How Living in a Disadvantaged Neighborhood May Affect the Brain

By Emeran Mayer, MD

In a recent publication in the journal, Communications Medicine, investigators from the UCLA Division of Digestive Diseases and the Goodman Luskin Microbiome Center at UCLA showed evidence suggesting that living in a disadvantaged neighborhood can affect food choices, weight gain and even the microstructure of the brain.

There is an extensive literature demonstrating a wide range of negative health effects associated with poverty, lower socio-economic status, and with living in disadvantaged neighborhoods. Numerous factors have been identified that underlie this association, including but not limited to food insecurity, higher rates of violence, and less access to high quality healthcare. Neighborhood disadvantage is defined by a combination of factors, such as low median income, low education level, crowding, and lack of complete plumbing.

“…by impairing the flexibility by which the brain processes information related to reward, emotion regulation, and cognition.”

The UCLA study included 92 participants – 27 men and 65 women – from the greater Los Angeles area. Demographic and body mass index information was collected, and neighborhood disadvantage was assessed as area deprivation index (ADI) using the University of Wisconsin School of Medicine and Public Health’s Neighborhood Atlas. The study showed that poor quality of available foods, increased intake of calories from foods high in trans-fatty acids, and living in environments that do not foster physical activity, all prevalent in disadvantaged neighborhoods, play an important role in one’s mental health, by impairing the flexibility by which the brain processes information related to reward, emotion regulation, and cognition.

The researchers did a detailed analysis of the brain’s cortex to determine how living in a disadvantaged area can change specific areas of the brain that play different roles in cognitive and emotional processes. “We found that neighborhood disadvantage was associated with differences in the fine structure of the cortex of the brain. Some of these differences were linked to higher body mass index and correlated with high intake of the trans-fatty acids found in fried fast food,” said Arpana Gupta, PhD, co-director of the Goodman-Luskin Center and Director of the Neuroimaging Core. “Our results suggest that regions of the brain involved in reward, emotion, and the acquisition of knowledge and understanding might be affected by aspects of neighborhood disadvantage that contribute to obesity,” said Gupta, the senior author of the publication. “This highlights the importance of addressing dietary quality issues in disadvantaged neighborhoods to protect brain health.”

“…higher risk of obesity due to the poor quality of available foods, increased intake of calories from foods high in trans-fatty acids, and environments that do not foster physical activity.”

Earlier studies have found that people living in disadvantaged neighborhoods are at a higher risk of obesity due to the poor quality of available foods, increased intake of calories from foods high in trans-fatty acids (including French fries, doughnuts and fried chicken), and environments that do not foster physical activity. In the UCLA study, researchers focused on the relationship between the ADI, a validated measure of neighborhood disadvantage, and brain imaging results at four levels of the brain to investigate in more refined detail the connections between neighborhood disadvantage and brain structure. Participants underwent two types of MRI scans that, when analyzed in combination, provide insights into brain structure, signaling and function.

According to the results, worse ADI ratings were associated with connectivity changes between brain regions that are important for social interactions. Other changes occurred in regions involved in reward, emotion regulation, and higher cognitive processes – and these changes appeared to be affected by trans-fatty acid intake. Even though the study only revealed associations and not causative relationships between measures of deprivation, dietary intake and brain features, the findings suggest that factors prevalent in disadvantaged neighborhoods that encourage poor diet and unhealthy weight gain compromise the brain networks involved in reward, emotion regulation, and cognition.

“Identifying the relationship between socioeconomic status, food quality and specific health consequences is the first step in improving nutrition and health for all.”

The role of socioeconomic factors in the current epidemic of non-contagious diseases has not received sufficient attention amid the raging discussions about gut health, inflammatory diets, supplements, probiotics and healthy food. Unhealthy fast foods of low dietary quality are marketed aggressively towards populations suffering from food insecurity, who don’t have the financial means to shop in higher end markets offering healthy, organically-grown foods. After all, taking your family out for dinner at a fast food restaurant costs a less than a fraction of eating in restaurants offering healthy dishes in the affluent neighborhoods of a city. After all, taking your family out for dinner at a fast food restaurant costs a less than a fraction of eating in restaurants offering healthy dishes in the affluent neighborhoods of a city. Identifying the relationship between socioeconomic status, food quality and specific health consequences is the first step in improving nutrition and health for all.

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, the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience and the Founding Director of the Goodman-Luskin Microbiome Center at UCLA.

The Stress That Evolution Has Not Prepared Us For

By Emeran Mayer, MD

For most people an increasing load of chronic stress has become a regular aspect of modern life, regardless if they are aware of it or not. This chronic stress is fueled and amplified by the relentless bombardment with negative news from the media, in particular the internet: the pandemic, catastrophic climate events, a displacement of millions of people resulting in a seemingly uncontrollable refugee crisis, increasing political polarization and a raging war in the middle of Europe are just the most recent examples. On top of that, health books, influencers and social media constantly feed us worrisome and conflicting negative information about our food, dietary habits and our health. This situation has led to what Michael Pollan has rightfully called a national eating disorder epidemic adding anxiety and stress to what normally should be one of our most rewarding times in life, enjoying food with family and friends.

“Our biology has not evolved in an adaptive way to deal with this type of constant … stress exposure”

Our biology has not evolved in an adaptive way to deal with this type of constant and repeated exposure to stress 24 hours a day, 7 days a week. The mismatch between our ancient highly effective biological acute stress response systems which are turned on and off quickly by powerful regulatory mechanisms, and this new form of chronic perturbation of the body’s homeostasis (also referred to as allostatic load) is one of the major factors affecting our health.

“Acute, often life-threatening stress has been part of human life for millions of years…”

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 not only kept our species alive through natural disasters, wars, famines and pandemics, but also has resulted in the dominance of planet Earth by our species. There are two such systems in our body: the older immune stress response system and the brain’s acute stress response system, and both are often engaged together.

“The engagement of the brain’s and the immune system response generally occurs in synchrony optimizing the outcome.”

The immune system typically responds to an invasion of pathogens (microbes that are harmful to us) with the initial engagement of the innate immune system, like dendritic cells, leading to the recruitment of different immune cells and powerful tools of the adaptive immune system, as well as the release of both inflammatory and anti-inflammatory cytokines. The balance between these opposing forces determines the severity and duration of the inflammatory response.

The brain also responds to a wide range of perturbations ranging from systemic infections, injuries, psychosocial stressors to worries about potentially harmful events which may occur in the future. Depending on the type and severity of the stressor, and the subjective stress responsiveness of a person, the brain responds with the engagement of the two arms of the stress response system, the sympathetic nervous system and, with increasing severity of the stress, the release of cortisol by the HPA axis. The engagement of the brain’s and the immune system response generally occurs in synchrony optimizing the outcome.

“… the worry about being shot remains a persistent stress for a significant segment of the population”

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

For the majority of people today, acute psychological stress occurs in daily situations like being stuck in traffic, being late for an important appointment, or having arguments with your spouse. In general, these stressors are of short duration and we don’t have to worry about their negative effect on our health.

“Our metabolism and the mechanisms controlling our eating behavior are simply not equipped to resist the constant bombardment with commercials promoting unhealthy food…”/span>

Today’s serious 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 this means poverty, discrimination, food insecurity, chronic health conditions). Many people are so used to this chronic stress that they may not even be aware of it. It is as if the stress response systems are never turned off, but idling in neutral affecting our general well-being, vitality and energy.

Stress is not limited to psychological stress. There are many perturbations targeted at the gut, including an unhealthy diet, enteric infections, antibiotics, and toxins. So in the same way that a brain-directed stress perturbs the balance first within your brain, spreading to the rest of the brain gut system, the gut-directed stress perturbs first the balance in the complex gut connectome and then spreads to the nervous system.

One important chronic perturbation of our gut and our metabolism is caused by the unhealthy Standard American Diet. Our metabolism and the mechanisms controlling our eating behavior are simply not equipped to resist the constant bombardment with commercials promoting unhealthy food, the grotesque portion sizes in most restaurants and the unhealthy contents of our ultra-processed food, full of saturated fat, sugar, and added chemicals including non-nutritive sweeteners, residues of pesticides in our vegetables and fruits, and microplastic in our seafood.

“The relentless engagement of our stress systems comes at an increasing cost to the health of our bodies and minds.”

Unfortunately, these two type of stressors often occur together, in particular in individuals from lower socioeconomic segments of our society. 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 kind 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 mediators cortisol and noradrenaline, and chronic systemic engagement of the immune system (the low grade systemic immune system activation everybody is talking about) are responsible for many aspects of our current chronic non-infectious disease epidemic as I have described in detail in The Gut Immune Connection and in the upcoming paperback The Mind 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 prenatally, in utero, and postnatally, 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 and live to the age of 100 years, the other one developing a chronic disease and dying early. In other words, one person will have a longer health span before chronic disease sets in. Important factors that have been shown to influence the outcomes of living in a chronically stressful world is the quality of social interactions, and the adoption of a eudemonic lifestyle, which means doing meaningful things in life, including doing good for others.

If you want to learn more about this topic, you might also be interested in my upcoming book The Mind-Gut-Immune Connection that you can preorder now, and in the excellent recent book by bestselling author Elissa Epel, PhD, The Stress Prescription which will show you simple techniques how to deal with our current stress dilemma. I will be discussing this topic with Dr. Epel on Tuesday, September 19, 2023 in the evening at a free online event organized by the UCLA Friends of the Semel Institute. See information of how to register for this exciting event at the bottom of this blog.

Weight Loss Drugs for Medication-Induced Weight Gain

By Amanda Johnson with Emeran Mayer, MD

Psychoactive medication are often the only option for patients living with mental illness, in particular in situations where there is an increased risk of self-harm. Antipsychotics, antidepressants, anxiolytics (also referred to as anti-anxiety medication), and mood stabilizers have all been proven to be highly effective medications, often in combination with behavioral therapies, in reducing symptoms, but often they come with some serious unwanted side effects, such as weight gain.

As these medications can be life saving for many patients, weight gain may not appear to be such a relevant problem at first glance. However, one should not underestimate both the physical and psychological effects that weight gain may have on an individual suffering from a mental illness. Patients can gain significant weight while on the medication within just the first year of taking it. Furthermore, studies have shown that taking antipsychotics and mood stabilizers can lead to metabolic syndrome a syndrome with impaired glucose metabolism, high levels of cholesterol and blood lipids, and arterial hypertension. Metabolic syndrome is a significant risk factor for other chronic health problems, including cardiovascular diseases. Based on the findings from a meta-analysis of 77 publications, an overall rate of 32.5% of patients diagnosed with schizophrenia who were taking antipsychotic medication had developed metabolic syndrome. The increased frequency of metabolic syndrome resulting as side effects of these medications, has shown to be a contributor in the lower life expectancy of schizophrenic patients, where cardiovascular disease is now the leading cause of death among adults with schizophrenia.

“Many of these antipsychotics and mood stabilizers that are often prescribed to treat pervasive mental disorders, such as bipolar disorder and schizophrenia, have been shown to lead to significant weight gain, diabetes, and heart disease.”

Additionally, the psychological side effects can also contribute to the mental problems of the patient. Obesity can become a psychological burden to an individual and it has been reported that obese patients suffer from anxiety and/or depression at a greater rate compared to the general population. The emotional distress that obesity can cause may decrease quality of life, self-esteem, and mood. Unfortunately, these individuals cannot just simply lose the weight through lifestyle changes which may lead them to experience a lack of control around their situation and result in feelings of hopelessness. The psychological strain that weight gain can have on an individual should be acknowledged and validated by all medical professionals and addressed with the best solution at hand.

“Obesity can cause a psychological burden to an individual and it has been reported that obese patients can suffer from anxiety and/or depression at a greater rate compared to the general population.”

Fortunately, there are new anti-obesity treatment options for patients experiencing significant weight gain from their psychiatric medications. One of these options is the GLP1 agonist Wegovy, a popular weight loss drug which we have often discussed in previous newsletters. Patients taking antipsychotic drugs often report the development of uncontrollable craving for food. With weight loss medication like Wegovy, these patients can maintain healthy eating habits and regain their normal weight. Patients are reporting the positive effects that the weight loss medication has had on their self-confidence and wellbeing as they lose around 15% of their body weight, making Wegovy one the most effective weight loss treatments on the market.

However, there are potential risks involved in medication-induced weight loss. Since the weight loss is so significant, some psychiatrists treating eating disorders have been hesitant to use it because they are wary that their patients may become too hyper fixated on their weight and body image. There is also legitimate concern for the wellbeing of patients prescribed weight loss medications and how it may affect their mental disorder. Additionally, the United States Food & Drug Administration (FDA) has also forewarned doctors to watch out for the potential resurgence of depression and suicidal thoughts in their patients, as drug regulators in Europe have received multiple reports of patients experiencing suicidal thoughts after being prescribed to take Wegovy, even though the safety data for Wegovy have not shown a link between taking the medication and having suicidal thoughts. Aside from mental health issues, weight loss medications still require close monitoring to ensure the medication is safe and effective for the health of the patient. Due to both the physical and psychological aspect of starting a weight loss medication in combination with psychiatric medications, patients ideally should be followed both by a psychiatrist and endocrinologist.

“Patients are reporting the positive effects that the weight loss medication has had on their self-confidence and wellbeing as they lose around 15% of their body weight, making Wegovy one the most effective weight loss treatments on the market.”

The weight problems associated with psychiatric medication, in particular with antipsychotic drugs should not be ignored despite the positive impact these medications have on the patient’s mental health and quality of life. While not everyone will gain weight from psychiatric medications, if a patient is presenting the first signs that their weight is being affected, it may be best to prescribe weight loss medication before there is an overwhelming amount of physical and psychological damage that the patient could face.

Amanda Johnson is a recent graduate from the University of Southern California where she received her degree in Psychology. In addition to her university studies, she earned her Integrative Nutrition Health Coach certification from the Institute of Integrative Nutrition (IIN). Amanda works as a Health Coach and strives to educate her clients more about the gut-brain axis.

SuperAgers and Alzheimer’s Disease

By Amanda Johnson and Emeran Mayer, MD

Why is it that some individuals are able to live well into old age while maintaining their full cognitive abilities while other elderly individuals are being faced with memory loss and the development of Alzheimer’s disease (AD)? While it has been assumed that age is the number one driving factor for dementia and AD, scientists have yet to fully understand what exactly sets apart those who live well into their elder years with optimal cognitive abilities (e.g. those with a long health span) and those who suffer from cognitive impairments. Could this be due to major differences in the development of degenerative brain changes? Or are there other factors that allow many elderly to maintain cognitive function despite the unavoidable development of age related neurodegenerative changes?

Researchers at the University of California, Irvine conducted a study to try to find an adequate explanation to further understand how the changes in the brain compare from individuals who exhibit impressive cognitive abilities for their age (so called “SuperAgers”) and individuals who are diagnosed with memory-related illnesses like AD. There is limited research on the physical brain changes of individuals aged ninety and older (“oldest-old”) who are able to maintain excellent cognitive function despite their old age.

“In the United States alone, the number of adults who live beyond ninety has tripled in the past few decades. Additionally, this number is expected to quadruple in the next few decades.”

90+ Study began in 2003 and set out to understand the link between longevity and dementia. Researchers began studying the oldest groups of the elderly population in the United States (“oldest-old”) to see if there was a potential link between neurodegenerative diseases and age. The study had a total of 1,600 participants enrolled making it one of the largest studies of its kind throughout the whole world. In the United States alone, the number of adults who live beyond ninety has tripled in the past few decades, and is expected to quadruple in the next few decades.

One major goal of the 90+ study was to identify pathological brain changes in SuperAgers and compare them with brain changes observed in same age individuals with cognitive decline. They found that SuperAgers, individuals who are ninety years old and over with superior cognitive abilities for their age, displayed some of the same brain pathology as observed in those with AD as well as other neuropathological signs. However, the ability to withstand these neural changes and maintain full cognitive function was one of the main features that differentiated those with full cognitive abilities from those with cognitive decline.

Previous autopsy studies on the 90+ Study participants had reported that individual and multiple comorbid neuropathologic features were common in “oldest-old” individuals and were associated with increased likelihood and severity of cognitive impairment. As expected, the presence of higher levels of multiple neuropathologic features were associated with a lower likelihood of superior cognitive performance. AD neuropathological changes (ADNCs) considered biomarkers of AD (such as neurofibrillary tangles and amyloid plaques) were found in 87% of study participants but surprisingly, were not associated with cognitive performance. This finding was not unexpected given that ADNCs are almost ubiquitous in this “oldest-old” cohort, and it has been commonly reported in individuals without dementia in a recent meta-analysis on 17 population-based autopsy studies with age of death 65 years and above. Furthermore, a previous analysis on eight participants from The 90+ Study reported the presence of plaques and tangles—the hallmarks of ADNC—in the brains of “SuperAgers”.

“Despite some of the brain pathology being the same, these SuperAgers had the ability to resist the changes and maintain their cognition.”

When viewed together, the current and previous study results indicate that superior cognitive performance in “oldest-old” can be explained by concepts of both resilience and resistance. In cognitively normal “oldest-old”, the superior global cognitive performers were resilient to ADNC, i.e., they maintained superior cognition despite having AD-specific neurodegenerative changes. On the other hand, other neurodegenerative neuropathologic features, particularly Lewy Body disease and a particular form of degeneration of the hippocampus, the major brain area concerned with memory, were very rare indicating resistance, i.e., their ability to escape the development of these changes in the brains.

“If scientists were successful in understanding this, they could determine ways to detect dementia and potentially treat it in early stages.”

Since individuals in the United States and other parts of the world are beginning to live far past ninety years old, so it is important to start to develop a better understanding how to increase the health span (longevity without disease even through old age) of individuals. Alzheimer’s disease is on the rise and becoming increasingly more common in older adults. Since age is such a prominent factor, it is very critical to understand the link between age and dementia. Luckily, the 90+ Study has been doing just that for over the last twenty years. While the factors influencing the correlation between pathological brain changes and clinical performance remain incompletely understood, we now know that it is not that SuperAgers do not experience brain changes, but they are more resilient to them. In addition to promoting lifestyle factors that promote resistance to the development of ADNCs, including diet, exercise, sleep and social interactions, it will be essential to explore the driving factors behind the ability of SuperAgers to remain resilient despite the physical changes in their brain.

Ketamine and Major Depressive Disorder

By Amanda Johnson with Emeran Mayer, MD

The number of individuals diagnosed with major depressive disorder (MDD) in the US has increased between 2005 and 2018 from 13.7 million to 17.5 million, with the prevalence rate rising from 6.8 to 7.1% . The rising prevalence is unevenly distributed by age, with the greatest increase seen among 18- to 34-year-olds.

Starting in early 2020, the pandemic resulted in new, stressful, and at times overwhelming worries about the health effects of the virus itself, heightened concerns about potential loss of employment, and prolonged social isolation involving greatly reduced interaction with family and friends. Recent data from the Centers for Disease Control and Prevention (CDC) show that the US prevalence of MDD has increased substantially from 7% prior to the pandemic to 27% during the first year of the pandemic, and MDD with anxiety disorders has increased from 11 to 38%.

While all mental illness can have serious negative implications on well-being, MDD is one of the most burdensome illness globally causing symptoms of feelings of deep loneliness, suicidal thoughts, and a general lack of enjoyment towards life.

“Since the disease varies extensively from person to person, it has been difficult to find a generally effective treatment plan. Additionally, individuals with MDD can be resistant to treatments.”

While the complexity and heterogeneity of MDD has made it challenging for mental health professionals to find effective treatment strategies, there are several therapies that work for a large number of patients, including Cognitive Behavioral Therapy and medications such as Selective Serotonin Reuptake Inhibitors (SSRIs). CBT was found to have a 43% success rate in patients with depression. In a study with 100 participants, around 40-60% saw a reduction in their depression symptoms on SSRIs. In a study with 100 people, around 40-60 of the participants saw a reduction in their depression symptoms upon taking medication for treatment. While these first line approaches work well in some patients, others may require more advanced treatments such as Electroconvulsive Therapy (ECT) to obtain symptom relief. ECT has been shown to be the most effective treatment so far for MDD, yet it is typically resorted to last after previous approaches have been proven to be ineffective for the patient. It is only used as a last resort approach due to its high rate of side effects, including memory impairments which may continue to persist long after completing ECT.

There has been a recent increase in the study of psychedelic compounds in the treatment of several psychiatric disorders, in particular MDD and PTSD. John Hopkins School of Medicine investigators have reported evidence from multiple carefully controlled studies suggesting that psychedelics are effective in the treatment of mental disorders. A brain imaging study performed by scientists at UC San Francisco and Imperial College London analyzed fMRI brain scans from nearly 60 people who had participated in two psilocybin trials. The first one was an unblinded study in which all the participants had treatment-resistant depression and knew they were being given psilocybin. The second study was a randomized, placebo-controlled trial in which the participants had milder depression symptoms and were not told whether they had been given psilocybin or escitalopram, an SSRI antidepressant. In addition to the drugs, all the participants received the same type of psychotherapy.

The scans, which were done before and after treatment, showed that psilocybin treatment reduced connections within several brain networks that are tightly connected in depression and increased connections to other regions of the brain that had not been well integrated.

Participants also improved clinically, being less emotionally avoidant and experiencing improvements in cognitive functioning. The improvement in their depressive symptoms correlated with the observed brain changes, and these improvement persisted until the study ended three weeks after the second psilocybin dose.

This new research has encouraged scientists to dive deeper into the efficacy of psychedelics, such as ketamine, in the treatment of mental health disorders. Ketamine is a drug primarily prescribed for short term general anesthesia in infants. However, when administrated in intravenous doses, lower than those required to induced anesthesia, the drug has the ability to induce a psychedelic experience where individuals may experience hallucinations. Subanesthetic doses of ketamine have been administrated to treat patients with mental health disorders over the past two decades, but this approach has only recently received a lot of attention.

“…researchers wanted to see how using infusions of ketamine would compare in the efficacy of treatment in patients diagnosed with treatment resistant MDD. Their results were revolutionary to the developments of potential future treatments for patients.”

While ECT is more commonly used by medical professionals due to their familiarity with the treatment, researchers wanted to see how intravenous ketamine administration compares with ECT in the treatment in patients with treatment resistant MDD. A recent study published in The New England Journal of Medicine (NEJM) compared the effectiveness between ketamine infusions and ECT in the treatment resistant MDD .

“Following their completion of treatments, they found that 41.2% of the ECT group had reported a response from the treatment and 55.4% of the ketamine group had a response from their sessions of treatment.”

The study participants were split into two groups. All of the participants were diagnosed with treatment resistant MDD and had been referred to seek out ECT as a last resort treatment. Researchers initially recruited a total of 403 patients who were then assigned in a 1:1 ratio to be treated with either infusions of ketamine or ECT, where 170 were in the ketamine group and 195 were in the ECT group after 38 of the recruited patients had withdrawn. Researchers used self-report measures to evaluate the response in patients after the two groups received their different treatments. The ECT group completed a total of nine sessions and the ketamine group completed a total of six sessions. Following their completion of treatments, they found that 41.2% of the ECT group had reported a positive response from the treatment compared to 55.4% of the ketamine group. The two groups reported a similar improvement in their quality of life. Side effects of memory loss were seen amongst the ECT group as well as adverse musculoskeletal effects. In the ketamine group, milder side effects such as disassociation were observed. Disassociation may result in feelings of daydreaming, causing an individual to feel detached from their current reality and result in difficulties around retaining short-term memories. Aside from possible disassociation, minimal side effects were reported in the ketamine group.

In summary, the results of the well-controlled study in patients with MDD found that infusions of ketamine were more effective than ECT and presented little to no side effects. Even though more studies like this are needed to confirm these findings, the NEJM study suggest that subanesthetic intravenous ketamine may be a good option for those with treatment resistant major depression.

Ketamine has only been a recent therapy approach used for treatment resistant MDD, and some psychiatrist still feel hesitant about the safety and efficacy of the drug. Some medical professionals have even been entirely resistant to using it and other psychedelic drugs for their patients diagnosed with mental disorders. Future research around the safety and efficacy of ketamine is still needed, but these studies are helping to revolutionize the treatment of common and disabling mental disorders. It is likely that the stigma surrounding the use of psychedelics to treat mental illness will disappear when the drug being used for treatment in patients is found to be both safe and effective in clinical trials.

Surprising News about Diet and Alzheimer’s Disease

By Emeran Mayer, MD

In the Mind Gut Connection Blog, we have often addressed the relationship between a healthy, Mediterranean-style diet and brain health. We have based many of our recommendations on the consumption of a largely plant-based diet with at least 75% of food coming from a variety of fruits and vegetables, seeds, nuts and olive oil, in addition to an avoidance of ultra-processed foods and sugar. The effects of such a diet on brain health are supported by findings from a number of observational studies (1, 2, 3, 4, 5, 6, 7). In such studies (which make up the majority of published studies on health and diet), researchers compare brain and health outcomes between two usually large groups of individuals, one of which consumes a regular diet, often the Standard American Diet, and the other one consumes a healthy diet. Some evidence links high consumption of green leafy vegetables, nuts, berries, and olive oil with a reduction in the hallmark neuropathologic features of Alzheimer’s disease, such as β-amyloid deposition. As I have discussed in The Gut Immune Connection, even though the proposed underlying mechanisms point to beneficial, anti-inflammatory effects of the microbial metabolites of fiber and polyphenol molecules contained in plant-based foods, a causative role of such a Mediterranean-style diet or of its major ingredients has rarely been demonstrated. Animal models have shown the potential importance of vitamin E and the omega-3 docosahexaenoic acid (DHA) for healthy brain functioning, including protection against lipid peroxidation, neuron loss, β-amyloid deposition, and decline in memory and learning.

A recent study, led by a team of investigators under lead author Dr. Lisa Barnes from Rush University, the Harvard Medical School Department of Nutrition, and the T.H. Chan School of Public Health, published in the prestigious New England Journal of Medicine describes the results of a clinical trials aimed to test the hypothesis that consumption of the MIND Diet compared to a standard American diet led to improved measures of cognition and brain health.

The MIND Diet (The Mediterranean–DASH Intervention for Neurodegenerative Delay), is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, both of which are Mediterranean-style diets with modifications to increase the amounts of foods that have been putatively associated with a decreased risk of dementia. The diet has been introduced by the late Martha Morris (I did a podcast with Dr. Morris several years ago), who also performed several clinical trials with this diet in patients with cognitive decline with positive results.

The investigators performed a two-site, randomized, controlled trial involving healthy older adults without cognitive impairment but with a family history of dementia, a body mass index (BMI) greater than 25, and a suboptimal diet, as determined by a food frequency questionnaire. Even though the study group did not have signs and symptoms of cognitive decline, the increased BMI and a family history of AD are risk factors for the disease. The study compared the cognitive and brain effects of the MIND diet with mild caloric restriction with a control diet with mild caloric restriction. All study participants were followed for 3 years with repeated cognitive testing and received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)–derived measures of brain characteristics in a smaller number of a non-random sample of participants.

A total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. Surprisingly, from baseline to year 3, small improvements in global cognition scores were observed in both groups, without statistically significant differences. Similarly, the structural grey and white matter changes detected by MRI in a smaller subsample were similar in the two groups. In other words, among cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction.

Previous meta-analyses of diet trials have shown mixed results and generally do not affirm the beneficial effects of diet on cognition that were observed in epidemiologic studies and suggested by preclinical studies. Discrepancies between results from Observational studies or preclinical studies and well-designed intervention trials are common, and there are several reasons that could explain this discrepancy. The presence of bias and confounding in observational studies is one possibility. The notorious unreliability of diet estimates assessed by food frequency questionnaires (FFQs) is another potential confounder. There may be a difference in lifestyle factors other than diet between the groups. In the early studies of the Mediterranean diet, investigators emphasized the importance of such non-dietary lifestyle factors like close and meaningful social interactions and regular daily physical exercise playing an important role in the observed health benefits.

In addition, group differences in the presence of preexisting coexisting medical conditions play a role. The authors also mention the possibility that the participants in the control-diet group probably improved their diet, given evidence of weight loss that was similar in the two groups. And they suggest that it is also plausible that practice effects of repeated cognitive testing could account for improvement in both groups, as has been observed in previous randomized trials.

Based on these study results, should we walk away with the conclusion that dietary interventions have little impact on the development of early cognitive decline and Alzheimer’s disease? Absolutely not! In my opinion, such a reaction would ignore the vast amount of clinical and preclinical research that has been dedicated to reveal the mechanism underlying the development of Alzheimer’s disease. However, given its complex pathophysiology including genetic, environmental, metabolic, immune and gut microbial factors, it does seem unlikely that dietary factors alone are sufficient to explain the development of the disease and the effectiveness of treatments.

The Benefits of a Modified Mediterranean Diet for Irritable Bowel Syndrome

By Emeran Mayer, MD

Dietary interventions, such as the low Fermentable Oligo-, Di-, Monosaccharides and Polyols (FODMAP) diet, which are low in many plant-based foods are considered by many IBS experts as first line treatments for IBS, even though they are bad for our overall health.

The low FODMAP diet focuses on the elimination of foods than can trigger symptoms. However, these interventions are restrictive, difficult to maintain, may lead to deficiencies of certain nutrients when maintained over a period of time, and importantly have a negative influence on the health of the gut microbial ecosystem. Furthermore, they also reinforce food-related fears that drive anxiety and IBS symptoms.

A wealth of evidence has demonstrated benefits of the Mediterranean diet for cardiovascular, metabolic and brain health as well as longevity (reviewed in The Gut Immune Connection). Some data suggest that a low adherence to the Mediterranean diet, in other words a low consumption of fruits and vegetables, is also associated with a higher prevalence of IBS and other disorders of gut-brain interactions.

There is no question, adherence to a Mediterranean-type diet is the best thing you can do for healthy aging, even if you have IBS. Our group at UCLA studied dietary habits, IBS symptoms and gut microbial compositions in 106 IBS patients and 108 healthy control subjects. Scores measuring the adherence to the Mediterranean diet were similar between IBS and healthy control subjects, and did not correlate with such cardinal IBS symptoms as abdominal pain or bloating.

However, amongst IBS participants, responses to individual food items were inconsistent. For example, fruits many of which are high in FODMAPs were associated with higher abdominal pain, bloating, and higher scores on the IBS symptom questionnaire, while vegetables were associated with higher scores on the visceral sensitivity index, an instrument measuring food related anxiety. However, surprisingly, higher consumption of beans, legumes, and soy was associated with lower overall and less severe IBS symptoms. On the other hand, higher consumption of butter, creams and margarine were associated with higher bloating and IBS severity scores.

A higher adherence to a modified Mediterranean diet was associated with relative abundances of health-promoting bacteria in the gut microbiome. The take home message from this study, consistent with my previous recommendations are the following:

A modified Mediterranean diet consisting of fruits and vegetables is not only essential for many aspects of your health, but it is generally NOT associated with worsening of IBS symptoms, as long as patients reduce the intake of certain food items.
Reducing or sometimes eliminating the intake of certain food items, such as lactose containing dairy products, certain fruits and non-nutritive sweeteners will result in a personalized Mediterranean diet that is good for many aspects of your health, including IBS symptoms.

What Do Social Connectedness and the Mediterranean Diet Have in Common?

By Emeran Mayer, MD

The earliest publications by Ancel Keys about the health benefits of the Mediterranean diet have emphasized the importance of the close social interactions of people living on the island of Crete in Greece, as well as the health benefits of dietary habits.

Keys described the Mediterranean diet as consumed by people in post WWII Crete in this way: “… homemade minestrone, pasta of all varieties, with tomato sauce and a sprinkling of Parmesan, only occasionally enriched with a few pieces of meat or served with a small fish of the place … beans and macaroni …, so much bread, never removed from the oven more than a few hours before being eaten, and nothing with which spread it, lots of fresh vegetables sprinkled with olive oil, a small portion of meat or fish maybe a couple of times a week and always fresh fruit for dessert.”

While specific ingredients of the Mediterranean diet, like olive oil, fresh fruit, vegetables, and fish have received a lot of attention in terms of the wide-ranging health-promoting effects of dietary fiber, plant-based fats, polyphenols and minimal consumption of red meat, the importance of the social aspect of this dietary pattern has received much less attention.

Keys and many authors, including The Blue Zones author, Dan Buettner, write about the benefits of the Mediterranean diet with regard to longevity, and have emphasized the essential role of close social interactions between people living around the Mediterranean region. I have experienced this social connectedness around food first hand in my visits to Italy, and have often wondered if this non-dietary component of the Mediterranean food culture could outweigh the negative health effects of dramatic changes in lifestyle, including the increased consumption of red and processed meat in today’s Italy compared to the dietary pattern that Keys described in Crete in the 50s. I still have vivid memories of a recent visit to Parma, the origin of Parmesan cheese and Parma ham (prosciutto). While it was nearly impossible to find foods on the menu of restaurants that I would have called typical traditional, largely plant based Mediterranean dishes (e.g. without ham, cheese and lots of pasta), the bustling interactions between friends and family members enjoying their dinner in the many outdoor restaurant or walking around town until late into the night was different from anything I have ever experienced in the United States. And surprisingly, when I compared the life expectancy in different regions of Italy with very different dietary patterns, there doesn’t seem to be a significant difference between the Emilia Romana region of Parma and coastal regions with high fish consumption, suggesting some factors other than dietary ingredients at play..

So how important is social connectedness for the health benefits described for the Mediterranean diet, and for healthy aging, and what are the consequences of social isolation and often associated loneliness? As a matter of fact, there is a lot of science addressing this topic. In a recent interview with Dr. Wayne Jonas, he gave me the following surprising answer:

“For example, the longest study on healthy longevity ever done, gone out of Harvard, still going on, when they looked at all the factors that contributed to remaining healthy and living a long time, the biggest factor was social connections. Deep social, satisfactory connection. The second biggest factor was meaningful activity. …Those were the two biggest factors. Those were bigger than whether you smoked, whether you exercised, even what your diet was like. Not that those lifestyle factors were not important, but they weren’t necessarily the most important”.

I looked up the Harvard Study of Adult Development that Dr. Jonas had mentioned in our interview. This long-running study was started in 1938 with the goal to identify the factors which make people flourish, mentally, physically and spiritually. The co-leaders of the study, Harvard professors Drs. Robert Waldinger and Marc Schultz discussed the results and implications of the study results in a fascinating book, The Good Life: Lessons From the World’s Longest Scientific Study of Happiness, an excerpt from which was published in the January 19, 2023 issue of the Atlantic magazine. Here is a quote from their article: “Loneliness has a physical effect on the body… It can render people more sensitive to pain, suppress their immune system, diminish brain function, and disrupt sleep, which in turn can make an already lonely person even more tired and irritable.”

Research has found that for older adults, loneliness is far more dangerous than obesity. Ongoing loneliness raises a person’s odds of death by 26 percent in any given year. A study in the U.K., the Environmental Risk (E-Risk) Longitudinal Twin Study, recently reported on the connections between loneliness and poorer health and self-care in young adults. This ongoing study includes more than 2,200 people born in England and Wales in 1994 and 1995. When they were 18, the researchers asked them how lonely they were. Those who reported being lonelier had a greater chance of facing mental-health issues, partaking in unsafe physical-health behaviors, and coping with stress in negative ways. Add to this the fact that a tide of loneliness is flooding through modern societies, and we have a serious problem. Recent stats should make us take notice.”

As a matter of fact, the public recently has taken notice of this hidden epidemic. The topic of loneliness and social isolation has recently made the news headlines in the US when United States Surgeon General, Dr. Vivek Murthy, released a new Surgeon General Advisory calling attention to the public health crisis of loneliness, isolation, and lack of connection in the US.

As quoted from Murthy’s report: “Even before the onset of the COVID-19 pandemic, approximately half of U.S. adults reported experiencing measurable levels of loneliness. Disconnection fundamentally affects our mental, physical, and societal health. In fact, loneliness and isolation increase the risk for individuals to develop mental health challenges in their lives, and lacking connection can increase the risk for premature death to levels comparable to smoking daily.”

In a study conducted online that sampled 55,000 respondents from across the world, one out of every three people of all ages reported that they often feel lonely. Among these, the loneliest group was 16-to-24-year-olds, 40 percent of whom reported feeling lonely “often or very often.” …In Japan, 32 percent of adults expected to feel lonely most of the time during 2020. In the United States, a 2019 study suggested that three out of four adults felt moderate to high levels of loneliness.”

According to this report, “The physical health consequences of poor or insufficient connection include a 29% increased risk of heart disease, a 32% increased risk of stroke, and a 50% increased risk of developing dementia for older adults. Additionally, lacking social connection increases risk of premature death by more than 60%. Given the close interactions between our emotions, the immune system and the gut microbiome, it is not surprising that the same diseases which make up the chronic non-contagious disease epidemic are amongst the negative health outcomes of both the lack of social connections and an unhealthy diet.

As explained in detail in my forthcoming The Mind-Gut-Immune Connection, the negative influences of chronic psychosocial stress (generated by loneliness and social isolation) and of chronic dietary stress (in form of the Standard American Diet) interact to alter the gut microbiome leading to systemic immune activation.

In addition to our physical health, loneliness and isolation contribute substantially to mental health challenges. In adults, the risk of developing depression among people who report feeling lonely often is more than double that of people who rarely or never feel lonely. Loneliness and social isolation in childhood increase the risk of depression and anxiety both immediately and well into the future. And with more than one in five adults and more than one in three young adults living with a mental illness in the U.S., addressing loneliness and isolation is critical in order to fully address the mental health crisis in America.”

Murthy’s report continues: “Social connection is beneficial for individual health and also improves the resilience of our communities. Evidence shows that increased connection can help reduce the risk of serious health conditions such as heart disease, stroke, dementia, and depression. Communities where residents are more connected with one another fare better on several measures of population health, community safety, community resilience when natural disasters strike, prosperity, and civic engagement.”

Returning to the Mediterranean diet, the lifestyle associated with this diet and practiced in countries around the Mediterranean would seem to be an effective way to counteract both the widespread social isolation and the detrimental metabolic effects of the Standard American Diet. Eating a home-delivered pizza or pasta alone while watching TV, eating your caprese sandwich while driving to work, or while listening to a presentation at work, will deprive you of the aspect of social connectedness traditionally associated with the Mediterranean diet.

The Surgeon General’s Advisory lays out a framework for the United States to establish a National Strategy to Advance Social Connection. However, until such policies change the national social infrastructure, individuals should become aware of the importance to not only eat healthy food, but also to work actively to maintain family ties, regular relationship with friends, and use food as a social glue to bring us closer together.

Understanding and Treating Irritable Bowel Syndrome

By Emeran Mayer, MD

“We all know that the mind plays a role in disease, but it cannot be studied scientifically.”

From the beginning of my medical career, I was interested in understanding how the brain and the mind interact with the body, and how a dysregulation in these interactions can result in a range of medical problems, from heart attacks to unexplained abdominal pain, and from asthma attacks to non-cardiac chest pain. When I tried to find a thesis advisor for my dissertation in medical school in the early 70s, I typically got the answer from the leading professors that “we all know that the mind plays a role in disease, but it cannot be studied scientifically”. Luckily, after 5 failed attempts, I found the right mentor at the Institute of Physiology at the University of Munich, and embarked on a 4-year period of studying the influence of the brain and specifically the sympathetic nervous system on blood flow to the different layers of the heart. Even though I switched my focus from the heart to the gut during my subsequent clinical training in gastroenterology, I never lost my keen interest in studying brain gut interactions.

Around 10% of the US population suffer from chronically recurring symptoms of abdominal pain, discomfort and altered bowel habits, which are the hallmark symptoms of IBS. Even though IBS is the quintessential disorder of brain gut interactions, it has only been very recent that experts of the largest professional IBS organization, the ROME Foundation, came to agree on this definition.

“IBS is a disorder of neurotic housewives.”

What I experienced during these 50 years could fill a whole book with entertaining anecdotes, hard-to-believe statements by leading IBS authorities at the time, 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 short period postulating an inflammatory process underlying IBS symptoms, and a period obsessed with “excessive intestinal gas production” to today’s theories about the role of an altered gut microbiome. While the new theories about IBS that appeared every few years – including the most recent focus on an altered gut microbiome – captured the imaginations of clinicians and investigators in the field, encouraged the pharmaceutical industry to come up with new medications, and the supplement industry with new microbiome-targeted treatments, my early conceptualization of IBS as a brain-gut disorder was rejected by the majority of IBS experts – until now.

“The Lumpers and Splitters”

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 its own postulated mechanism and treatment recommendation, we suggested from early on that alterations in brain gut interactions, including increased perception of visceral signals (“visceral hypersensitivity”), and increased stress responsiveness, 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 intestine. Paralleling the different concepts about pathophysiology, treatment recommendations over the decades have ranged from drugs aimed at slowing or speeding up transit through the gut (so called motility drugs), and antibiotics (still in widespread use today). Dietary recommendations have ranged from high fiber diets to the today’s promotion of the “low FODMAP diet”, a diet devoid of many fiber-containing foods. Not surprisingly such a diet cannot be recommended for long term use due to its detrimental effects on metabolic health. Along the way have also been a wide range of supplements ranging from pro- and prebiotics to peppermint oil. While each of these treatment approaches has been shown occasionally to lead to a relieve of some IBS symptoms, none of them turned out to be the miracle treatment which had been expected.

“The majority of proposed treatments have not been much more successful than a placebo pill.”

It is ironic that while these various concepts promoted over the years have primarily fueled the careers of investigators, the output of modified classifications by the ROME Foundation and the profits of the pharmaceutical industry, they have not provided consistent and lasting relief for the millions of patients suffering from symptoms of chronic abdominal pain and discomfort. The majority of proposed treatments have not been much more successful than a placebo pill.

Patients who are interested to learn more about simple ways to self-manage their symptoms, may want to try my IBS class. I provide information and treatment recommendations which I have given to hundreds of IBS patients in my clinic over the years. This information is based on research performed at our center at UCLA, as well as by a few outstanding research groups around the world. For a recent summary of this research and a comprehensive concept of IBS pathophysiology, I refer to our recent review article The Neurobiology of IBS. 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 with IBS who didn’t embrace this information, was relieved by finally having a plausible explanation for their “unexplainable” symptoms, and who has not experienced significant symptom improvement from the recommended therapeutic approach.

Prev 1 of 1 Next

Gut Health Insights #2 with Dr. Emeran Mayer | Irritable Bowel Syndrome (IBS)

Prev 1 of 1 Next

Is Moderate Alcohol Consumption Beneficial For Your Health?

By Emeran Mayer, MD

For decades, scientific studies suggested that moderate drinking was better for most people’s health than not drinking at all, and that it could even contribute to longevity. Supporting this view, a previous meta-analysis of the association between alcohol use and all-cause mortality found no statistically significant reductions in mortality risk at low levels of consumption compared with lifetime nondrinkers. However, according to a recent study, the risk estimates may have been affected by the number and quality of studies then available. A recent publication in the Journal of the American Medical Association has concluded that many of these earlier studies were flawed and that the opposite is true, in particular for women and younger individuals.

“…the risks of dying prematurely increase significantly for women once they drink 25 grams of alcohol a day, which is less than … two 5-ounce glasses of wine.”

This new systematic review and meta-analysis of 107 cohort studies involving more than 4.8 million participants found no significant reductions in risk of all-cause mortality for drinkers who drank less than 25 g of ethanol per day (about 2 Canadian standard drinks compared with lifetime nondrinkers) after adjustment for key study characteristics such as median age and sex of study cohorts.

The review found that the risks of dying prematurely increase significantly for women once they drink 25 grams of alcohol a day, which is less than two standard cocktails containing 1.5 ounces of distilled spirits, two 12-ounce beers or two 5-ounce glasses of wine. The risks to men increase significantly at 45 grams of alcohol a day, or just over three drinks.

“… light and moderate drinkers are systematically healthier than current abstainers on a range of health indicators unlikely to be associated with alcohol…”

Like the majority of food and lifestyle related studies, most studies on the effects of alcohol on health have been observational, meaning they could identify links or associations caused by factors other than alcohol consumption. They could therefore be misleading and did not prove cause and effect. In particular, that light and moderate drinkers are systematically healthier than current abstainers on a range of health indicators unlikely to be associated with alcohol use such as, dental hygiene, exercise routines, diet, weight, and income. At the same time, lifetime abstainers may be systematically biased toward poorer health, including “sick quitters”, or former drinkers, many of whom cut down or stop for health reasons. In addition, people who abstain completely from alcohol are a minority, and those who aren’t teetotalers for religious reasons are more likely to have chronic health problems. These so-called confounding factors and not the moderate alcohol consumption may have caused the more positive health outcomes in several studies.

Another more important confounding factor is the close association of daily, moderate red wine consumption with longevity in so called Blue Zones, regions around the world with an increased percentage of so-called centenarians, e.g. individuals that live into their hundreds without major health problems. A large number of studies has identified several lifestyle factors, including regular moderate physical exercise, food and the regular consumption of 1-2 glasses of red wine. Even though moderate wine consumption has been practiced for thousands of years and is an essential part of the culture of Mediterranean and Latin countries, it may be the intricate association of the Mediterranean lifestyle, in particular the close social interactions, with the consumption of moderate amounts of wine that produce the observed health benefit.

“…wine — and particularly red wine — developed a reputation for having health benefits after news stories appeared around its high concentration resveratrol and other polyphenols.”

In more recent decades, wine — and particularly red wine — developed a reputation for having health benefits after news stories appeared around its high concentration resveratrol and other polyphenols. Polyphenols are large, poorly absorbable molecules which are produced by most plants, providing multiple benefits to the plants’ health, including protection against UV light, pests and drought. Once consumed by humans, these large molecules are converted by our gut microbes into smaller absorbable entities which are beneficial for the health of our gut microbiome, for gut health and for many organs in our bodies, including the brain. In addition to the stilbene Resveratrol, red wine contains different members of the Flavonoid family, including flavanols (also contained in cocoa beans), flavonols (also contained in green leafy vegetables and onions) and anthocyanins (also contained in black and blue berries). Berries as well as the skin of red grapes also have high concentration of resveratrol. It has been suggested that these health promoting molecules contained in wine not only contribute the unique flavor to different wines, but that they are the reason for the health benefit of moderate wine consumption.

But the moderate alcohol hypothesis has come under increasing criticism over the years as the alcohol industry’s role in funding polyphenol research has come to light. Newer studies have found that even moderate consumption of alcohol — including red wine — may contribute to cancers of the breast, esophagus and head and neck, high blood pressure and a serious heart arrhythmia called atrial fibrillation.

“Regular moderate consumption of red wine (e.g. 2 glasses per day) when embedded into a healthy lifestyle with regular physical exercise, a healthy diet and close social interactions are likely to have a synergistic effect which is good for our physical and mental health.”

My personal opinion on this topic is somewhat different from the recommendation based on the recent meta-analysis. Regular moderate consumption of red wine (e.g. 1 glass per day) when embedded into a healthy lifestyle with regular physical exercise, a healthy diet and close social interactions are likely to have a synergistic effect which is good for our physical and mental health. This view is not only supported by a large number of epidemiological studies; thousands of years of experience of people living in the Mediterranean basin practicing such a lifestyle cannot be wrong.

What Is All the Fuss About Boosting Our Immunity?

By Emeran Mayer, MD

“… 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.”

Accompanying the popularization of gut microbiome science in the lay media and on the web, 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. Podcasts, master classes, social media posts, and advertisements for supplements, pre- and probiotics, as well as bestselling books have all driven the frenzy around these topics, while scientific evidence from well controlled human studies to support the findings obtained in mouse models have lagged way behind. As a clinician and scientist who has studied the gut, its endocrine, nervous, and immune systems as well as the brain for the better part of my career, it is remarkable to follow this explosion of information and interest.

The “advice” that lay audiences get from books and experts on social media implies that they either have to adopt anti-inflammatory measures such as anti-inflammatory diets or supplements, or that they need interventions to boost their immune system. All implying that there is a blunted, inadequate or compromised response of the immune system contributing to many of our chronic health problems.

“… 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 epidemic.”

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 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 group of chronic diseases, 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 brakes, once activated. An important factor in this compromised braking mechanism is related to an inadequate production of short chain fatty acids from complex carbohydrates by the gut microbiota, and the resulting insufficient activation of a group of immune cells that produce the powerful anti-inflammatory molecule interleukin 10 (IL-10). This insufficient production of the immune system’s own powerful anti-inflammatory molecules can occur long before we are born, or can develop later in life.

“… when pregnant women eat a largely plant-based diet rich in fiber, short chain fatty acid-producing microbes thrive, … which not only have an anti-inflammatory effect on the mother’s gut and body, but …. On the developing fetus as well.”

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, derived from the fermentation of dietary fiber by intestinal microbes in the mother’s gut. The amounts and types of these molecules that are produced there and transferred to her baby via the placenta depend on the maternal microbial ecosystem, which in turn is shaped by the mother’s diet. As discussed in detail in The Gut Immune Connection, when pregnant women eat a largely plant-based diet rich in fiber, short chain fatty acid-producing microbes thrive, and increased amounts of them, in particular butyrate, not only have an anti-inflammatory effect on the mother’s gut and body, but these same molecules are transferred to the developing fetus as well. Recent research suggests that butyrate not only can counteract inflammation, but also can influence the maturation and reactivity of the fetal immune system. Specifically, they stimulate the development of a population of immune cells (so called regulatory T cells), 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.

Butyrate produced by the mother’s microbiota doesn’t only play a crucial role for the health of the developing fetus. 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 spread of the inflammation to other organs, a process called metabolic endotoxemia.

“Reduced butyrate and short chain fatty acid production leading to a hyperresponsiveness of the immune system, may also play a role in the greater susceptibility and clinical course that were observed in some patients with COVID-19 infections.

Reduced butyrate and short chain fatty acid production leading to a hyperresponsiveness of the immune system, may also play a role in the greater susceptibility and graver outcomes that were observed in some patients with COVID-19 infections. Individuals with pre-existing metabolic or cardiovascular chronic diseases were more vulnerable to the infection, and hyperreactivity of the immune system (“cytokine storm”) has been associated with more severe and longer lasting symptoms. On the other hand, patients on immunosuppressive medications have NOT been found to be more susceptible to the virus.

In summary, our bodies regulate their own immune support very effectively as long as we feed our microbes a healthy diet full of fiber and polyphenols, a group of large molecules targeted at the gut microbes. Even though messages in social media and promotions of “immune boosting” supplements may tell you otherwise, there is no scientific evidence that additional “immune support” or boosting of our immune system is needed.

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. It afflicts 150,000 Americans, 250,000 Europeans and 1 million people worldwide annually, and nearly one third will die. 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. Rather than taking a closer look at the root cause of this problem, the response of the medical system to this alarming trend has been the promotion of colon cancer screening without paying much attention to the role of lifestyle factors that have dramatically changed in the past 75 years, in particular dietary changes. Screening with colonoscopies has permitted early detection and recent studies have clearly shown that this early detection is associated with a significant reduction in mortality rates. 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. Recently, when I asked an expert on colon cancer screening if individual dietary habits are considered as risk factors to determine how closely individuals with a positive finding on an initial screening colonoscopy have to be followed, the surprising answer was “this would be a great idea”.

“…new cases have been increasing in young and middle-aged adults…”

As is the case for many of our non-communicable chronic diseases, the burden of CRC is rapidly shifting to younger individuals. In the United States, despite declines in older adults, 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. 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 be a major factor underlying the upward trend in early-onset CRC.

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, 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 increasingly in younger age groups and 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.

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

Reviewing the current evidence, I feel strongly that diet-induced changes in the interactions between the gut microbiome and the gut-associated immune system are a key mechanism underlying the current 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 (including high fructose corn syrup) and animal products (red meat and animal fats), paired with a greatly reduced consumption of variable fruits and vegetables containing fiber and polyphenols, as well as 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. A study published in the journal Nature Communications in 2015 compared the effect of diet on CRC risk in African Americans and rural Africans. The authors of the study focused on the importance of diet in African Americans and to explore the hypothesis that CRC risk is determined by the influence of the diet on the microbiota to produce molecules that either decreased (anti-neoplastic) or increased (pro-neoplastic) the risk of colon cancer.

“Animal protein and fat intake were two to three times higher in Americans, whereas consumption of complex carbohydrates and fiber, primarily in the form of resistant starch, were higher in Africans.”

They observed that the diets of African Americans here in the United States, and Africans living in rural villages in South Africa, were fundamentally different in preparation, cooking and composition. Animal protein and fat intake were two to three times higher in Americans, whereas consumption of complex carbohydrates and fiber, primarily in the form of resistant starch, were higher in Africans. Looking at colonoscopies, African Americans had more polyps and higher rates of mucosal proliferation. The dietary differences were shown to be associated with profound differences in the gut microbiota. In Americans, the genus Bacteroides dominated, whereas the genus Prevotella dominated in South Africans. The two groups also differed in the functional capacity of their microbes: Africans had higher levels of starch degraders, carbohydrate fermenters and short chain fatty acid (butyrate) producers, while secondary bile acid producers dominated in Americans. It is well known that products of fiber fermentation, in particular the short chain fatty acid butyrate, are anti-inflammatory and anti-neoplastic, while the products of microbial bile acid conjugation, e.g. different types of secondary bile acids, are carcinogenic. These findings suggested two potential mechanisms for diet-associated colon cancer risk: the protective effect of dietary fiber in increasing the production of butyrate, and the pro-neoplastic effect of dietary fat on stimulating bile acid synthesis by the liver.

In summary, considerable epidemiological evidence supports an important role of diet in colon cancer risk. However, it is important to keep in mind that the cause of cancer is multifactorial, including several lifestyle factors and exposure to environmental chemicals and toxins.

Why Are More and More People Living to 100?

By Emeran Mayer, MD

Having had the personal experience of seeing parents and loved ones struggle through the last few years of life, often admitting that they would much prefer to die than to go on with the consequences of physical and mental decline, I wonder about the fascination of scientists to unravel the biological keys to super longevity, and the growing popularity of books and online information dealing not only with how to live to 100 and beyond, but even reach immortality.

“…millions of years of evolution on our planet have come up with this universal cycle of birth and death…”

Ageing and dying are natural parts of life. Millions of years of evolution on our planet have come up with this universal cycle of birth and death, optimizing reproductive and survival mechanisms, including age-adjusted muscle strength, cardiovascular and pulmonary function, and reaction times at certain ages when there is a particular need for these functions, and a slow functional decline towards the end of life, when they are no longer essential for survival. In my opinion, these are basic facts that we should accept as the wisdom of evolution.

So, do we really want to alter a system that has evolved to provide immense adaptive value for us living in harmony with this planet, and risk major disruptions in the planetary ecosystem by trying to change it? And what about the psychological, sociopolitical, and economic problems that rapidly aging societies with low birthrates, like Japan, South Korea and China have been experiencing?

….[should our goal be] to enable healthy aging with minimal medical and surgical interventions within the biological bandwidth?”

Or should we primarily be interested in interventions that build on conserved mechanisms of aging, and optimize these systems through lifestyle modifications, with the primary goal being not to prolong the human lifespan beyond its evolutionary programmed upper limit, but to enable healthy aging with minimal medical and surgical interventions within the biological bandwidth?

As described by Patricia S. Daniels in the Feb 7, 2023 issue of the National Geographic magazine, two basic mechanisms have been implicated in the natural aging process. According to Daniels, “…one group of theories holds that the body ages because of wear and tear that accumulates in the tissues over the years. Waste products build up in cells, backup systems fail, repair mechanisms gradually break down, and the body simply wears out like an old car. The second group of theories says that aging is driven by our genes—by an molecular clock set to a particular timetable for each species.” As I will discuss in this post, there is evidence for both of these theories. Biologists point out that from an evolutionary point of view, the effects of natural selection greatly decline after reproductive age, as evolution favors genes that are beneficial early in life, putting the body’s resources into reproduction and leaving fewer available for long-term maintenance”.

“…current population trends around the world seem to be moving into a different direction as evolution had in mind.”

However, current population trends around the world seem to be moving into a different direction as evolution had in mind. For poorly understood reasons, falling birthrates and increasing longevity have been going hand in hand in several countries around the world, turning large portions of these countries into what have been called Blue Zones. According to the Blue Zone concept, there are geographic regions around the world with an unusually high proportion of individuals living into their hundreds, so called centenarians. However, a closer look at epidemiological trends tells us that this phenomenon is not restricted to Blue Zones any more. Based on a 2022 estimate by the United Nations, there are currently 593,000 centenarians around the world and this population is growing fast. The UN projects there will be 3.7 million centenarians alive by 2050.

Even though centenarians make up a very small percentage of the relatively young countries China and India, they make the list mainly because of their large populations. However, centenarians make up a larger share of the total populations of rapidly aging Japan and Italy. Today, there are 4.8 centenarians for every 10,000 people in Japan and 4.1 in Italy. By comparison, the US is aging at about half the rate compared to Japan and Italy, partly due to its higher fertility and immigration rates. By 2050, China is expected to have the largest centenarian population, followed by Japan, the U.S., Italy, and India.

What is the main reason underlying this rapid aging of some of the most populated countries in the world?

What is the main reason underlying this rapid aging of some of the most populated countries in the world? In terms of aging of entire populations, as demonstrated by the countries listed above, the combination of decreasing birthrates and increased longevity seem to be the main factors. But in terms of the rapidly increasing number of centenarians, the answers is not so clear. Humans have obviously not changed genetically in the past 75 years which suggests that non-genetic, environmental or lifestyle factors should primarily be responsible. One of these factors has been the massive multi-trillion interventions in modern medicine and surgery which have greatly reduced mortality from infectious and age-related diseases, without reducing the number of people afflicted by most of these chronic diseases, the so-called prevalence rates. On the contrary, the prevalence of our most common chronic diseases have been increasing over the last 75 years in the US and countries around the world which have adopted sedentary lifestyles and the unhealthy Standard American Diet. In view of this chronic disease epidemic, it is highly unlikely that the increase in number of centenarians is related to the adoption of a healthier lifestyle, in particular diet, regular physical activity and social interactions.

Aging affects almost all of the body’s systems: the senses, the digestive organs, the cardiovascular system, the immune system, the bones, the muscles, and even the gut’s microbiome. Interestingly, in a healthy individual, the central nervous system—the brain and spinal cord—is among those least affected by age. In most tissues, the normal decline in function in the absence of neurodegenerative disorders like Alzheimer’s and Parkinson’s disease is not drastic, but it greatly accelerates in situations of chronic stress, unhealthy diets, and disease, as we are witnessing in the form of the unfolding chronic non-communicable disease epidemic, including accelerated cognitive decline.

Changes to bones (osteopenia) and muscles (sarcopenia) affect an older person’s daily life perhaps more than anything else. Between the ages of 30 and 60, bone density and muscle mass decrease in both men and women. In industrialized countries, between the ages of 30 and 75, about half the body’s muscle mass disappears, while the amount of fat doubles. Rather than being a normal part of aging, a major reason for this decline in musculoskeletal function is related to the predominantly sedentary lifestyle that modern societies have adopted.

The heart, blood vessels, and lungs are durable structures, built for a long lifetime. The fact that so many older people develop heart and lung problems has less to do with the aging process than with lifestyle factors, such as smoking, obesity, consuming an unhealthy diet, and lacking exercise. Many large-scale epidemiological studies are supporting this major role of lifestyle.

Several studies have explored the potential role of the gut microbiome in healthy aging. In contrast to our tissues and organs, the microbes living inside of us have their own genome, 100-fold larger than our own. As I have extensively discussed in my book, The Gut Immune Connection, current microbiome research strongly suggests potential connections to many health conditions including obesity, metabolic disorders, inflammation, cancer, and depression.

“Throughout the human life span, the gut microbiome follows some predictable temporal patterns…”

Throughout the human life span, the gut microbiome follows some predictable temporal patterns, with rapid change from infancy to age three, remarkable stability up until middle age, and then accelerated change starting in late adulthood. Previous studies have found gut microbiome pattern differences between older adults who are lean and physically active compared to their less fit and healthy contemporaries. Other research has connected early development of frailty to less gut microbial diversity.

“…older adults who had a more unique, personalized pattern of changes to their GI microbe profile with age also tended to be healthier and live longer…”

In a recent study, published in the prestigious journal Nature Metabolism, a group of prominent investigators from several US universities with lead author Tomasz Wilmanski analyzed gut microbiome genetic sequences and a wealth of other health and survival outcomes data from more than 9,000 people between the ages of 18 and 101. The investigators found that older adults who had a more unique, personalized pattern of changes to their GI microbe profile with age also tended to be healthier and live longer than peers with less microbiome divergence. According to this study, the identified microbiome pattern of healthy aging is characterized by a depletion of core taxa found across most humans, primarily the genera Bacteroides. Retaining a high Bacteroides dominance into older age, or having a low gut microbiome uniqueness measure, predicted decreased survival in a four-year follow-up.

“The loss of core groups of microbes, and the increase in α-diversity reported in long-lived individuals suggest that gut microbiomes may become increasingly unique, to each individual as they age.”

Several studies conducted on centenarian populations provided potential insight into gut microbial trajectories associated with aging. One of these demonstrated that gut microbiomes of centenarians (≤104 years of age) and supercentenarians (104+ years) show a depletion in core abundant taxa (Bacteroides, Roseburia and Faecalibacterium, among others), complemented by an increase in the prevalence of rare taxa. Similar findings have since been reported in other centenarian populations across the world, in particular in regions identified as Blue Zones, such as in Sardinian, Chinese and Korean centenarians, relative to healthy, younger controls. Some studies have also reported higher levels of gut α-diversity in centenarians compared to younger individuals, indicating that gut microbiomes continue to develop within their hosts, even in the latest decades of human life. The loss of core taxa, the exact identities of which may vary across different human populations (Bacteroides vs. Prevotella), and the increase in α-diversity reported in long-lived individuals suggest that gut microbiomes may become increasingly divergent, or unique, to each individual as they age.

“…those with less diverse gut environments used more medications and were nearly twice as likely to die during the study period.”

In the Wilmansky study, people whose gut microbiomes had grown more unique with age were able to walk faster and had better overall mobility than peers who showed less GI microbe changes with age. Plus, those with less diverse gut environments used more medications and were nearly twice as likely to die during the study period. Unsurprisingly, the research team suggested that modern diets like the Standard American Diet, rich in salty, sugary, or fatty processed foods may be responsible for the microbiome changes in less healthy individuals, may be the main factor underlying the observed age-related changes.

“…the progressive, exponential increase in centenarians in certain countries in the world, cannot simply be explained by dramatic lifestyle changes.”

In summary, a wealth of epidemiological and observational studies support the concept that our bodies and brains have evolved to last up to 100 years at high functional capacity. Obviously, not everybody reaches that goal, depending on variabilities in genes, environmental factors, lifestyle, and access to modern healthcare. Longevity occupies a certain bandwidth, within which people can die at a relatively young age, or live to 100. Where we find ourselves in this wide bandwidth depends a lot on our lifestyle choices, a conclusion supported by a wealth of scientific evidence.

The big unanswered question is why we are witnessing a progressive, exponential increase in centenarians in certain countries around the world. In developing countries this increase may in good parts be due to the benefits of modern medicine and public health measures, in the form of antibiotics, vaccinations and increased hygiene. However, the increased longevity is harder to explain in the developed world, which has been experiencing an epidemic of chronic diseases during the last 75 years, driven in large parts by negative lifestyle and environmental factors.

How can this epidemic with increased morbidity be associated with a rising number of centenarians? The answers to this question will have major implications for our future. On the other hand, in the developed world, leading a healthy lifestyle is certainly the most effective way to move to the upper limit of this bandwidth without requiring an ever-increasing number of supplements or futuristic genetic engineering.

A New Holistic Understanding of IBS

By Emeran Mayer, MD, Hyo Jin Ryu and Ravi Bhatt

IBS is one of the most common disorders of brain-gut interaction globally, with prevalence rates between 5 and 10% for most Western countries and China. In contrast to many chronic non-communicable diseases, such as metabolic, neurological, cardiovascular and some forms of cancer, which we have often discussed in this blog, there has been no progressive increase in prevalence during the past 75 years.

“Based on questionnaire data, women are 1.5–3.0 times more likely to have IBS.”

Based on questionnaire data, women are 1.5–3.0 times more likely to have IBS, reflecting a prevalence in women of 14% and in men of 8.9%. However, based on healthcare system utilization, women are up to 2–2.5 times more likely to see a healthcare provider for their symptoms.

Based on the current symptom criteria, IBS is defined by chronically recurring abdominal pain associated with altered bowel habits in the absence of detectable organic disease. IBS symptoms can be debilitating in a small number of patients, but are mild to moderate in the majority of affected individuals. Based on this definition, other frequently associated somatic or visceral pain and discomfort, as well as anxiety and depression are considered so called comorbid conditions.

“IBS is commonly associated with anxiety, depression, and other types of pain…”

The gut-restricted definition of the Rome criteria overlooks the fact that a large number of individuals who meet diagnostic criteria for an anxiety or depressive disorder have IBS and vice versa, and a majority of IBS patients show elevated levels of trait anxiety and neuroticism, or meet diagnostic criteria for an anxiety disorder. Currently, the commonly associated psychiatric and somatic symptoms are generally referred to as comorbidities, separate from the primary GI diagnosis and not present in all patients. However, detailed patient histories, frequently reveal symptoms of abdominal discomfort, anxiety and behavioral disturbances starting in early childhood in a majority of patients.

“IBS has genetic abnormalities in both the brain and in the little brain of the gut…”

A large recent genetic epidemiological study has provided an intriguing explanation for the cooccurrence of abdominal and psychiatric symptoms in IBS patients on the basis of several shared gene alterations (so called single nucleotide polymorphisms or SNIPs). These new findings are consistent with genetic vulnerabilities affecting both the central and the enteric nervous system, and argue against the long held linear pathophysiological concepts that emotional factors may cause IBS symptoms, or that chronic IBS gut symptoms lead to anxiety and depression.

“Traditional understanding of IBS mechanisms has been limited and restricted to gut symptoms…”

Much of research and drug development in IBS patients has been based on descriptive and symptomatic features, rather than on biology-based disease definitions. These definitions suggest a core abnormality shared by all IBS patients (chronic, recurrent abdominal pain) as well as heterogeneity based on self-reports of predominant bowel habit. However, a comprehensive identification of distinct biology-based subgroups of patients including those based on sex, with different underlying pathophysiological components and differential responsiveness to specific therapies, has not been achieved.

In our recently published review article in the prestigious journal Molecular Psychiatry, we discuss the evidence supporting an integrative brain gut microbiome (BGM) model. This model incorporates a large body of evidence from studies on peripheral and central neurobiological disease mechanisms, brain and gut targeted influences of stress and the environment, and results from recently reported large scale genetic analyses with relevance for neuronal dysfunction of the central nervous system and the enteric nervous system (the “little brain” of the gut). The proposed model is consistent with the frequent comorbidity of IBS with other so-called functional gastrointestinal disorders affecting the esophagus, stomach, and other gut areas, and with other chronic pain outside of the gastrointestinal tract, and psychiatric disorders, in particular with anxiety. We also discuss the implications of this model for a better understanding of the biology underlying IBS symptoms and for the development of more effective multidisciplinary treatment approaches.

The Amazing Evolution of the Goodman-Luskin Microbiome Center at UCLA

By Emeran Mayer, MD

Studying the bidirectional interactions between the brain and the gut in health and disease has been the focus of my 40 years in academic medicine, an interest that was preceded by my research on the interactions between the brain and the heart during my dissertation in Medical School.

From the beginning, I realized that irritable bowel syndrome (IBS) was the quintessential disorder of altered brain gut interactions, a concept that was virtually ignored by my colleagues in gastroenterology (“a disorder of neurotic housewives”) and which was a difficult research area to get funding for. At the time, patients were equally reluctant to accept the brain gut interaction model, as they were concerned it would reinforce the widespread prejudice that IBS was all in the head, and not a real disorder.

After spending several decades of NIH- and philanthropy-supported research combined with close clinical interactions with patients suffering from brain gut disorders, from the esophagus, stomach to the large intestine, I was able to obtain a generous gift from the Oppenheimer Family Foundation to establish the Center for Neurobiology of Stress and Resilience. I felt confident that the brain-gut model was able to fully explain the development and symptoms, and provide a rational treatment approach to my patients with IBS. It was particularly rewarding that some 40 years after I had first published and lectured about altered brain-gut interactions, the field gradually accepted our original concept and suddenly started referring to these syndromes for the first time as “disorders of gut–brain interaction, related to any combination of the following: motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered Central Nervous System.”

The story took a new turn after several intriguing animal studies were published in the literature, which suggested that microbes living in the gut may play a significant role in these brain-gut interactions as well. Although initially skeptical about these findings, together with my colleague Dr. Kirsten Tillisch, I performed the first research study in healthy human participants that confirmed the ability of microbes (given as a probiotic cocktail) to communicate with the brain. Following these initially startling findings, our group published close to 100 manuscripts strongly suggesting a link between the 40 trillion microorganisms in our gut and structure and function of the brain.

My research interest rapidly expanded beyond IBS to other putative brain-gut-microbiome disorders such as autism spectrum disorders, early cognitive decline, Parkinson’s disease and inflammatory bowel disorders. Collaborations with investigators with clinical and research interests in these disorders developed across the UCLA campus and beyond, to investigators at USC, UCSD, Duke University and Baylor University. Based on these collaborations and the growing scientific interest in the field of brain-gut-microbiome interactions, I elicited the interest of the chief of the Vatche & Tamar Manoukian Division of Digestive Diseases at UCLA, Dr. Eric Esrailian, to support the development of a translational research center.

After two years of hard work to bring together a group of outstanding investigators working in different areas of medicine on the role of the gut microbiome, I became the founding director of the new center, and a dream came true when Andrea and Donald Goodman and Renee and Meyer Luskin made a $20 million gift to establish the UCLA Goodman–Luskin Microbiome Center.

This new center will facilitate multidisciplinary collaborations among experts across the campus on the role of the human microbiome in health and disease. By funding senior faculty, drawing talented new researchers into the field, and building a strong infrastructure for these studies through the development of core facilities, the center will work to identify the microbiome’s role in disease prevention and the body’s immune response with the goal of developing new treatments for a range of conditions including inflammatory and irritable bowel diseases; obesity and eating disorders; neurodevelopmental and neurodegenerative diseases such as autism, Alzheimer’s and Parkinson’s disease; liver disease, substance use and psychiatric disorders.

The new center, based in the UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, will bring together researchers from across the UCLA campus in interdisciplinary efforts to study how the trillions of microorganisms that inhabit the human gut are implicated in wide-ranging health-related conditions — and how those findings can be translated into new strategies for prevention, treatment, and health promotion.

Looking back over the past 40 years, I couldn’t be more excited that my interest in brain body interactions which started in Medical School persisted over nearly half a century and culminated in the publication of more than 415 manuscripts, two bestselling books, an upcoming PBS documentary and the launching of a cutting-edge research center in an area with immense implications for health and disease. I am glad to have stuck with my gut feelings!

SIBO – Debunking Popular Myths in Irritable Bowel Syndrome

By Emeran Mayer, MD

As the COVID-19 pandemic has engulfed the world, there has never been a time in which topics related to 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 (such as bloating and abdominal distension) and to promote controversial novel treatments. Podcast, master classes, social media posts and advertisements, bestselling books have all driven the frenzy around topics like SIBO, special gut friendly diets and cleansing protocols, while scientific evidence from well controlled human studies have been lagging behind.

I am convinced that a significant number of individuals striving for improved gut health are suffering from IBS or related disorders of brain gut interactions. In this post, I would like to focus on one such topic: 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”.

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 not only by functional and integrative medicine practitioners and by the lay media, but also by the medical establishment and the pharmaceutical industry. SIBO has been promoted as a diagnosis explaining some of the most common symptoms of abdominal discomfort such as bloating, abdominal distension and altered bowel habits. The concept has fueled a whole new “industry” of breath testing, and most worrisome, has led to the widespread and in my opinion totally 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.

“…there is currently no universally acknowledged or validated ‘gold standard’ for diagnosis, and no FDA-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, and most importantly, in my opinion should never be used as justification to prescribe antibiotics .

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 serious 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.

“…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, and put 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 reducing bloating symptoms 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 by the colonic microbiota 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.

In my opinion, future research focused on defining the normal small bowel microbiome with novel genomic and metabolomic technologies, and on the clinical utility of breath tests is required before making a valid diagnosis of SIBO and before routinely ordering the available breath test.

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. As explained in a previous post 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, reduction or elimination of certain food items that reproducibly increase GI discomfort, and the unique gut cleansing motility patterns (“migrating motor complex”) to keep a normal gradient of microbial density throughout the gut.

Choosing The Right Seafood For Optimal Health

By Emeran Mayer, MD and E. Dylan Mayer

If you have been following a gut- and brain-healthy diet, such as the traditional Mediterranean diet or a Pescatarian diet, you already know that seafood and plant-based foods should be your main sources of meat, replacing red meat. Seafood and poultry should make up about 25% of your total dietary intake. Importantly, you should enjoy the fish without being obsessed with fears of consuming toxins with your meal.

“Fish are a lean, healthy source of protein and some of them deliver those heart- and brain-healthy omega-3 (also called n-3) fatty acids that [are good for your brain].”

Fish are a lean, healthy source of protein–and the oily kinds, such as salmon, tuna, and the family of small fish such as sardine, mackerel, and anchovies–deliver those heart- and brain-healthy omega-3 (also called n-3) fatty acids that you should be getting in your diet. Studies have shown that while consuming a higher ratio of n-6 to n-3 fatty acids tends to promote inflammation, consuming a more balanced ratio can reduce inflammation. In addition, omega-3 fatty acids have been shown to promote neurogenesis (the development of new nerve cells) in a particular region of the hippocampus, the dentate gyrus and there is a strong correlation between omega-3 intake and hippocampal-dependent memory tasks. In the traditional Western diet, polyunsaturated fatty acids (PUFAs) are currently consumed at a ratio of approximately 1:16, whereas it has been estimated that our ancestors consumed a diet with a ratio closer to 1:1. Smaller, fatty fish, like sardines have the highest concentration of omega-3 fatty acids as a consequence of their consumption of omega-3 rich algae. By feeding on the small fish, larger fish like salmon enrich their meet with omega-3 fatty acids. So the decision to select fish with high omega-3 concentration is an easy one. However, there are two additional considerations that you should consider before making your choice. The fish should have low levels of contaminants in particular mercury and PCBs, and it should come from a sustainable fishery, and should not use fishing methods damaging other ocean species.

“Fortunately, there are trustworthy sources of information which can help you chose the right fish…”

Fortunately, there are trustworthy sources of information which can help you to navigate this dilemma, such as The Blue Ocean Institute and Seafood Watch, the program run by the Monterey Bay Aquarium. These programs have combined data from leading health organizations and environmental groups such as the Environmental Defense Fund (EDF) to come up with a list of seafood that’s good for you and good for the environment.

The following is adapted from an excellent blog by Brierley Wright, published by One Medical, a national, modern primary care practice pairing 24/7 virtual care services with inviting and convenient in-person care at over 100 locations across the U.S.

According to Seafood Watch, there are six fish/shellfish that are healthy for you and the planet.

1. Farmed Oysters
A 3-ounce serving contains over 300 mg of omega-3s and about a third of the recommended daily values of iron). Oysters are not only good for you, but for the environment. Oysters feed off the natural nutrients and algae in the water (which provides them with large amounts of omega-3), and which improves water quality.

2. Wild caught Pacific Sardines
The tiny, inexpensive canned sardine which has been popular in Europe for a long time, contains more omega-3s (1,950 mg!) per 3-ounce serving than salmon, tuna, or just about any other food; it’s also one of the few foods that’s naturally high in vitamin D. Many fish in the herring family are commonly called sardines. Sardines are a highly sustainable food source as they have a fast reproduction rate. Pacific sardines have rebounded from both overfishing and a natural collapse in the 1940s.

3. Wild caught Alaska Salmon
The numbers of wild salmon returning to spawn in Alaska’s rivers is being closely monitored, and if the numbers begin to dwindle, the fishery is closed before it reaches its limits. This close monitoring, along with strict quotas and careful management of water quality, means Alaska’s wild-caught salmon are both healthier (they pack 1,210 mg of omega-3s per 3-ounce serving and carry few contaminants) and more sustainable than just about any other salmon fishery.

4. Farmed Freshwater Coho Salmon
Freshwater coho salmon is the first–and only–farmed salmon to get a Super Green rating. All other farmed salmon still falls on Monterey Bay Aquarium’s Seafood Watch “Avoid” list for a few reasons. Many farms use crowded pens where salmon are easily infected with parasites, may be treated with antibiotics, and can spread disease to wild fish (one reason Alaska has banned salmon farms). Also, it can take as much as three pounds of wild fish to raise one pound of salmon. Coho, however, are raised in closed freshwater pens and require less feed, so the environmental impacts are reduced. They’re also a healthy source of omega-3s–one 3-ounce serving delivers 1,025 mg.

5. Farmed Rainbow Trout
Nearly all the trout you will find in the market is farmed rainbow trout. In the US, rainbow trout are farmed primarily in freshwater ponds and “raceways” where they are more protected from contaminants and fed a fish meal diet that has been fine-tuned to conserve resources.

6. Troll- or pole-caught Albacore Tuna from the US or British Columbia
Many tuna are high in mercury but albacore tuna–the kind of white tuna that’s commonly canned–gets a Super Green rating as long as it is “troll- or pole-caught” in the US or British Columbia. The reason: Smaller (usually less than 20 pounds), younger fish are typically caught this way (as opposed to the larger fish caught on longlines). These fish have much lower mercury and contaminant ratings and those caught in colder northern waters often have higher omega-3 counts. The challenge: You need to do your homework to know how your fish was caught or look for the Marine Stewardship Council (MSC) blue eco label.

Fish to Avoid

A number of environmental organizations have advocated taking many fish off the menu. The large fish listed below are just six examples of popular fish that are both depleted or threatened by extinction and, in many cases, carry higher levels of mercury and PCBs. Unfortunately, many restaurants continue to serve these fish on their menus and customers pay high prizes for what they think is a special treat.

1. Bluefin Tuna
In December 2009, the World Wildlife Fund put the bluefin tuna on its “10 for 2010” list of threatened species, alongside the giant panda, tigers, and leatherback turtles. Though environmental groups are advocating for protected status, the bluefin continues to command as much as $177,000 a fish. Bluefin have high levels of mercury and their PCBs are so high that EDF recommends not eating this fish at all.

2. Chilean Sea Bass or Patagonian Toothfish)
Slow-growing and prized for its buttery meat, Chilean sea bass has been fished to near depletion in its native cold Antarctic waters. The methods used to catch them–trawlers and longlines–have also damaged the ocean floor and hooked albatross and other seabirds. The EDF has issued a consumption advisory for Chilean sea bass due to high mercury levels.

3. Grouper
High mercury levels in these giant fish have caused EDF to issue a consumption advisory. Groupers can live to be 40 but only reproduce over a short amount of time, making them vulnerable to overfishing.

4. Monkfish
This strange fish resembles a catfish in that it has whiskers and is a bottom-dweller, but its light, fresh taste made it a staple for gourmets. The fish is recovering some after being depleted, but the trawlers that drag for it also threaten the habitat where it lives.

5. Orange Roughy
Like grouper, this fish lives a long life but is slow to reproduce, making it vulnerable to overfishing. As Seafood Watch puts it: “Orange roughy lives 100 years or more–so the fillet in your freezer might be from a fish older than your grandmother!” This also means it has high levels of mercury, causing EDF to issue a health advisory.

6. Salmon (farmed)
Most farmed salmon (and all salmon labeled “Atlantic salmon” is farmed) are raised in tightly packed, open-net pens often rife with parasites and diseases that threaten the wild salmon trying to swim by to their ancestral spawning waters. Farmed salmon are fed fish meal, given antibiotics to combat diseases and have levels of PCBs high enough to rate a health advisory from EDF. Recently, however, freshwater-farmed coho salmon have earned a Best Choice status from Seafood Watch. Consumer pressure may encourage more farms to adopt better practices.

7. US freshwater fish – Hot off the press
According to a research study just published in the journal Environmental Research, eating just one serving of freshwater fish, caught in lakes and streams each year could have the same effect as drinking water heavily polluted with “forever chemicals” for an entire month, a new study finds. According to the study, the equivalent monthlong amount of water would be contaminated at levels 2,400 times greater than what’s recommended by the Environmental Protection Agency’s (EPA) drinking water health advisories. The research added that locally caught freshwater fish are far more polluted than commercial catches with per- and polyfluorinated substances (PFAS) — so-called forever chemicals that are notorious for their persistence in the body and the environment.

“Three criteria make it relatively easy for an informed consumer to decide which fish to buy”

In summary, using the 3 criteria of health benefit, low contamination and sustainability makes it relatively easy for an informed consumer to decide which fish to buy. While many popular fish types are on the Avoid List, the top three choices for you and the planet are small fatty fish, oysters and wild caught Alaskan salmon.

E. Dylan Mayer is a graduate from the University of Colorado at Boulder, with a major in Neuroscience and minor in Business. He is currently completing his master’s degree in Human Nutrition from Columbia University. Dylan is fascinated by the close interactions between nutrition, exercise and human health, especially with regard to the brain-gut-microbiome system – and regularly posts his content on his Instagram (@mayerwellness).

Depression and The Gut Microbiome – The Unresolved Chicken and Egg Question?

By Emeran Mayer, MD

Depression is one of the most common mental disorders experienced worldwide with an average lifetime prevalence of 11–15%. As I discussed in The Gut Immune Connection, about 160 million people suffered from major depressive disorder in 2017, young people being the highest risk group. A Blue Cross Blue Shield report showed that in 2016, 2.6% of youths between twelve and seventeen years of age were diagnosed with major depression, a 63% increase from 2013. In addition to these disturbing numbers, the prevalence of depression has doubled and, in some countries, even tripled during the COVID-19 pandemic, suggesting a strong role of environmental factors (the so called “exposome”) in its pathogenesis. The importance of the exposome which includes lifestyle, diet, and exposure to chemicals is further supported by the low to moderate heritability and the small effects of genetic variants identified in large genome-wide association studies of depression.

“…the prevalence of depression has doubled and, in some countries, even tripled during the COVID-19 pandemic…”

Despite a wealth of preclinical and clinical knowledge published during the past decades, pharmacologic treatment options, based primarily on the prevalent disease model implicating an imbalance of monoamine neurotransmitters like serotonin, dopamine, and norepinephrine, are sub-optimal with most antidepressants performing only marginally better than placebo. In the hope to overcome these limitations, researchers have expanded the traditional narrow focus on these monoamine neurotransmitters and strategies (in particular reuptake inhibitors for serotonin, like SSRIs and norepinephrine (NSRIs), to other disease mechanisms and treatment strategies, such as diet (nutritional psychiatry), psychedelic compounds (like ketamine or psilocybin) and the microbiome.

“…animal studies suggest that the gut microbiota might have impact on the neurobiological features of depression.”

Based on a series of paradigm shifting preclinical studies in mice, the gut microbiome has emerged as another promising candidate in the pathophysiology of human depression. Several animal studies suggest that gut microbiota might have an impact on the neurobiological features of depression. For example, a study showed that transferring gut microbiota from depressed human patients to “germfree” rats without a gut microbiome showed that the recipient animals developed depression-like behaviors suggesting (but not proving) that gut microbiota may be causally involved in the development of depression. However, there have been very few studies systematically exploring the association between gut microbiome and depression in humans. Further, the existing studies are based on very small samples, lacking statistical power to detect robust and reproducible associations. The majority of published studies in humans did not adjust for confounding lifestyle factors and medication use, which are known to modify the gut
microbiome.

“Two large recent studies have confirmed the association of a group of gut microbes with symptoms of depression.”

In a recent study, published in the prestigious journal Nature Communications, a team of European investigators aimed to overcome limitations of earlier studies by investigating the association of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from a large existing data set (the Rotterdam Study cohort) and validate these findings in another data set of 1,539 subjects (the Amsterdam HELIUS Cohort). In this impressive study, the investigators identified an association of thirteen microbial taxa with depressive symptoms. These microbes are known to be involved in the synthesis of butyrate, an anti-inflammatory short chain fatty acid, and the central neurotransmitters glutamate, serotonin, and gamma amino butyric acid (GABA), which are molecules long implicated in the pathophysiology of depression. Based on their findings, the author suggested that the gut microbiome composition may play a key role in depression.

In a companion paper, the same group of investigators analyzed samples from 3211 individuals from the same HELIUS cohort, with the aim to characterize gut microbial changes and their associations with depressive symptoms in 6 ethnic groups (Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish, Moroccan), living in the same urban area. While gut microbial diversity predicted depressive symptom levels, these associations did not differ between ethnic groups. Bacterial genera associated with depressive symptoms belonged to multiple microbial families. In summary, analyses of a large and ethnically diverse population demonstrated robust associations between features of the gut microbiome and depressive symptoms. These associations were largely invariant across ethnic groups and withstood adjustment for a uniquely large set of potential confounders, including demographic, behavioral, and medical factors.

“Is current evidence enough to establish some of these microorganisms as causing or contributing to depression?”

When viewed together, a growing number of well-designed high-quality studies in large human data sets have demonstrated a significant association of a group of gut microbes with known functions and symptoms of depression. Is it enough to establish some of these microorganisms as causing or contributing to depression? The answer is yes and no.

The preclinical and clinical evidence published over the past few years is certainly highly suggestive of a causal relationship. The identification of microbes capable of producing neurotransmitters involved in depression, and in anti-inflammatory butyrate provides plausibility of the findings. But the proof can only come from longitudinal intervention studies showing that an intervention-related change in the gut microbial alterations in patients with depression is associated with an improvement of clinical symptoms. For ethical reasons, it is obviously not possible to use the same strategy used in animal models, in which the transplant of fecal material from a donor mouse with depression-like behavior results in depression symptoms in the recipient. If the altered gut microbiome does play a clinically relevant change in depression, the question is why has the prevalence of depression increased in the last 10 years, particular in younger patient groups, and most dramatically during the pandemic? Which lifestyle changes that have a strong influence on the gut microbial ecosystem may be underlying this increase in symptoms? Is it the same diet-related systemic immune activation that has been implicated in the different diseases of the chronic non-communicable disease epidemic?

On the other hand, well characterized brain changes in animal models of depression and in human patients are associated with well-studied changes in the top-down influences of the brain on the gut and its microbiome. In my opinion, it is equally likely that these brain to gut influences, mediated by the autonomic nervous system and the central stress system are responsible in part for the observed microbiome changes.

In my personal view, there is still a long way to go before we can say for sure that the gut microbiome plays a role in depression which is causative and clinically relevant, and that interventions targeted at the gut microbiome are effective enough to be clinically meaningful, and don’t simply represent a placebo response.

One More Word About Extra Virgin Olive Oil

By Emeran Mayer, MD

Extra-virgin olive oil (EVOO) is one of the key health-promoting ingredients of the traditional Mediterranean diet, even though other dietary as well as lifestyle factors are likely to contribute to the health benefits of this diet, including but not limited to a high percentage of plant-based foods (high in vitamins, polyphenols and fiber), low red meat consumption and regular consumption of seafood (with a high ratio of omega-3 to omega-6 fatty acids).

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 several epidemiological clinical studies. Even though well controlled clinical trials with EVOO are not available, these benefits may be applicable to a wide range of metabolic disorders and cardiovascular diseases, which are all part of the current chronic non-communicable disease epidemic.

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

In addition to the high concentration of monounsaturated fatty acids (primarily oleic acid), evidence suggests that the high content of polyphenols in some of these oils (primarily oleuropein and hydroxytyrosol) contribute to the observed health benefit. As explained many times in this blog, the majority of polyphenols don’t act as antioxidants when consumed, but 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. And keep in mind, not every brand of EVOO containing the label Made in Italy contains the desired amount of polyphenols. The olives for many marketed brands of EVOO are grown in other Mediterranean countries but pressed and bottled in Italy.

“…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. But unlike FDA approved medications, the production and marketing of EVOO is not controlled, resulting in a variety of brands with many unsupported health claims. 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.

And don’t forget, the consumption of EVOO should not been viewed in isolation but rather as one important component of a gut and mind healthy lifestyle. Just like taking probiotics or various supplements while consuming the Standard American Diet (SAD), not doing regular physical exercise and going through life without mindfulness is not better for your health than taking a placebo pill, adding expensive olive oil to such an unhealthy lifestyle, wont move the needle towards better health!

Adapted from my book, The Gut Immune Connection

Non-Nutritive Sweeteners – Good or Bad for our Metabolic Health?

By Elvira Rostanzo, MSc and Emeran Mayer, MD

The global rising of obesity has become a worldwide public health crisis and represents one of the main challenges for prevention policies. In 2017, it has been estimated that over 2.1 billion people, or nearly 30% of the global population, are overweight or obese. Moreover, the obesity rate among US children and adolescents has tripled in the last three decades. It is estimated that 9.6% of children aged 6–11 years and 18.1% of adolescents aged 12–19 years are obese.

Obesity is not just a cosmetic problem, but it is also associated with multiple serious comorbidities including type 2 diabetes, metabolic syndrome, cardiovascular disease, as well as an increase in the risk to develop many types of cancer (breast, ovarian, renal, pancreatic among others).

“The growing rate of obesity is related to dramatic changes in eating habits, with the widespread adoption of the so-called Western Diet in both high- and low-income countries.”

The growing rate of obesity is related to dramatic changes in eating habits, with the widespread adoption of the so-called Western Diet (the US version of this diet is the Standard American Diet or SAD) in both high- and low-income countries. The Western Diet is characterized by a regular intake of ultraprocessed foods (containing additives like emulsifiers and hidden sugars such as high fructose corn syrup), “fast food” products, unhealthy snacks, and sugary soft drinks. Not surprisingly, the consumption of sugary soft drinks and the rate of obesity and type 2 diabetes have risen in parallel.

In response to this diet-induced health crisis, the food industry has made a major effort to replace “classic” sugary sweeteners such as sucrose, dextrose, and high-fructose corn syrup with non-nutritive sweeteners (NNS) that can be classified as artificial (saccharin, sucralose, aspartame, acesulfame-K) or natural (stevia, monk fruit and xylitol).

At first glance, there are obvious advantages of making this switch, which promises to allow lovers of sweet tasting foods to “have the cake and eat it too”. The main advantages of using NNS (in addition to their low cost) are the fact that some of these substances are either non-absorbable (sucralose), or have such high sweetening power that they can produce the desired sweet taste, without the negative metabolic effects of high sugar absorption. The perception of sweet taste is mediated by so called sweet taste receptors on your tongue, but also throughout the small intestine. As a result, NNS have become popular thanks to their negligible caloric content, and NNS-sweetened products (in particular beverages) are labeled as “zero calories” or “no sugar added”. However, because of the various functions of sugar, removing sugar from food products not only influences sweetness, but can also affect the overall functionality, flavor perception, texture, and overall liking of food.

But do NNS really live up to their promises of weight loss, and prevention of glucose intolerance and type 2 diabetes mellitus? Unfortunately, there are conflicting findings reported regarding their effects on body weight control, glucose homeostasis, and underlying biological mechanism.

Trying to find an answer may be not so easy. NNS are widely-used and to find people that do not use NNS on a regular basis is challenging, leading to several studies which have been either negative (not showing any benefit) or inconclusive. A recent research study from the research team led by Eran Elinav at the prestigious Weizmann Institute in Tel Aviv published in the journal Cell explored the effect of three of these NNS on glycemic response, and on the human microbiome. The same group of investigators had published results from an earlier study showing that consumption of the three most commonly used NNS — saccharin, sucralose and aspartame — directly induces the development of obesity and glucose intolerance in mice. In this earlier study, the investigators showed that these effects were mediated by changes in the composition and function of the mice’s intestinal microbiota of the mice and that the deleterious metabolic effects could be transferred to germ-free mice by faecal transplantation and were abolished by suppressing the altered microbes in the recipient mice by antibiotic treatment. Demonstrating the translational relevance of these findings for human health, the authors were able to induce changes in the gut microbiome and glucose intolerance by the ingestion of NNS in healthy human subjects.

“Two of the tested sweeteners, saccharin and sucralose, significantly elevated the glycemic response during consumption…”

The recent study by the Weizmann Institute investigators was conducted on 120 subjects in good metabolic health and lasted 29 days. All the participants were normal weight (according to Body Mass Index, BMI) and had not been consuming any NNS. Two of the tested sweeteners, saccharin and sucralose, significantly elevated the glycemic response during consumption, while neither aspartame nor stevia had a significant effect on glucose tolerance during this time period. These results indicated that short-term consumption of sucralose and saccharin, even in doses lower than the Acceptable Daily Intake, can negatively impact glycemic responses in healthy individuals, and that not all NNS had the same negative effects.

“The results of both studies highlighted that NNS are not inert compounds, even when consumed in very small amounts…”

Similar to their findings in the 2014 study, all four tested NNS (saccharin, sucralose, aspartame, and stevia) significantly and distinctly altered the human intestinal and oral microbiome, as well as gut microbial metabolites in circulation, impacting the gut microbial ecosystem through several direct and indirect mechanisms. NNS inhibited the growth of some bacteria, while the prevalence of other bacterial species increased in the presence of NNS. Importantly, germfree mice which received microbiomes from human subjects from each of the four NNS-supplemented groups exhibited glycemic responses largely reflecting those noted in the respective human donors. In other words, the specific gut microbial changes induced by saccharin, sucralose, aspartame, and stevia consumption were able to cause similar metabolic changes as seen in the human subjects in the recipient mice. Based on their findings, the authors concluded that human NNS consumption may induce person-specific, microbiome-dependent changes in glucose absorption.

The results of both studies highlighted that NNS are not inert compounds, even when consumed in very small amounts, and that such small amounts can produce significant metabolic changes in our body even when the NNS are consumed in doses lower than the Acceptable Daily Intake. One of the reasons for these unexpected, and largely unknown, findings is the role of the gut microbiome. Further studies are needed to better elucidate their effects on human health on long term.

NNS have long been used to restrict caloric intake and prevent or reverse obesity; the label “zero calories”, “with natural sweeteners” or “no added sugar” may suggest that these sugar alternatives are better for our health. However, there is no scientific evidence that this is indeed the case. On the contrary, it has been shown that the growing rate of overweight and obesity occurs primarily among children who are most exposed to foods and beverages rich in NNS. Thus, while people with hyperglycemia, type 2 diabetes, or metabolic syndrome have been advised to avoid or limit sugar intake, the recommended alternative to replace sugar with NNS seems to increase the risk to develop the very metabolic disorders that they are thought to prevent.

“The extract is 150-250 times sweeter than table sugar, has zero calories and carbs, and does not raise blood glucose levels.”

As the recent Suez study showed differences in negative metabolic effects between synthetic NNS and those derived from plants, one may ask if natural NNS like Stevia and monk fruit may be a better alternative to replace sugar. Stevia sweeteners are derived from the leaves of the Stevia rebaudiana plant, an herbal shrub native to South America. This plant has been used for food and medicinal purposes for hundreds of years. Monk fruit, or lo han guo, is a small green melon native to southern China and named after the monks who first cultivated it centuries ago. Monk fruit gets its sweetness from natural compounds called mogrosides, which are also thought to have anti-inflammatory effects. Monk fruit sweetener is made from extract derived from dried fruit. The extract is 150-250 times sweeter than table sugar, has zero calories and carbs, and does not raise blood glucose levels. Its health benefits have been well-known in Traditional Chinese Medicine (TCM) for decades, long before it became a popular topic in the wellness conversation. According to a 2011 study, based on its anti-inflammatory effects, monk fruit has been used in TCM for centuries to make hot drinks that relieve sore throats.

Most NNS can cause side effects like gas, bloating, or allergic reactions. Based on the assessment that there are no known side effects of monk fruit sweeteners, the Food and Drug Administration has given monk fruit the label of “generally recognized as safe” (GRAS) for everyone, including pregnant women and children, even in the absence of controlled scientific studies on the effects of long-term use.

“Unless specifically stated on the label, one should not assume that all monk fruit products are carb- and sugar-free.”

Even though the ingestion of monk fruit is generally safe for those with diabetes (as it doesn’t increase blood sugar levels), foods and drinks sweetened with monk fruit (as well as some monk fruit sweetener blends) may include added sugars and other ingredients that increase calorie counts or affect insulin sensitivity. Unless specifically stated on the label, one should not assume that all monk fruit products are carb- and sugar-free.

In conclusion, a growing number of studies have identified negative metabolic effects in response to the ingestion of certain NNS. One of the reasons for these largely unknow negative effects are related to the interaction of these molecules with the gut microbiome which plays a key role in maintaining glucose homeostasis. As shown in these studies, the microbiome can be altered by some NNS and even healthy people can be affected. Based on current evidence, plant-derived NNS like stevia and monk fruit do not have the same metabolic side effects as synthetic compounds, even though definitive clinical evidence remains to be established.

Elvira Rostanzo, MSc is a registered Biologist who graduated in Human Nutrition. She is a practicing nutritionist and is currently attending the Specialization School of Food Sciences at University of Siena in Italy.

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

By Emeran Mayer, MD and Jill Horn

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.

Jill Horn is a recent UCLA graduate with a degree in 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

By Emeran Mayer, MD

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.

How Living in a Disadvantaged Neighborhood May Affect the Brain

The Stress That Evolution Has Not Prepared Us For

Weight Loss Drugs for Medication-Induced Weight Gain

SuperAgers and Alzheimer’s Disease

Ketamine and Major Depressive Disorder

Surprising News about Diet and Alzheimer’s Disease

The Benefits of a Modified Mediterranean Diet for Irritable Bowel Syndrome

What Do Social Connectedness and the Mediterranean Diet Have in Common?

Understanding and Treating Irritable Bowel Syndrome

Gut Health Insights #2 with Dr. Emeran Mayer | Irritable Bowel Syndrome (IBS)

Is Moderate Alcohol Consumption Beneficial For Your Health?

What Is All the Fuss About Boosting Our Immunity?

The Crucial Role of Diet in Colorectal Cancer Risk

Why Are More and More People Living to 100?

A New Holistic Understanding of IBS

The Amazing Evolution of the Goodman-Luskin Microbiome Center at UCLA

SIBO – Debunking Popular Myths in Irritable Bowel Syndrome

Choosing The Right Seafood For Optimal Health

Depression and The Gut Microbiome – The Unresolved Chicken and Egg Question?

One More Word About Extra Virgin Olive Oil

Non-Nutritive Sweeteners – Good or Bad for our Metabolic Health?

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

The Exciting New Science Underlying IBS Treatments