a fleeting emotion, or a mood, but an optimal state of being. Happiness is also a way of interpreting the world, since while it may be difficult to change the world, it is always possible to change the way we look at it.”

Such an inner state of happiness is more urgently needed than ever to deal with the ubiquitous negativity around us. Based on our inability to fundamentally change the way we live, we can expect that it will only get worse in the coming years. Unfortunately, most of the national and global problems that are currently unfolding are beyond our control. The transient state of dopamine-driven pleasure will be over for the majority of people after the Holiday Season, and pessimism, fear and anxiety will return. What remains will be a craving for the next pleasure- providing high.

This may be a good time to reflect on the true meaning of happiness. As stated so clearly by another Tibetan monk, Dilgo Khyentse Rinpoche, “those who seek happiness in pleasure, wealth, glory, power and heroics are as naïve as the child who tries to catch a rainbow and wear it as a coat.”

True happiness, as defined above, is a state that most people in the United States and other industrialized societies have forgotten how to achieve. But the good news is that there is a growing popularity of contemplative practices, such as mindfulness meditation, and the nurturing of empathy and compassion. As we have discussed in many previous editions of our newsletter, these contemplative practices are not only essential to obtain a state of lasting happiness and equanimity, but they protect us against the ill health effects of negative emotional states and associated lifestyles.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Anxiety and IBS – Two Sides of the Same Coin?

For as long as I can remember in my career as a gastroenterologist (30+ years) every new publication and every presentation about IBS which affects around 10% of the population has always started with the same caveats: IBS is a diagnosis based on (regularly changing) “subjective symptom criteria”, the pathophysiology is “incompletely understood” and available treatments are “unsatisfactory”.

“Commonly used IBS treatments, ranging from dietary exclusion, motility modulating drugs to psychoactive medications, are largely ineffective…”

The commonly used IBS treatments, ranging from dietary exclusion, motility modulating drugs to psychoactive medications, are largely ineffective (in most clinical trials they performed not better than 10% above placebo) and their variety (targeting smooth muscle, water secretion, gut microbes) reflects the uncertain etiology of the syndrome. Even though behavioral therapies have proven more effective than most medications, they have not been widely accessible even though web-based versions of cognitive behavioral therapy (CBT), gut directed hypnosis and mindfulness-based stress reduction are rapidly becoming available.

Considering the number of efforts and funding invested in research studies aimed at identifying the cause of the syndrome and demonstrating effectiveness of a variety of medications (largely unsuccessful), it is surprising that the list of these caveats has remained virtually unchanged over more than 3 decades. Another recurrent theme in scientific and clinical meetings has been the debate about whether IBS is a gut disorder (a “real disease”) or is related to alterations in the brain (“just psychological symptoms”). Recent epidemiological data suggested that, in individuals developing both IBS and psychological features, the former preceded the latter in two thirds of cases and the latter preceded the former in one third. However, in my own practice, a thorough history taking reveals psychological factors often dating back to infancy in the majority of patients presenting with IBS symptoms, even those with so called post infectious IBS.

“IBS has finally been officially recognized as a disorder of altered brain gut interactions”

The good news is that after decades of these fruitless arguments and debates, and based on overwhelming clinical and scientific evidence, IBS has finally been officially recognized as a disorder of altered brain gut interactions.

A recent study by a large group of investigators in the UK and US, provides new and strong evidence supporting the brain gut disorder concept. (Even though there have been many previous studies in smaller groups of patients that had already strongly implicated the brain gut disorder concept). The new study was based on the hypothesis that identifying genes (so called single nucleotide polymorphisms or SNPs) that increase the likelihood of IBS (so called susceptibility genes) could highlight the mechanisms that are responsible for the symptoms. The investigators conducted a genome-wide association study (probing every one of the 20,000 genes making up the human genome) with 53,400 cases of individuals meeting IBS symptom criteria and 433,201 healthy controls and then replicated their findings of significant associations in a database from the genetic testing company 23andMe (205,252 IBS cases and 1,384,055 healthy controls). IBS subjects were identified using a digestive health questionnaire that was administered to cases in the database of the UK Biobank together with a battery of tests for digestive, psychological and pain symptoms and combined identified cases with IBS with independent cohorts.

“IBS showed the strongest genome-wide overlap with anxiety, neuroticism, depression…”

Their study identified and confirmed six genetic susceptibility loci (genes that increase the likelihood for IBS). Four of these genes were associated with mood and anxiety disorders, are expressed in the nervous system (brain and enteric nervous system), or both. Mirroring these genetic associations, they also found strong genome-wide correlation between the risk of IBS and psychological traits. IBS showed the strongest genome-wide overlap with anxiety, neuroticism, depression, and schizophrenia. Even though based on clinical symptoms, anxiety scores correlated with IBS severity and 34.3% of cases with IBS had sought or had been treated for anxiety versus 16.1% of controls the genetic correlation (between susceptibility genes for IBS and psychological syndromes) appeared quantitatively even greater. Additional analyses performed on this massive dataset suggested that these associations between genes, GI symptoms and symptoms of altered mood and affect was a consequence of shared pathogenic pathways for both groups of disorders, rather than, for example, anxiety or depression causing abdominal symptoms.

“…anxiety and IBS symptoms can be viewed as two sides of the same coin…”

The sheer size of this study, the confirmation of the initial findings in a second large data set, and the use of rigorous epidemiological and genetic methodology will make it difficult to challenge these findings. The results from the study confirm the genetic basis of IBS as a brain gut disorder, in which neither psychological symptoms produce GI symptoms, nor chronic GI symptoms lead to anxiety or depression. As I have always explained to my patients, anxiety and IBS symptoms can be viewed as two sides of the same coin, or in other words, whatever happens in the brain is mirrored in the gut and vice versa. The new study will make this concept even easier to explain.

The sharing of similar susceptibility genes between IBS and psychological symptoms may also explain the recent explosion of public interest in gut health and gut-friendly diets in a time of worldwide increases in anxiety and depression. Some people are responding to the stresses posed by the COVID-19 pandemic and political divisiveness with belly pain and altered bowel habits, while others experience anxiety, and a third group experiences both. The brain gut disorder concept also implies that the best treatment for the majority of IBS patients is multipronged, aiming both at the brain (with CBT, hypnosis, or mindfulness-based stress reduction) and at the gut (with a healthy gut friendly diet) at the same time.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

The Mindful Way to Celebrate Thanksgiving

Ever since I first came to the US in the late 1960s, Thanksgiving has always been my favorite holiday. Thanksgiving is the only American holiday celebrated by nearly every family, regardless of race, political orientation, religion, country of origin or immigration status. Thanksgiving is one of the few events left in our age of extreme political and cultural polarization that is universally agreed upon, more than Christmas, Easter, Hannukah, New Year, Diwali, or Kwanzaa.

Some prevalent myths about Thanksgiving

As we approach Thanksgiving and the holiday season, many families are preparing to celebrate this holiday with gratitude, food, and quality time together. This is what makes this time so unique. But stories told about the first Thanksgiving put into question some of its history and cover up some difficult truths. “Thanksgiving facts and Thanksgiving myths have blended together for years like so much gravy and mashed potatoes, and separating them is just as complicated.”

Over the years, I have learned a few things about Thanksgiving that makes me experience this wonderful Holiday in a more mindful way. In our age of obsession with healthy food, well-being, and longevity, it is worth looking at some lessons that we can learn from this annual nation-wide family ritual of celebrating a successful harvest by consuming some 245 million turkeys each year.

It wasn’t the Pilgrims that first came up with the holiday of Thanksgiving.

We all know the official story of Thanksgiving. According to that story, the Mayflower brought the Pilgrims to North America from Plymouth, England, in 1620, and they disembarked at what is now Plymouth, Mass., where they set up a colony. In 1621, they celebrated a successful harvest with a three-day gathering that was attended by members of the Native American Wampanoag tribe. It’s from this story that we derive Thanksgiving as we know it. However, it is worth remembering that the celebration of a successful harvest each fall has predated the American holiday for centuries, and was deeply engrained both in European history, the history of the first settlers, and the indigenous peoples of the Americas. In the United States, the holiday wasn’t made official until 1863, when President Abraham Lincoln declared it as a kind of thank you, for the Civil War victories in Vicksburg, Miss., and Gettysburg, Pa.

There’s no evidence that Native people were invited.

Possibly the most common misconception is that the Pilgrims extended an invitation to the Native Americans for helping them reap the harvest. The truth of how they all ended up feasting together is unknown. According to the historian Mary Sheehan, “The English-written record does not mention an invitation, and Wampanoag oral tradition does not seem to reach back to this event.”
As discussed by Maya Salam in a 2017 New York Times article, school children are taught that the Native American Tisquantum, known as Squanto, did play a large role in helping the Pilgrims. His people, the Patuxet, a band of the Wampanoag tribe, had lived on the site where the Pilgrims settled. According to historical records, when they arrived, he became a translator for them in diplomacy and trade with other native people, as well as showed them the most effective method for planting corn and the best locations to fish.
However, the rest of this story of tolerance and gratitude is rarely mentioned. Squanto was captured by the English in 1614 and later sold into slavery in Spain. He returned to New England in 1619, only to find his entire Patuxet tribe dead from smallpox, making him the last member of his tribe. He met the Pilgrims in March 1621. The story of Squanto is important to remind us, that Thanksgiving also comes with painful colonial origins, and a reminder of the atrocities indigenous peoples had to face in their interactions with the first settlers.

The myths about the turkey

There is little evidence that a roasted turkey played a big role in the early days of this holiday, even though historical records indicate that wild turkey was abundant in the area. What is known, is that the Pilgrims harvested crops and that the Wampanoag brought five deer. While experts agree that there was no mention of turkey being at the 1621 bounty, there was certainly some wild fowl — possibly goose, duck, or turkey — served along with the venison brought by the Natives. There is also little evidence that the feast included pumpkin pie either. Settlers lacked butter and wheat flour for a crust, and they had no oven for baking.

Industrial agriculture, that I have often written about in my book and blog posts, turned the annual turkey feast into something most people don’t want to be reminded about when they sit down on the dinner table. Mass produced turkeys are genetically bred to grow fast and, typically, grow such big breasts that they can barely walk by the time they are killed. Furthermore, they are regularly fed antibiotics and hormones to grow faster and fight off infections. The vast majority spend their short lives in artificially lit, windowless, barren warehouse barns. In order to keep turkeys from pecking one another in these crowded barns, their beaks are painfully trimmed. No animals raised on factory farms are kept and killed under worse conditions than turkeys and chickens, which make up most of the animals raised for food in the U.S.

While it is good to be mindful of some of the myths and dark sides of the Thanksgiving ritual, there are some wonderful lessons that we can learn from it when we consume our food – not just the turkey, but our meals in general.

The lessons of a mindful Thanksgiving meal

  1. The original meal was certainly a lot healthier than our Standard American Diet (SAD) diet version of it, and didn’t involve all the negative aspects of animal cruelty. There is no reason why we couldn’t return to such a healthier and compassionate way of eating our Thanksgiving dinner today, as vegetarians and vegans have done so.
  2. The social connectedness around a communal meal the early settlers experienced (as do many people around the world, including the Indigenous people at the time), is an essential aspect of a healthy diet. Such feelings of connectedness translate into a healthy pattern of brain-gut-microbiome interactions and enhance the health benefits of our food. Thanksgiving may be a good time to reevaluate our modern eating habits, in which the close interactions between family members and close friends sitting around the dinner table for hours have certainly become the exception in our modern lifestyles.
  3. Gratitude (1, 2)is an essential part of a contemplative lifestyle. Research studies have shown that gratitude is associated with specific activity in brain networks, and that a mindset of gratitude and eudaimonia can influence gene expression patterns in blood cells which are conducive to our health. In the United States and other Western countries, there are many reasons to express gratitude at Thanksgiving. For the abundance of food that most of us have access to, to the workers that are involved in growing, harvesting and distributing our food often under harsh conditions, and to lasting peace that many of us have enjoyed over the last 70 years

A Season of Gratitude

In this season of gratitude, we want to express our heartfelt Thanks to all the individuals – including podcast hosts, blog post and recipe contributors, and newsletter co-editors- that have contributed to the success of our efforts to promote Health and Wellness of not only body, mind, and spirit, but also of the soil, the environment, and the planet. A special thanks goes to all the subscribers of the Mind Gut Connection Newsletter, to the regular viewers of the Mind Gut Conversation podcast, and the followers on our social media channels.

We wish you all a Wonderful and Mindful Thanksgiving!


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

The Good News About Italian Pasta

As mentioned in my previous post, we recently experienced first-hand the paradox of the modern Italian diet, when we spent some time in Parma, in the Emilia Romana region of Italy. Instead of the expected traditional health-promoting, largely plant-based Mediterranean diet, we discovered that most people in this city were thriving on a diet high in animal products and pasta. And even more surprising was the fact that on average, people were not obese, and had a similar high life expectancy as those living in other regions. In my last post, I focused on the high amounts of animal products (ham and cheese) in the diet of people living in Parma, which didn’t seem to fit with our general concepts of the Mediterranean diet of one high in plant-based foods, with small amounts of red meat. But what about the ubiquitous pasta dishes in the Italian cuisine? Based on the prevalent carbohydrate phobia in the United States, this unique Italian pasta preference should also not be consistent with current dietary recommendations. I decided to look into this question and was helped by a very recent publication by an international group of investigators from Italy, Finland and Canada, with lead author Francesca Scazzina from the Department of Food and Drug, University of Parma.

“…the consumption of pasta elicits lower postprandial blood sugar and insulin responses compared to foods like bread and pizza…”

It had previously been shown in the scientific literature, that the consumption of pasta elicits lower postprandial blood sugar and insulin responses compared to foods with similar ingredients (like bread and pizza), but different structures. Such postprandial glucose responses of foods are of importance since diets containing foods eliciting lower responses favorably affect the risk of common diseases that make up the modern chronic non-infectious disease epidemic. Earlier studies had shown that pasta has a lower impact on postprandial glycemia compared to many other carbohydrate-rich foods, such as couscous and bread.

“…pasta consumption within the limits recommended for total carbohydrate intake has been found to be inversely associated with body mass index…”

Equally unexpected, pasta consumption within the limits recommended for total carbohydrate intake has been found to be inversely associated with body mass index in several observational studies and was not associated with worsening of glucose control, measures of adiposity, and major cardiovascular risk. Finally, in a recent systematic review and meta-analysis of randomized controlled clinical trials, pasta has been found to reduce body weight and BMI, when compared with higher-glycemic index dietary patterns.

To explain this paradox, it has been proposed that structure and protein-starch interactions in pasta products may be responsible for lower postprandial glycemic responses compared with other grain-based foods. The study by Saara Vanhatalo, Francesca Scazzina and collaborators aimed to provide a definitive test of this hypothesis in two randomized controlled trials (n = 30/trial) performed in healthy normal weight adults by evaluating the processing of carbohydrate portions (50g) of durum wheat semolina spaghetti, penne, couscous, and bread. In addition to measuring postprandial glucose and insulin responses, the investigators assessed in great detail the structural and mechanical properties of the ingested carbs.

“…both penne and spaghetti induced lower postprandial glucose and insulin responses than bread or couscous.”

The study showed that both pasta products (penne and spaghetti) induced lower postprandial glucose, insulin, and C-peptide (an indicator of insulin production) responses than bread or couscous, even though they were made from the same ingredients and consumed in equal amounts. Interestingly, spaghetti induced a lower postprandial C-peptide response than penne, presumably due to the structural differences between the two pasta types. They also found that both pasta products required more chews than bread or couscous, and that pasta boluses contained the highest proportion of large particles (greater than 10 mm) while the couscous bolus contained the highest proportion of the smallest particles (less than 1 mm), while the bread bolus values lay in the middle. All the boluses contained a protein network made up of gluten in which starch granules were embedded.

The results of this study elucidate how pasta structure delays starch digestion causing lower postprandial glucose, insulin and C-peptide responses in humans compared to other commonly consumed grain products like bread and couscous, and certainly compared to highly processed sugary foods and juices. Although these other grain-based dishes may be made with the exact same raw material, they differ extensively in the technological processes applied to obtain the final food product.

“…the protein network made up of gluten molecules seems to play an important role in slowing the rapid absorption of wheat carbohydrates in the small intestine.”

Several factors could explain these surprising findings. Contrary to the prevalent gluten phobia in the US, the protein network made up of gluten molecules seems to play an important role in slowing the rapid absorption of wheat carbohydrates in the small intestine. The strong protein network is slowly digested and protects starch granules from enzymatic action in the small intestine. Although couscous had a strong protein network (as seen through microscopy), due to its small granule size, it was more prone to enzymatic action, thus resulted in smaller particles compared to the pasta boluses after in vitro digestion. It would be interesting to know if gluten-free pasta, as now commonly marketed in the US, would show the same favorable slow digestion as the traditional pasta containing gluten.

The observed differences in particle size may play another important role. Earlier studies have clearly demonstrated that the rate of gastric emptying of food is greatly influenced by particle size of food in the stomach: no ingested food is emptied from the stomach into the small intestine, until the stomach grinds it down to particles less than 1 mm in diameter. This explains why the large pasta particles reach the small intestine much slower than the small ones made from bread and couscous. Even though not tested in this study, the traditional Italian way of preparing pasta “al dente”, e.g., with some resistance to the bite and not overcooked, may further contribute to the slower gastric emptying. Finally, the pasta-derived particles (large and smooth-rimmed in shape) have low surface to weight ratio and are thus generally more resistant to enzymatic action compared with small and shredded particles with larger surface area.

“…enjoy the dish in the company of friends and relatives, as the Italian do!”

There are several take home messages from this research study. Not all carbs are bad for us, and the way carbs are processed into pasta may play an unexpected role in making them more gut friendly and mitigating the undesired glycemic effects. The much-maligned gluten molecule seems to be playing an important role in this beneficial effect that is lost in gluten-free pasta products. Whole wheat pasta, containing fiber molecules that slow gastric emptying and absorption may even have an additional advantage. Eating pasta in reasonable quantities, and without burying it in cheese and other high caloric additives will further enhance their health benefit. And most of all, enjoy the dish in the company of friends and relatives, as the Italian do!


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

What Is All the Hype About SIBO?

By Emeran Mayer, MD

As the COVID-19 pandemic has engulfed the world, there has never been a time in which topics like Gut Health, Immune Support, Gut Cleansing, and Improvement of Gut Health have been more popular. Suddenly self-declared experts from different fields of medicine, nutrition and wellness have all jumped on this new trend to explain old symptoms and to promote novel treatments. Podcast, master classes, social media posts and advertisements, bestselling books have all driven the frenzy around these topics, while scientific evidence from well controlled human studies have been lagging behind. In the last issue of Gut Health Insights, I have discussed the flawed concepts about the need for “Immune Support” to make it through the pandemic.

“There are few concepts and syndromes in Medicine and particularly in Gastroenterology which have gone through a similarly remarkable historical transformation as SIBO”.

Another one of these highly popular, yet controversial topics is Small Intestinal Bacterial Overgrowth, better known by its acronym SIBO (other references: 1, 2). There are few concepts and syndromes in Medicine and particularly in Gastroenterology which have gone through a similarly remarkable historical transformation as SIBO. The term first emerged in the literature more than 80 years ago and was a relatively rare diagnosis. However, the concept was adopted more recently by functional and integrative medicine practitioners, by the lay media and even the medical establishment and the pharmaceutical industry and has been promoted in social media as a diagnosis explaining some of the most common symptoms of abdominal discomfort. Unfortunately, it has led to the widespread and in my opinion unnecessary use of antibiotic treatments for symptoms most likely unrelated to gut microbes.

“…the diagnosis and overall conception of SIBO has become mired in uncertainty and controversy…”

SIBO is a clinical disorder that was first described in the 1930s in patients with serious symptoms of malabsorption, bloating, abdominal pain, and diarrhea, following surgical alterations of the gastrointestinal tract. However, since these early descriptions, the concept of SIBO has undergone significant change and challenges in light of emerging insights and speculations from studies into the gut microbiome. The diagnosis of SIBO which originally was limited to a small number of individuals with a specific medical history, has all of a sudden been given to a large number of patients complaining of such common, non-specific symptoms of abdominal bloating, sensations of gas and irregular bowel movements, and is now widely used as a seemingly plausible explanation for many IBS symptoms. However, as well summarized in a recent review article by Bushyhead and Quigley, the diagnosis and overall conception of SIBO has become mired in uncertainty and controversy, as there remains a lack of consensus or “gold standard” for diagnosis, an absence of causality to clearly link clinical symptoms to alterations in the gut microbiota (“dysbiosis”). In addition, the often-prescribed treatment with antibiotics is highly controversial.

To better understand the controversy, it is good to briefly review the role of our gut microbes residing in different parts of the intestinal tract. In a healthy individual, the number of microorganisms increases about tenfold from the beginning of the small intestine down to the large intestine. The majority of small intestinal microbes are thought to originate from the oral microbiome, and a small number migrating there from the large intestine. It has been suggested that such small bacterial counts ensure that the small bowel, our major site of digestion and absorption of nutrients and calories does not face competition for nutrients by the microbes following the ingestion of a meal. In contrast, in the more densely populated colon, typical the large number of bacteria accomplish many essential tasks, including the breakdown of large, unabsorbable molecules from ingested fiber and polyphenols (both contained in plant-based foods), and the transformation of these molecules into absorbable health promoting, anti-inflammatory and neuroactive substances, such as the short chain fatty acid butyrate and various phenolic compounds (reviewed extensively in The Gut Immune Connection).

“A healthy small bowel uses several different protective mechanisms – including concentrated hydrochloric acid produced by the stomach as well as bile and pancreatic secretions to suppress and kill many microbes entering from the mouth, preventing them from colonizing the small intestine and thereby keeping relatively low bacterial numbers.”

A healthy small bowel uses several different protective mechanisms – including concentrated hydrochloric acid produced by the stomach as well as bile and pancreatic secretions to suppress and kill many microbes entering from the mouth, preventing them from colonizing the small intestine and thereby keeping relatively low bacterial numbers. Importantly, several patterns of contractions of the small intestine, in particular the so-called migrating motor complex, a powerful wave of contractions that moves through the entire gut every 90 minutes when it is empty, make it difficult for large number of microbes to set foot in the small intestine, and greatly limit their growth. In addition, a particular valve between the end of the small intestine and the beginning of the colon prevents backward movement of colonic bacteria into the small intestine. However, under rare circumstances when pathologic microbial colonization of the small intestine does occur, it can result in a number of pathologic disturbances, including injury of the intestinal lining or malabsorption of carbohydrates. Given the variety of multiple, synergistic mechanisms preventing small bowel colonization with microbes summarized above, SIBO would be expected to be a rare condition, primarily appearing as a complication of chronic digestive disorders such as chronic pancreatitis, cirrhosis and rare disorders of intestinal motility and anatomic abnormalities.

“…there is currently no universally acknowledged or validated “gold standard” for diagnosis, and no FD-approved medications.”

Although there is no specific symptom of SIBO, patients given this diagnosis generally present with abdominal pain and distension, bloating, flatulence, and diarrhea, a nearly identical symptom complex as reported by IBS patients. Because these symptoms are neither exclusive to, nor predictive of SIBO, and SIBO is often treated with antibiotics, one would expect that such a diagnosis should only be made based on objective, generally accepted, and validated biological tests. However, despite recent advances in the scientific community’s understanding of the microbiome, there is currently no universally acknowledged or validated “gold standard” for diagnosis, and no FD-approved medications. Even though several tests are available and commonly used, including the direct analysis and quantification of small bowel microbiota and various breath tests measuring the production of hydrogen and methane by intestinal microbes, the validity of all these tests has been questioned and has generated substantial controversy. According to a North American Consensus Statement, such test results should be interpreted with caution.

Surprisingly, although there are no Food and Drug Administration–approved medications to treat SIBO, the mainstay of treatment has been oral antibiotics.

Given the well-known risks of antibiotic therapy – in particular when administered repeatedly- such as reduction of gut microbial diversity, the promotion of drug-resistant bacteria and the development of Clostridium difficile colitis, one would expect that data on the efficacy of antibiotics for SIBO should be unambiguous. Unfortunately, antibiotic regimens for SIBO have, in general, been poorly studied, largely in trials involving small numbers of patients and lack of placebo controls. For example, a systematic review and meta-analysis of rifaximin, a popular, nonabsorbable antibiotic, demonstrated that the overall eradication rate (based on the controversial breath tests mentioned above) was only about 70%. Importantly, the authors of the study noted that the quality of included studies was generally poor, as only a single study was placebo- controlled.

Other treatment modalities that may have a theoretic benefit in restoring healthy GI microbiota such as changes in diet, pro- and prebiotics and even fecal microbiota transplantation (FMT) have not been adequately studied for the treatment of SIBO. I will come back to the question of treatment at the end of this post.

“…the most problematic claim relating to the diagnosis of IBS has been its implication in the pathogenesis of IBS.”

As if the topic of SIBO is not controversial enough, the most problematic claim relating to this diagnosis has been its implication in the pathogenesis of IBS. An early study demonstrating both a higher prevalence of positive lactulose breath tests in patients with IBS (thought to reflect abnormal numbers of gut microbes in the small intestine) in comparison to healthy control subjects and significant improvement in IBS symptoms following normalization of breath tests with antibiotic therapy suggested a strong association between IBS and SIBO. However, a systematic review and meta-analysis of SIBO in IBS challenged the validity of this association. Although the pooled prevalence of a positive lactulose breath test in this review was 54%, the stricter criteria of a greater number of microbes (more than the 105 colony forming units/mL) found in a jejunal aspirate from IBS patients and culture was only 4% and not higher than controls, putting both the validity of the breath test as well as the diagnosis of SIBO into question. Significant problems in study design and reporting, as well as the possibility that a positive lactulose breath test may simply signify an abnormally fast transit time through the small intestine.

As there is some suggestion that the pathophysiology of IBS entails abnormal colonic rather than small bowel fermentation of complex carbohydrates, it is possible that the efficacy of antibiotic treatments in some IBS patients is due to an impact on colonic rather than small bowel bacterial populations (it is worth noting that a subgroup of IBS patients actually reports a worsening of their symptoms after antibiotic treatment). In view of the well demonstrated hypersensitivity of the colon to distension, even a small reduction of normal intestinal gas production could lead to some reduction in symptoms of bloating and gas. As the involvement and precise mode of action of rifaximin in SIBO remains poorly understood, it has been suggested that the effect of the drug on bacterial numbers may be minimal and effects may be related more to perturbations of bacterial metabolism. However, to date this remains a speculative hypothesis.

“…it is not possible to make any valid conclusions about a putative role of intestinal microbiota, SIBO and IBS”.

In summary, both the relationship between SIBO and altered intestinal gut microbial density, and the association between SIBO and IBS remains controversial. Whether current testing methods accurately reflect SIBO, and whether abnormal breath test results are causally related with IBS or IBS-like symptoms remains open to question. Because SIBO lacks a gold standard for diagnosis, and IBS is a diagnosis based on symptom criteria (the so-called Rome criteria) and of exclusion that lacks a validated biomarker, it is not possible to make any valid conclusions about a putative role of intestinal microbiota, SIBO and IBS. Future research focused on defining the normal small bowel microbiome with novel genomic and metabolomic technologies, and on the clinical utility of breath tests.

It shouldn’t come as a surprise to the readers of this post, that I have never made a diagnosis of SIBO in any of my patients, who did not have any of the established risk factors mentioned above, nor have I treated any IBS or IBS-like symptoms with antibiotics. My approach to patients is to take advantage of the gut’s own regulatory mechanisms, including a high fiber diet to assure normal transit of food through the small intestine, and the unique gut cleansing motility patterns (“migrating motor complex”) to keep a normal gradient of microbial density throughout the gut. You can read about this approach in the next email edition of Gut Health Insights.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

There Is More to Health and Longevity Than Diet Alone

By Emeran Mayer, MD

I had the pleasure to recently visit a good friend and prominent food scientist in Parma, Italy who is the Head of the School of Advanced Studies on Food and Nutrition, at the University of Parma. Besides his general interest in food science, Professor Daniele Del Rio is an internationally recognized expert in the field of polyphenol research.

After a lovely stroll through the old city of Parma, we had dinner at the Angiol D’Or restaurant, named after the golden angel on top of the cathedral’s bell tower close to restaurant. Over an appetizer of small chunks of Parmigiano cheese with some chestnut honey, Daniele and his wife Francesca explained to us that visitors generally come to Parma for two main reasons: to visit the birthplace of famous Italian composer Giuseppe Verdi (who is being celebrated with an annual festival of Verdi’s operas) and to experience Parma’s unique cuisine and food culture.

Thanks to its workshops, trattorias, food companies and restaurants, Parma, also known as the capital of Italy’s “Food Valley”, is the first Italian city proclaimed by UNESCO a “Creative City for gastronomy” for its unique abilities in gastronomy as the result of “tradition, talent and innovation”.

When it came to ordering our dinner, both my wife and I adhering to a traditional Mediterranean diet without red meat but rich in variety of vegetables and fresh fruit, had a hard time finding something on the extensive menu amongst all the ham and pork dishes that would meet our general criteria of the healthy Mediterranean diet. Following Daniele’s advice, we ordered two typical local pasta dishes, called Tortelli, and accompanied by sparkling Lambrusco wine. One of pasta dishes was called “Tortelli d’erbetta” (stuffed with white cheese and some greens) and “Tortelli di patate” (stuffed with mashed potatoes). Daniele explained that traditionally these dishes need to “drown” in butter and get wet in grated parmesan cheese to be delicious!! So much for our low animal fat mantra!

“The dinner was delicious but I found the dramatic difference of the food preferences in Parma, from the celebrated health promoting Mediterranean diet, intriguing, to say the least.”

We had a very similar experience the next evening (an incredibly busy Saturday night) in another restaurant and realized that everybody around us was enjoying primarily dishes of cured pork, pasta and parmesan cheese, three of the most popular food items in this region of Italy.

With all the epidemiological evidence for the superiority of the traditional Mediterranean diet in terms of reducing the risk of cardiovascular disease, cognitive decline, colon cancer and healthy longevity (reviewed in The Gut Immune Connection), I suspected that people in Parma and in the surrounding Emilia-Romagna region would be less healthy and have shorter lifespans than those living in other regions of Italy, like Tuscany or Apulia. On the other hand, I would expect to see comparable numbers in the health statistics when compared to the northern regions of Trentino and Alto Adige (South Tyrol), which have similar meat-rich dietary habits. However, as I learned from the literature, in terms of longevity, predominant dietary habits in the different Italian provinces don’t seem to make any significant difference, with numbers for average life expectancy at birth in 2019 varying insignificantly between 80.8 and 82.1 for men, and between 86.2 and 85.2 for women. Obviously, there are other well known factors that have an important influence on life expectancy, including meaningful social interactions and regular physical exercise.

“This observation wasn’t missed in the early scientific reports about the health benefits of the Mediterranean diet.”

Experiencing first hand how the entire city transformed in the evening into an amazing number of people strolling on the streets, and parks and outdoor restaurants being absorbed in animated and joyful conversations late into the night, was a dramatic demonstration of the power of such social interactions in everyday life in Parma (as well as in the rest of Italy). This observation wasn’t missed in the early scientific reports about the health benefits of the Mediterranean diet, which often mentioned these interactions as an integral part of the diet’s health benefits.

“In addition to the unique social life, the regular physical exercise associated with life in this city, is another well known factor contributing to healthy longevity.”

To get some objective assessment of the amount of exercise performed naturally by young people jogging and groups of middle aged individuals doing group exercises in the city park and by just about everybody pursuing their daily activities by walking rather than driving in cars, we checked the Health App on our iPhones after returning to our hotel in the evening. To our surprise we logged in between 10,000 and 15,000 steps or 4 to 5 miles a day without being on a treadmill or doing our regular daily hike at home!

Obviously none of our observations made during a few days in this wonderful Italian city can replace published scientific evidence. In my cursory review of the literature, I was unable to find solid evidence for regional differences in the rates of chronic non-communicable diseases such as cardiovascular, metabolic disorders, colon cancer or neurodegenerative diseases.

I looked up a publication by S. Toselli and colleagues from the Universities of Bologna and Ferrara about food habits and nutritional status of adolescents in the region of Emilia-Romagna which reported on survey and study results from nearly 600 male and female adolescents (11-14 years of age). They found that protein, carbohydrate and total fat intakes of the adolescents were higher than the recommended ranges in all age groups and in both sexes. Not surprisingly, the overweight and obese adolescents in the study population consumed less fiber than their normal weight and underweight counterparts.

In summary, my “field study” of the modern Italian diet in the city of Parma showed a significant deviation from the traditional, largely plant-based Mediterranean diet as first reported in the 1960s on the Greek island of Crete. The fact that this deviation didn’t have a significant effect on longevity emphasizes the important influence of other lifestyle factors, such as social interactions and regular physical exercise on health and longevity.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

How Do We Prevent the Next Pandemic?

By Emeran Mayer, MD

Even at a time when the world is still struggling to end the COVID-19 pandemic, many scientists and public health experts believe that future pandemics are unavoidable. At the same time, suggestions have been made how to prevent such a scenario and how to attenuate its impact when it occurs. The big question is, will these recommendations be implemented soon enough to prevent the next pandemic? Or will they go the path of increasingly urgent recommendations by politicians about climate change, without effective implementation?

The Harvard Global Health Institute and the Center for Climate, Health, and the Global Environment at Harvard T.H. Chan School of Public Health recently published a comprehensive report of the Scientific Task Force on Preventing Pandemics, which is “intended to serve as a scientifically sound reference for the many important discussions taking place globally about the steps needed to greatly reduce the chances of a future pandemic.

“…preventing another pandemic with the magnitude of COVID-19 should be on top of the priority list of every human concern.”

Considering the devastating widespread impact on human physical and mental health, as well as the world economy, preventing another pandemic with the magnitude of COVID-19 should be on top of the priority list for every human-being on this planet. According to the World Health Organization, a pandemic is, “an epidemic occurring worldwide, or over a very wide area, crossing international boundaries and usually affecting a large number of people.” Vaccines, drugs, tests, reducing vulnerabilities to severe forms of infection and strengthening of the healthcare system are all critical to contain disease outbreaks once they occur, and have had remarkable successes in these areas. In particular, widespread testing as well as rapidly developed and highly effective COVID-19 vaccines have greatly reduced the impact of the current pandemic.

Current evidence suggests that pre-existing conditions, like diseases that make up our current chronic non-communicable disease epidemic, not only increase the risk for COVID-19 infections, but also for a greater severity and long-term complications of the disease. As I have laid out in The Gut Immune Connection, healthy diets with anti-inflammatory effects on the gut’s immune system, attenuating its hyper-reactivity to the virus in the lungs and other organs, are not only able to reduce the prevalence of these pre-existing conditions, but may also be able to reduce the acute and long-term complications of COVID-19 .

“…most attention and financing to address future pandemics has been directed towards pandemic preparedness.”

To date, most attention and financing to address future pandemics has been directed towards pandemic preparedness. As critical as these actions are, they do not address the root cause of pandemic risk: the spillover of microorganisms, primarily viruses from animals to humans. Addressing this root cause leads directly to the implications of the One Health concept that I address in The Gut Immune Connection: the intricate connectedness between human and animal health, soil and plant health, and overall planetary health.

Spillover of the viruses currently understood to have pandemic potential occurs primarily from land use change. In particular the destruction of tropical forests (to make room for monocultures and expansion of agricultural lands), livestock and farmed wildlife intensification, and wild animal hunting and trade. The majority of these land use changes can be related to overpopulation, and the consequences of industrial agriculture, and preferences of food consumption (e.g., excessive consumption of animal products).

Interestingly, animals associated with zoonotic viruses (an infectious disease that is transmitted between species from animals to humans) have been less likely to be threatened with extinction and more resilient to human impacts such as land use change, pollution, and to invasive species, gradually increasing infection risk. Among threatened wildlife species, those with population reductions owing to exploitation and loss of habitat may be more likely to share viruses with humans. Furthermore, more abundant and generalist microbial species that adapt to humanized environments generally have more opportunity for contact with livestock and people.

“The increasing ratio between domesticated animals and wild animals is therefore directly related to an increase in spillover risk.”

Similar to the findings of spillover in wild animals, the number of viruses shared between domesticated animals and humans scales with livestock abundance. Domesticated animals also share more zoonotic viruses with humans than those known at present in wild animals. As the ratio between domesticated and wild animals has dramatically increased during the last 50 years, significantly increasing our chances of another pandemic. According to a study published in Proceedings of the National Academy of Sciences, domesticated livestock, mostly cows and pigs, account for 60 percent, and wild mammals for only 4 percent of overall animal populations. The same holds true for birds, mainly chickens. The biomass of poultry is about three times higher than that of wild birds.

The need to consider actions that prevent spillover as a key objective in pandemic prevention has been underscored by the difficulties in containing COVID-19. Even with the unprecedented short interval between disease emergence and the availability of vaccines as well as rapid and effective testing, the disease continues to spread, aided by the evolution of variants that are more contagious. More so, political divisions that prevent the implication of scientifically proven intervention, and the spread of misinformation by politicians and through the internet don’t help the situation at hand.

“…reliance on post-spillover interventions must be considered in light of rapid global loss of biological diversity and an unstable climate…”

The report further emphasizes that reliance on post-spillover interventions must be considered in light of rapid global loss of biological diversity and an unstable climate, which has the potential to greatly worsen the current situation. The fact that human activity has reduced the biomass of wild marine and terrestrial mammals by six times and the biomass of plant matter by half by dramatically changing land use and agricultural practices, illustrates the magnitude of the problem.

“…forest conservation, dramatic changes in food production and global dietary habits offer the potential to reduce pandemic risk…”

Vaccines, drugs, and tests neither buffer against these drivers of infectious disease emergence, nor do they address their potential to damage human health and welfare more broadly. However, actions directed at the root causes of spillover prevention, such as forest conservation, dramatic changes in food production and global dietary habits offer the potential to reduce pandemic risk, avoid more expenditures on post-spillover containment, and reduce damages from climate change.

The urgency of these measures was emphasized in the specific recommendations made in January 2019 by the EAT Lancet Commission. As expressed by one of the co-chairs of the commission: “Global food production threatens climate stability and ecosystem resilience. It constitutes the single largest driver of environmental degradation and transgression of planetary boundaries. Taken together the outcome is dire.” Recurrent pandemics represent one of these dire outcomes.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Do We Really Need to Boost Our Immunity?

By Emeran Mayer, MD

As the COVID-19 pandemic has engulfed the world, there has never been a time in which topics like Gut Health, Immune Support, Gut Cleansing, and Improvement of Gut Health have been more popular. Suddenly experts from the fields of functional and integrative medicine, nutrition and wellness have all jumped on this new trend. Podcast, master classes, social media posts and advertisements, bestselling books have all driven the frenzy around these topics, while scientific evidence from well controlled human studies have lagged behind.

As a clinician and scientist who has studied the gut, its endocrine, nervous and immune systems, and the brain for the better part of my career, it is remarkable to follow this explosion of information and interest.

In this edition of the Gut Health Insights, I start with one of the main topics of discussion, the Immune System, and will continue in future editions with Gut Cleansing, Leaky Gut, SIBO and Gut Health in general.

The great majority of advice that lay audiences get from books and the experts on social media, implies that we need interventions to boost our immune system, implying that there is a blunted, inadequate, or compromised response of the immune system contributing to many of our chronic health problems, ranging from autoimmune diseases and allergies to colon cancer and Parkinson’s disease, and including the COVID-19 epidemic. However, looking at the science, it becomes quickly apparent, that nothing could be more wrong.

As I explain in great detail in The Gut Immune Connection, a maladaptive increase in the engagement of the immune system in response to diet-induced changes in the gut microbiome does play a crucial role in most of the disorders making up our chronic non-communicable disease (CNCD) epidemic. The exaggerated, inadequately restrained response of the gut associated immune system is not only responsible for the number of autoimmune disorders (including inflammatory bowel disorders and celiac disease), allergies (asthma, food allergies) but also for the CNCDs, all of which have been increasing during the past 75 years.

Even though there are different immune mechanisms underlying these different groups of disorders, they all share one mechanism, which is the compromised ability of the immune system to turn on the breaks once activated. An important factor in these compromised breaking mechanisms is related to an inadequate production of short chain fatty acids by the gut microbiota, and the resulting insufficient activation of a group of immune cells that produce a powerful anti-inflammatory molecule call interleukin 10, or IL-10. This insufficient production of the immune system’s own powerful anti-inflammatory molecule can occur long before we are born or can develop later in life.

Let’s start with what happens during pregnancy. An important component of the maternal influence on the infant’s microbiome and immune system are short chain fatty acids (SCFAs), derived from the fermentation of dietary fiber by intestinal microbes in the mother’s gut. The amounts and types of SCFAs that are produced there and transferred to her baby depend on the maternal microbial ecosystem, which in turn is shaped by her diet. As discussed in detail in The Gut Immune Connection, when pregnant women eat a largely plant-based diet rich in fiber or Microbe Accessible Carbohydrates(MACs), SCFA-producing microbes thrive, and increased amounts of SCFAs, in particular butyrate not only have an anti-inflammatory effect on the mother’s gut and body but are transferred to the developing fetus as well. Recent research suggests that SCFAs not only control inflammation but influence the maturation and reactivity of the fetal immune system. Specifically, they stimulate the development of a population of immune cells (regulatory T cells, or Tregs), which produce anti-inflammatory molecules (in particular the cytokine IL-10) crucial for the prevention of inappropriate immune activation in the gut, leading to autoimmune diseases and allergic reactions.

In the adult, diet-induced short chain fatty acid production exerts an anti-inflammatory effect in the context of a leaky gut, reducing both the inappropriate immune activation in the gut, but also preventing the distal effect of metabolic endotoxemia on other organs.

As explained in a previous article from this newsletter, reduced butyrate and SCFA production, leading to a hyperresponsiveness of the immune system may also play a role in the greater susceptibility and graver outcomes in patients with COVID-19 infections. Individuals with NCNDs are more vulnerable to the infection, and hyperreactivity of the immune system (cytokine storm) has been associated with more severe symptoms. On the other hand, patients on immunosuppressive medications have NOT been found to be more susceptible to the virus.

In summary, our bodies generate their own immune support, as long as we feed our microbes a healthy diet full of fiber and other large molecules which act as prebiotics for our gut microbes. There is no scientific evidence that additional “immune support” or boosting of our immune system in the form of all kind of supplements is needed.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Can We Rejuvenate Our Brain Through a Fecal Microbial Transplant From a Young Individual?

By Emeran Mayer, MD

While the gut microbiota has been implicated as an important regulator of host immunity, brain health and healthy aging, and age-related changes in the gut microbiome have been linked to cognitive decline and frailty in elderly populations (discussed in detail in The Gut Immune Connection), there is limited evidence for a causal role of the gut microbiota in brain health during the aging process, or for an understanding of the molecular mechanisms involved in it.

“…transplantation of the fecal microbiome from young animals was successful in altering the microbial community structure of the microbiome from older animals.”

In a recent study published in the prestigious journal Nature Aging by lead author Marcus Boehme from the University College Cork, Cork Ireland, the investigators did a comprehensive study in mice to determine if the gut microbiome plays a role in age-related biological, and behavioral changes, and tried to identify the underlying mechanisms. As such experiments are nearly impossible to perform in human subjects, the investigators transplanted fecal microbiota from either young (age 3–4 months) or old (age 19–20 months) donor mice into aged recipient mice (age 19–20 months). While they found clear differences between young and aged mice in the diversity of microbes before the fecal microbial transplant (FMT), they detected no differences between the number of microbial groups gained or lost between the groups following FMT. However, following FMT, the baseline differences in diversity were no longer significant, e.g. old and young gut microbiota looked the same. his “equalization” involved twenty genera which transitioned in the old mouse microbiome towards young mouse abundance following FMT, including the genus Enterococcus. These findings confirmed that the transplantation of the fecal microbiome from young animals was successful in altering the community structure of the microbiome from older animals.

“…the successful transplantation of the microbiota from young donors not only changed several gut microbiota, but it reversed aging-associated differences in peripheral and brain immunity…”

Remarkably, the successful transplantation of the microbiota from young donors not only changed several gut microbiota, but it reversed aging-associated differences in peripheral and brain immunity, as well as the expression of metabolites and signaling molecules in the hippocampus, a key brain region involved in memory, of aging recipient mice. Structural and functional changes in the hippocampus has previously been identified in human patients with Alzheimer’s disease. As previously demonstrated, aging induced significant differences in hippocampal metabolites, and 35 metabolites of such age-related molecules were restored towards pre-aged levels by FMT from young mouse donors.

Specific aspects of gut-associated, circulating and hippocampal immunity were restored following FMT from young into aged mice, suggesting that this intervention drove restorations in immune functions. Alterations in these immune functions may underlie improvements in age-associated cognitive deficits which coincided with the improvements in behavior. The authors hypothesized that FMT- induced gut microbiota-derived signaling molecules may play a role in the alteration in hippocampal physiology through indirect or direct mechanisms, as several of the metabolites they identify are able to cross the blood–brain barrier.

“…microbiota derived from young donor mice attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host.”

To identify the mechanisms underlying hippocampal changes following FMT, the authors characterized microglial cells, the brain’s resident immune cells, in the hippocampus. Microglia are essential for regulating cellular aspects of cognition, supporting neuroplasticity and responding to various signals, including inflammatory cytokines. Higher populations of activated microglia, distinguished by enlarged somas, are prominent in neuroinflammatory and neurodegenerative conditions. Aged mice showed substantial enlargement in microglia cell size, consistent with the observed metabolic and immunological changes. This morphological abnormality was reversed by FMT from young donors without other changes in microglia complexity and morphology. At a functional level, the microbiota derived from young donor mice attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host.

Based on their fascinating results, the authors concluded that the microbiome may be a potential therapeutic target to promote healthy aging, opening up a new way to the development of new anti-aging medications. At the same time, the need for future studies was emphasized to elucidate how specific gut microbes drive these changes in “rejuvenating” the aging gut brain axis.

“Many factors have been implicated to explain the “lost in translation” phenomenon…”

However, before jumping to the premature conclusion that the findings of this study may be translatable to patients suffering from Alzheimer’s disease and early cognitive decline any time soon, it is important to remember that there are many stellar preclinical scientific publications demonstrating the ability to change emotional, social and cognitive behavioral traits by transplanting fecal material into germ free mice, the majority of which have failed attempts to translate them into clinical meaningful treatments for human populations. Many factors have been implicated to explain this “lost in translation” phenomenon, including (but not limited to) the dramatic brain differences between mice and men, the much greater genetic and phenotypic heterogeneity in humans and the problem of colonization resistance of the gut microbiome, which generally does not allow transplanted gut microbes to permanently settle inside the gut microbial ecosystem of another host.

While it is possible that science will ultimately identify microbial neuroactive metabolites that will slow and possibly even reverse the aging process of the brain, at the moment, the much more realistic and evidence-based approach to achieve the same goal is with lifestyle changes, in particular by focusing on microbiome-friendly anti-inflammatory diets. Evidence for such beneficial diet-related interventions has been discussed in previous editions of the MGC newsletter, and is summarized in The Gut Immune Connection. While rejuvenating microbiome transplants are a fascinating idea, and the impressive scientific evidence laid out in this publication supports their feasibility, their potential usefulness remains limited to mice!


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

The Crucial Role of Diet in Colorectal Cancer Risk

By Emeran Mayer, MD

“Colorectal cancer (CRC) is the second leading cause of cancer death in the Western world.”

Colorectal cancer (CRC) is the second leading cause of cancer death in the Western world. It afflicts 150,000 Americans, 250,000 Europeans and 1 million people worldwide annually, and nearly one third of affected individuals will die.1 The global burden of CRC is expected to increase to more than 2.2 million new cases and 1.1 million annual cancer deaths by 2030.2  Rather than taking a closer look at the root cause of this problem and implement interventions to reverse this trend, the response of the medical system has been the promotion of colon cancer screening without paying much attention to the role of life style factors that have dramatically changed in the past 75 years, in particular dietary changes.  There is no question that screening colonoscopy has permitted early detection and recent studies have clearly shown that this early detection is associated with a reduction in mortality rates. Screening colonoscopy has also given a dramatic boost to the income of hospital systems and gastroenterologists charged with performing these additional procedures.  However, the overall impact of colon cancer screening has been small, particularly among African Americans who shoulder the greatest burden of the disease in the United States.  When I recently asked an expert on colon cancer screening if individual dietary habits are considered as a risk factor to determine how closely individuals with a positive finding on a screening colonoscopy have to be followed, the surprising answer was “this would be a great idea”.

“CRC incidence has been on the rise among young adults aged 20 to 39 years since the mid-1980s”

Despite the success of colon cancer screening in older patients, in many industrialized countries, the burden of CRC is rapidly shifting to younger individuals, a trend seen for several other non-communicable chronic diseases as well.3, 4, 5 In the United States, despite declines in older individuals, the incidence has been increasing in young and middle-aged adults with 22% of CRC cases occurring in those younger than 55 years in 2013 to 2017.6 CRC incidence has been on the rise among young adults aged 20 to 39 years since the mid-1980s, and this elevated risk in generations born in the US after 1950 strongly indicates that widespread changes in early-life exposures, such as diet and lifestyle factors, may explain the upward trend in early-onset CRC.7,8

“Colon cancer shows all the hallmarks of a number of diseases that make up the current epidemic of non-communicable chronic diseases  affecting all organs…”

As I have explained in The Gut Immune Connection, colon cancer shows all the hallmarks of a number of diseases that make up the current epidemic of non-communicable chronic diseases  affecting all organs in our body and presenting as such different medical problems as cardiovascular disorders, non-alcoholic fatty liver disease, type 2 diabetes, metabolic syndrome, obesity, autism spectrum disorder and depression, and neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. These various diseases are not only connected with each other (e.g. the presence of one diagnosis often increases the risk for another), but they share the disease mechanism of low grade systemic immune system activation, occur at increasingly younger age groups, and in developing countries, and are strongly related to dietary habits and other lifestyle factors, including increased exposure to chemicals and certain medications. For example, studies in Japanese Hawaiians, have demonstrated that it only takes one generation for the immigrant population to assume the colon cancer incidence of the host country (e.g., the US), with adoption of the Western diet playing a major role.9

“…diet-induced changes in the interactions between the gut microbiome and the gut-associated immune system are a key mechanism in the current disease epidemic.”

Reviewing the current evidence, I have concluded that diet-induced changes in the interactions between the gut microbiome and the gut-associated immune system are a key mechanism in the current disease epidemic.  It is becoming increasingly clear that one dietary pattern in particular, the Standard American Diet (SAD) contains many of the components responsible for the negative health effects:  High consumption of ultra-processed foods, refined sugars, and animal products (red meat and animal fats), greatly reduced consumption of variable fruits and vegetables containing fiber and polyphenols, and a low consumption of naturally fermented foods.

A body of evidence suggests that the relationship between the SAD and colon cancer risk is multifactorial, in other words different dietary components play a role, in addition to genetic predisposition and exposure to environmental toxin. A study published by Stephen J.D. O’Keefe and colleagues in the journal Nature Communications in 2015 compared the effect of diet on colon cancer risk in African Americans and rural South Africans to explore the hypothesis that colon cancer risk is determined by dietary influences on the production of microbial metabolites which can decrease (anti-neoplastic) or increase (pro-neoplastic) colon cancer risk.

“…two potential mechanisms for diet-associated CRC risk: the protective effect of dietary fiber in increasing the production of the anti-inflammatory and anti-neoplastic short chain fatty and the cancer promoting effect of animal fat.”

As expected and confirming previous studies, the diets eaten by the two groups were fundamentally different in preparation, cooking and composition. Animal protein and fat intake was two to three times higher in Americans, whereas carbohydrate and fiber, chiefly in the form of resistant starch, were higher in Africans. On colonoscopy, African Americans had more polyps and higher rates of mucosal growth, considered precursors of colon cancer. These differences were shown to be associated with profound differences in the prevalence of microbial taxa: In Americans the microbial group Bacteroides dominated while in Africans Prevotella was the predominant taxa.  Notable differences included higher levels of microbial taxa that are able to break down starch, ferment carbohydrates and produce the short chain fatty acid butyrate in Africans, and higher levels of microbes able to produce potentially harmful metabolites, including secondary bile acids in Americans. These findings suggested two potential mechanisms for diet-associated cancer risk: the protective effect of dietary fiber in increasing the production of the anti-inflammatory and anti-neoplastic short chain fatty acid butyrate, and the cancer promoting effect of animal fat on stimulating bile acid synthesis by the liver, thereby increasing gut microbial production of carcinogenic secondary bile acids.

“Between 1965 and 1996, SSB intake among US adolescents more than doubled”

But a high consumption of animal products (red meat, animal fat, dairy and eggs), and a reduction in the intake of dietary fiber are not the only dietary factors that play a role in colon cancer risk as pointed out by a recent study led by Jinhee Hur and published in the journal Gut. This study focused on the high consumption of sugar in the form of sugar-sweetened beverages (SSB), particularly amongst adolescents and young adults. Incidence of early-onset colorectal cancer diagnosed under age 50 years has been on the rise in the US and many high-income countries over the past two decades.

Simple sugar, especially added fructose intake has steeply increased in recent decades largely due to the marked increase in SSB intake.10, 11 SBs (carbonated and noncarbonated soft drinks, fruit drinks, and sports drinks) are mostly sweetened with high-fructose corn syrup (usually 55% fructose and 45% glucose) or sucrose (half fructose and half glucose).12 In the United States, hidden sugar availability has risen dramatically since the 1950s – in beverages, sauces, salad dressings, baked beans, canned foods teriyaki and ketchup – paralleled by the rise of industrial agriculture with federally subsidized production of corn.

Between 1965 and 1996, SSB intake among US adolescents more than doubled (per capita g/d: boys 364 to 1046, girls 303 to 678).13 Compared with other age groups, adolescents had the highest SSB intake with approximately 10% of daily calories from SSBs in 2011 to 2014.  SSB consumption is also rapidly increasing worldwide, particularly in developing countries. In 53 low- and middle-income countries, 54% of adolescents consumed carbonated soft drinks at least once per day in 2009 to 2013.14, 15,16 A Mexican colleague told me at a medical conference that former president of Mexico and CEO of Coca Cola Mexico recommended Coke as a calming remedy for infants!

It had previously been known that the consumption of sugar-sweetened beverages can exert adverse metabolic repercussions throughout the course of life, including childhood and adulthood obesity and type 2 diabetes.  However, despite the highest level of sugary drink consumption being characterized among adolescents and young adults, the association between sugar consumption by this age group and early onset colon cancer had not been investigated.

The authors of the Gut manuscript used data from the Nurses’ Health Study II (1991–2015), to prospectively study the association of SSB intake in adulthood and adolescence with early onset CRC risk among 95,464 women who had reported adulthood beverage intake using validated food frequency questionnaires every 4 years. A subset of 41,272 participants reported beverage intake at age 13–18 years using a validated high school-FFQ in 1998.

“…each serving/day increment of SSB intake at age 13–18 years was associated with a 32% higher risk of early onset CRC.”

The authors identified 109 cases of early onset CRC in their study population.  Compared with <1 serving/week of SSB consumption, higher intake (i.e., ≥2 servings/day) in adulthood was associated with a 2.2-fold higher risk of EO-CRC. Amazingly, each serving/day increment of SSB intake at age 13–18 years was associated with a 32%

higher risk of early onset-CRC!

The take home message from these two studies is pretty clear.  CRC, in particular CRC in younger age groups is significantly related to key features of the Standard American diet, making it another striking example of the non-communicable chronic disease epidemic.   Policy makers might consider a reevaluation of subsidies to sugar producing agrobusinesses (e.g., heavily subsidized corn production), while intensifying public education of children and pregnant mothers about the negative health consequences of sugar consumption (as well as other aspects of the Standard American diet).  Such major policy changes may prevent that in 10 years from now, another lowering of the threshold for colon cancer screening to individuals in their 30s may be required.

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  15. Malik VS, Hu FB. Sugar-sweetened beverages and cardiometabolic health: an update of the evidence. Nutrients 2019;11:1840.
  16. Yang L, Bovet P, Liu Y, et al. Consumption of carbonated soft drinks among young adolescents aged 12 to 15 years in 53 low- and middle-income countries. Am J Public Health 2017;107:1095–1100.

Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

The Synergistic Health Benefits of High Fiber and Fermented Foods

“The chronic disease epidemic in industrialized societies has been paralleled by the rapid ‘‘westernization’’ of the microbiota in developing countries.”

There is growing consensus that the epidemic of non-communicable chronic diseases, including metabolic syndrome, cardiovascular disease, Parkinson and Alzheimer disease and colon cancer are largely driven by chronic systemic immune activation. The epidemic has gradually unfolded during the past 75 years with accelerating industrialization affecting food production and processing, and dramatically changing lifestyles. As I have discussed in detail in The Gut Immune Connection, while an increasing percentage of the US population has gotten sicker from these diseases, the enormous healthcare expenditures thrown at these problems in the form of colon cancer screening, coronary bypass surgery, blood pressure and cholesterol medications is keeping people alive and functional and has even led to an increase in life expectancy. The chronic disease epidemic in industrialized societies has been paralleled by the rapid ‘‘westernization’’ of the microbiota in developing countries and in US immigrants coming from other parts of the world, with reduction and loss of microbial functions and taxa accompanied by deteriorating, markers of host health, obesity and rising inflammatory markers typical in industrialized populations.

Changes in dietary habits, in particular a reduction in the ratio between plant-based (a variety of fresh fruits and vegetables) and animal-based (meat, dairy, and eggs) paralleled by a decrease in the consumption of dietary fiber, and an increase in the amount of ultra-processed foods with high sugar/low fiber content and chemical additives have been identified as a major factor in these global changes in health. In addition to the low consumption of fermented foods, the decrease in the amount and variety of dietary fiber (referred to as microbiota-accessible carbohydrates (MACs)) in the diet has generally been considered an important cause of the decrease in diversity and richness of the gut microbiota, and even the loss of certain taxa.

“While there has been a significant increase in the popularity of probiotic supplements and pills, the consumption of a wide variety of fermented foods has been lagging behind.”

Another less often mentioned aspect of the standard American diet (SAD) when compared to Asian or European diets is the limited consumption of naturally fermented foods, such as fermented dairy products, Kimchi, Kombucha or Sauerkraut which contain microorganisms often – and falsely referred to as probiotics. Fermented foods are those made through colonization of food components with microbes and resulting enzymatic conversion. Live microbes present in traditional fermented foods and beverages such as kombucha, yogurt, kefir, sauerkraut, kimchi, and many pickled foods typically do not meet the required evidence level for probiotics (“live microorganisms which when administered in adequate amounts confer a health benefit on the host”). While there has been a significant and continuing increase in the popularity of probiotic supplements and pills, the consumption of a wide variety of fermented foods as part of the regular American diet has been lagging.

In view of our incomplete understanding of the complexity of the gut microbiome and the absence of specific non-dietary interventions as treatment options for the most common chronic diseases, the integration of the gut microbiota into human biology, and dietary manipulation of gut microbes has the potential to improve many aspects of human health. Despite growing promotion in the media and by functional medicine practitioners of “anti-inflammatory diets”, a key question for scientists is whether diets that target the gut microbiome by increasing its diversity and richness can attenuate systemic inflammation in healthy individuals (not only in cells or mouse models) and reduce the prevalence of some of our most common diseases. Another question is whether there are broad, non-personalized dietary recommendations based on microbiota-host interactions for improved health across populations.

“…the study aimed to determine what role a diet high in fiber compared to a diet high in fermented foods play in gut microbial composition and function, as well as in the presence of systemic inflammatory markers.”

I have recently reviewed the pivotal study from the Sonnenburg Lab at Stanford University (Wastyk et al. Cell 2021;184:1-17) which was published the prestigious scientific journal Cell. They reported results from a well-designed study that aimed to determine what role a diet high in fiber compared to a diet high in fermented foods play in gut microbial composition and function, as well as in the presence of systemic inflammatory markers.

The investigators used a 17-week randomized, prospective study (18 participants per study arm) combined with measurement of many microbiome parameters and inflammatory markers in the blood to identify diet-specific effects. Blood and stool samples were collected longitudinally along a 3-week baseline period, followed by a 4- week ramp up phase during which participants gradually increased intake of their respective diets, then a 6-week maintenance phase where they maintained a high level of consumption of either fiber or fermented foods, and finally a 4-week “choice” period where they could maintain their respective diet to their desired extent. While participants’ gut microbiota at baseline did not differ between the two arms, both groups successfully increased their consumption of fiber or fermented foods respectively.

Fiber-rich foods were categorized into fruits, vegetables, legumes, grains, nuts and seeds, and other, and total fiber consumption increased from an average of 21.5 ± 8.0 g per day at baseline to 45.1 ± 10.7 g per day at the end of maintenance phase. (The American Heart Association recommends a daily fiber intake of 25-30 g/day, while the actual intake among adults in the United States averages a mere 15 grams a day). Fermented foods were grouped into yogurt, kefir, fermented cottage cheese, fermented vegetables, vegetable brine drinks, kombucha, other fermented non-alcoholic drinks, and other foods and total fermented food consumption increased from 0.4 to 6.0 servings per day.

“The high fiber diet did not increase microbial community diversity and richness, and even more surprising, inflammatory markers in the high fiber group on average remained unchanged.”

There is extensive preclinical and clinical evidence that a fiber rich diet is associated with increased gut microbial richness and diversity, in particular of microorganisms that have the enzymes to break down complex carbohydrates or MACs into short chain fatty acids, in particular butyrate (Sonnenburg ED and Sonnenburg JL. Cell Metab 2014;20:779-86). Butyrate has anti-inflammatory effects mediated by specific receptors on cells in the gut-associated immune and endocrine systems and throughout the body. As expected, the high fiber diet shifted the MAC-processing capacity and metabolic output of the microbiota, as reflected by the increase in these microbiota-produced fiber metabolizing enzymes. However, surprisingly, the increase in fiber metabolizing enzymes was not paralleled by an overall increase microbial community diversity and richness, and even more surprising, a battery of inflammatory markers in the high fiber group on average remained unchanged. However, the study identified subgroups of individuals based on their baseline, pre-study microbiome composition, and these subgroups included two low inflammation and one high inflammation cluster. The low inflammation group showed higher microbial diversity compared to the high inflammation group, as well as greater prevalence of beneficial microbes including Coprococcus, Ruminococcus and Anaerostipes, whereas Akkermansia was enriched in the high inflammation cluster. These findings were consistent with an earlier study which demonstrated that a dietary intervention of increasing soluble fiber, was less effective in reducing markers of systemic inflammation in individuals with lower microbiome richness. In other words, if you don’t have the required microbes to break down the fiber molecules into beneficial metabolites, the benefits of a plant-based diet may be less than if you start out with a diverse population of microbes.

“… the observed increased diversity in the fermented food group likely involved gut ecosystem remodeling rather than an immediate reflection of consumed quantities of microorganisms.”

On the other hand, the high-fermented-food diet steadily increased microbiota diversity and decreased systemic levels of inflammatory markers. Interestingly, the observed increase in microbiota diversity in the high-fermented-food-diet arm was not primarily due to the microbes consumed with the fermented food (as is commonly assumed), but rather a result of shifts in or even new additions to the existing microbial ecosystem. These findings suggest that the regular consumption of fermented foods has an indirect effect on microbiota diversity and different from the effects of fiber, apparently overcoming the colonization resistance of the microbial ecosystem and rendering it receptive to the incorporation or increased representation of previously undetected strains within the gut. Remarkably, and contrary to the well-known observation that ingested probiotic supplements disappear from the gut within 48 hours after stopping the probiotic pill intake, this diversity increase was sustained during the study period when participants were allowed to choose the number of fermented foods (“choice” period), when fermented food intake was higher than baseline but lower than at the end of maintenance. These findings strongly suggest that increased diversity likely involved gut ecosystem remodeling rather than an immediate reflection of consumed quantities of microorganisms contained in the fermented food diet.

“As fermentation of food has been practiced for tens of thousands of years, consuming fermented foods may offer an effective way to reintroduce evolutionarily important interactions between the gut and its microbiome.”

Fermented foods which have been a regular component of diets in most parts of the world (kombucha, fermented dairy products, kimchi, and Sauerkraut) have only recently gained popularity in the US as reports of potential health benefits in animal models and humans have emerged (Dimidi et al., 2019; Villarreal-Soto et al., 2020). Several studies have linked the consumption of fermented foods with weight maintenance and decreased risk for non-communicable chronic diseases. A recent longitudinal study of a subset of American Gut Project participants found differences in microbiota composition and fecal metabolome among fermented food consumers versus non-consumers (Taylor et al., 2020). As fermentation of food has been practiced to conserve food for tens of thousands of years, giving our human genes sufficient time to adapt to fermentation-associated microbes, consuming fermented foods may offer an effective way to reintroduce evolutionarily important interactions between the gut and its microbiome.

Before making premature conclusions about the relative health benefits of a fermented food-rich diet over a fiber-rich diet, several potential limitations of the study need to be considered. Importantly, high-fiber consumption did appear to increase stool microbial carbohydrate-degrading capacity, and altered short chain fatty acid production, indicating that fiber induced microbiome remodeling and change in function was occurring within the study time frame, but this was not accomplished through an increase in gut microbial composition. The study did not contain a control group without any dietary intervention, and the number of participants in each study arm was limited. Furthermore, participants in the high fiber group started out with a higher average fiber consumption than the US population. The two study groups may have differed in other factors that are known to influence the gut microbiome, such as physical exercise, stress and emotional factors and sleep.

Furthermore, there appear to be subsets of individuals with a unique gut microbial composition which respond differently to a high fiber diet intervention. As suggested by the authors, it is possible that the relatively short duration of the study was not sufficient to allow for the recruitment of new taxa to the microbiota in the high fiber diet group, which could be an indication that exposure to new microbes was limited within the urban environment of participants, due to increased hygiene, less exposure to microbes from soil and animals, and limited sharing of microbes between individuals. Fiber-induced microbiota diversity increases may be a slower process than fermented food induced increases, requiring longer than the 6 weeks of sustained high consumption achieved in this study.

“What are the conclusions of this and previous studies for the health-conscious consumer?”

What are the conclusions of this and previous studies for the health-conscious consumer, navigating through the jungle of recommendations for the most effective “anti-inflammatory” diet and the best cocktail of probiotic supplements?

  1. A regular diet high in a variety of plant-based and in fermented foods is optimal for the health of the gut microbiome, a reduction of systemic immune activation and a reduction of some of the most common chronic diseases.
  2. An increase in the regular intake of a variety of fermented foods has a rapid and persistent beneficial effect on the health of the gut microbiome and on systemic immune function.
  3. It is conceivable that the combination of a diet rich in fermented foods (causing persistent increases in richness and diversity), with a diet rich in varied plant-based products (increasing MAC production) results in a synergistic effect on reducing systemic immune activation.
  4. Consuming your cocktail of pro and prebiotic supplements while consuming the Standard American Diet, depleted in fiber and fermented foods, is unlikely to give you the health benefits that you strive for, while the addition of evidence-based pre and probiotic supplements to a healthy largely plant-based diet, may be the best way to improve your gut microbiome and reduce systemic inflammation.

* This post was originally published on July 27, 2021 and has been updated with new information.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

How to Reach 100 Years of Age Without Cognitive Decline

By Emeran Mayer, MD

Two recent articles in the New York Times addressed the topic of Alzheimer’s disease (AD), one based on a recent scientific publication that showed resilience and resistance to develop cognitive decline in centenarians, the other one addressing the recent controversial FDA approval of a new AD drug.

Fewer than 1 percent of Americans reach the age of 100, and new data from a recent clinical trial led by Dr. Henne Holstege at Vrije University in Amsterdam and reported in JAMA Network Open in January 2021 showed that these “super-agers” can reach their high age without significantly compromised cognitive decline.

As described by in Jane E. Brody’s NYT article, the JAMA study reported results from 340 Dutch cognitively healthy centenarians living independently at the time of enrollment. The 79 participants who neither died nor dropped out of the study returned for repeated cognitive testing, over an average follow-up of 19 months. The authors reported that these participants experienced no decline in major cognitive measures, except for a slight loss in memory function. Basically, the participants performed as if they were 30 years younger in overall cognition; ability to make decisions and plans and execute them, and not getting lost when they left home. Study results showed that the individuals who achieved that milestone with their mental faculties still intact are likely to remain so for their remaining years. Nearly a third of the participants agreed to donate their brains after death. Brain autopsies of 44 of the original centenarians revealed that many had substantial neuropathology common to people with and considered a biomarker of the disease, although they had remained cognitively healthy for up to four years beyond 100.

While cognitively healthy centenarians remain an exception at this point, about six million people in the United States and roughly 30 million globally have Alzheimer’s, a number expected to double by 2050. The estimated total healthcare costs for the treatment of Alzheimer disease in 2020 was estimated at $305 billion, and the cost is expected to increase to more than $1 trillion as the population ages. Like in many of the diseases making up our current healthcare crisis of non-infectious diseases, there are currently no medications that can prevent or stop the progression of AD, even though five medications approved in the United States can delay cognitive decline for several months in various Alzheimer’s stages.

The Holstege study in JAMA study contradicts the often-expressed view that the prevalence of AD will necessarily go up because of people reaching higher ages. Based on observational data, it is likely that one day a majority of people who are physically able to reach 100, may also be able to remain mentally healthy and be resilient to develop AD symptoms. Multiple studies in centenarians have revealed that a variety of lifestyle factors may contribute not only to AD resilience, but also to several other chronic mental or cardiovascular diseases among them moderate daily exercise, consuming a Mediterranean-style diet and socializing with other people.

Dr. Thomas T. Perls, a geriatrician at Boston University who directs the New England Centenarian Study said in an editorial that the Dutch participants represented a selected group of centenarians who were able to avert the onset of AD by at least 20 to 30 years. According to Perls, they seemed to be either resistant to the disease or cognitively resilient, somehow able to ward off manifestations of its brain-damaging effects. According to Perls, resistance may reflect a relative absence of brain damage conferred by a person’s genes or lifestyle. He states, they may have “protective biological mechanisms that slow brain aging and prevent clinical illness”.

In Brody’s NYT piece, Dr. Perls was quoted as saying, “Alzheimer’s disease is not an inevitable result of aging. Those genetically predisposed can markedly delay it or show no evidence of it before they die by doing the things we know are healthful: exercising regularly, maintaining a healthy weight, not smoking, minimizing red meat in the diet, and doing things that are cognitively new and challenging to the brain, like learning a new language or a musical instrument.”

As I have discussed in detail in my book The Gut Immune Connection, these lifestyles factors are associated with a reduction of low grade systemic immune activation, originating in the gut associated immune system and spreading throughout the body, including the brain. Dietary interventions with a traditional Mediterranean type diet have shown a slowing of early cognitive decline which was associated with changes in the gut microbiome, and reduced measures of systemic inflammation.

While there is extensive epidemiological and clinical study evidence to support a protective effect of the above-mentioned lifestyle factor, efforts by the pharmaceutical industry to come up with AD modifying drugs has been much less successful and even controversial. A good example is the recently approved AD drug aducanumab (Aduhelm). The drug is a monoclonal antibody that targets a protein, amyloid, that clumps into plaques in the brains of Alzheimer’s patients and is considered a biomarker of the disease. Even though both critics and supporters of Aduhelm’s approval agree that the drug substantially reduced levels of amyloid, there is no close relationship between amyloid level and cognitive function in many patients, as the Holstege study and previous studies have demonstrated.

What makes this FDA approval so controversial is the fact that clinical trials to date have failed to demonstrate a significant effectiveness of the drug, that serious risks with aducanumab involve brain swelling or bleeding experienced by about 40 percent of Phase 3 trial participants receiving the high dose, and the fact that the cost associated with its use is $ 56,000 per treatment plus tens of thousands of dollars in costs for diagnostic testing and brain imaging. The approval was so controversial that 3 members of the FDA scientific advisory committee resigned in protest. Not surprisingly the stock price of Biogen, the company producing the drug and anticipating a major windfall, surged 38 percent on Monday after the announcement, adding $16 billion to the company’s market value.
Obviously, it is understandable that desperate relatives of AD patients are anxious for new drug treatments for this devastating disease. However, one wonders if it is more prudent to promote healthy lifestyle measures, in particular a non-inflammatory diet and regular exercise at the earliest symptoms of cognitive decline, or in patients with genetic risk factors than to follow the empty promises of the pharmaceutic industry.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

Can We Trust Our Gut Feelings?

By Emeran Mayer, MD

“Every emotional experience – positive or negative – is stored in a vast database in our brain as a “videoclip of emotional moments…”

A question that I have often been asked by audiences or podcast hosts, relates to the phenomenon of our gut feelings. It is a topic that I spent a significant amount of time discussing in my first book, The Mind-Gut Connection, where I proposed a biological explanation for the frequently used link we make between intuitive decision making and events in our gut. By implicating the intricate bidirectional interactions between our brain and the gut, and the close associations between emotional states and gut function, I came up with the following hypothesis:

Every emotional experience – positive or negative – is stored in a vast database in our brain as a “videoclip of emotional moments”, and this videoclip includes both the experience as well as the associated gut reactions and gut sensations. During this process, every emotion creates a subliminal mirror image in the gut in terms of distinct patterns of contractions, sensory signals and gut microbial signals which are reported back to the brain – via the vagus nerve or through the systemic circulation – and added to the emotional videoclip, one might say as the soundtrack to the image.

“The generation of this vast database starts with the first experiences of a newborn of aversive and pleasant feeling states…”

The generation of this vast database starts with the first experiences of a newborn of aversive and pleasant feeling states – a feeling of being hungry is aversive, and one of satiation after being fed is pleasure. The encoding of these feeling states in our “personal database” is made possible by the intricate exchange of biological signals between our gut, its microbes and “interoceptive” networks in the brain. While we don’t remember these experiences from early childhood, the memories are firmly stored in our brain, together with hundreds of millions of such “emotional moments” that we experience throughout life. While many people will not be aware of these memories, many patients suffering from a hypersensitive gut, irritable bowel syndrome (IBS), or from anxiety disorders, can tell of decades of such experiences where negative emotional states, such as anger, worry and anxiety were associated with unpleasant gut sensations, including abdominal pain and discomfort.

“…Our brain can access almost instantaneously the most relevant answer from our emotional data base during a gut-based decision…”

In The Mind-Gut Connection, I further hypothesized that our personal database full of such recorded emotional moments, together with the associated gut feelings play an important role in the process of making intuitive decisions based on our gut feelings. Like the Google search engine being able to generally access the search results most relevant for us within milliseconds, based on the first two letters we type, our brain can access almost instantaneously the most relevant answer from our emotional data base during a gut-based decision, rather than going through the tedious, linear decision-making process that our prefrontal cortex is so good in. We may even use this mechanism to override decisions we have come up with after tedious generation of plus and minus lists, but which didn’t make intuitive sense to us.

“…Intuition is thinking that you know without knowing why you do…”

I was intrigued when I recently read a blog post by Jessica Stillman in Medium about a speech that Nobel Lauriat Daniel Kahneman gave a couple of years ago at the World Business Forum in NYC. According to Kahneman, “intuition has traditionally been defined as knowing without knowing how you know”. However, he emphasizes that a better definition — or a more precise one — would be that “intuition is thinking that you know without knowing why you do.” By this definition, the intuition could be right, or it could be wrong, he added, implying it may often not be a good idea to follow your gut feelings.

“…following our gut feelings is probably not a good idea to make decisions involving unpredictable phenomena like the stock market…”

Obviously, following our gut feelings is probably not a good idea to make decisions involving unpredictable extraneous phenomena like the stock market, the weather, or earthquakes. The same could be said about the decisions related to the COVID-19 pandemic which should be made based on scientific evidence, and not based on somebody’s gut feelings. However, anything involving personally salient issues like social interactions, friendships and marriage, career decisions, and even some life and death decisions (as the famous example of Stanislav Petrov illustrates, who saved the world from a nuclear holocaust with a gut-based decision), following the advice from your vast personal database of emotional moments is most often the right thing to do.

There are several questions related to my hypothesis which I have addressed in my book. What about the many individuals who have suffered from adverse early life events during the first years of their life and have formed many negatively biased gut feelings and emotional moments? Members of our center have reported research studies on the effect of such early adversity on brain gut interactions, most recently on the effect of such negative memories on the gut microbiome. What about the horrendous emotional experiences that millions of children in war zones and in refugee camps go through? Is their ability for intuitive decision making irreversibly compromised for the rest of their lives? What about individuals with anxiety disorders which often use a coping mechanism referred to as “catastrophizing” meaning they base their decisions on an assumption of a high likelihood of worst possible outcomes, even though there is no rational basis for this assumption?

From an evolutionary viewpoint, one could say that such negatively biased gut feelings in individuals with a history of early adversity are an adaptive mechanism that evolution has come up with as an automatic warning to protect them from future harmful events. Unfortunately, while such a mechanism may have protected our species from extinction many times during evolution, this evolutionary wisdom comes with a high price of mental and physical disorders in today’s world. Only the resilience of the human brain has prevented the toll of this early programming being even higher.

“…do the progressive changes in our gut health, in particular the interactions of our compromised gut microbiome with our gut based immune system have any influence on our gut-based decision-making process?”

And then there is the intriguing question if the progressive changes in our gut health, in particular the interactions of our compromised gut microbiome with our gut based immune system that I discuss in detail in The Gut-Immune Connection are having any influence on our gut-based decision-making process. Even though it is plausible that the altered gut signals that are being encoded in our data base of emotional moments may influence the “search results” when we make a gut-based decision, little is known about any concrete consequences of these changes.

So, can we trust our gut feelings in everyday decision making? My view is that when making personally salient decisions, the answer is a definite yes. If you are looking for a simple solution to predict the stock market or the weather, or if you should get the COVID-19 vaccine, intuition is not the way to go. Coming back to Kahneman’s talk at the World Economic Forum, here are the 3 questions he suggests asking yourself to find out if you can trust your intuitions:

  1. What areas of life have sufficient regularity for our brains to develop accurate intuitions?
  2. Have you had a lot of practice in observing environments with some level of pattern and regularity?
  3. Have you trained your intuition by finding out immediately if you got it right or wrong?

Other than paying any attention to the prominent role of the gut in his recommendations, Kahneman’s advice pretty much fits my own view of the issue.

If somebody has been unfortunate to have experienced negative programming of their gut-based decision-making process, and automatically gets it wrong every time they make a gut-based decision, they may require therapeutic interventions such as cognitive behavioral therapy or training in mindfulness practice as so eloquently expressed in Amanda Gilbert’s post (See Amanda’s new book here). These therapeutic interventions aim at minimizing or abolishing the negative bias out of gut-based decision making and greatly improve their accuracy.


Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.

What You Should Know About Probiotic Supplements

By Ana Schilke and Emeran Mayer, MD

“It has been generally assumed, but rarely proven, that these positive effects can be enhanced by taken probiotic pills.”

The human microbiome is composed of 3 major classes of resident microorganisms, bacteria, viruses and fungi. In an effort to maintain the delicate balance of this vast microbial ecosystem in our gut, and to restore such a balance after disturbing it through the intake of an antibiotic, many people have turned to probiotics which have become as popular as multivitamins and many other “health-enhancing” supplements. Many of these bacterial species, in particular those belonging to the class of Bifidobacteria and Lactobacillus reside in the adult digestive system in small numbers, where they aid in several beneficial processes such as digestion and nutrient absorption. It has been generally assumed, but rarely proven, that these positive effects can be enhanced by taken probiotic pills.

“…there is a small number of studies which have shown that certain probiotics are effective in reducing common digestive symptoms.”

According to the World Health Organization, “Probiotics are liv