What Role Does the Gut Microbiome Play in the Effectiveness of Anti-Obesity Drugs?


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The new class of anti-obesity drugs like Ozempic, Wegovy, Zepbound remain the most popular modern drugs which have been shown in large, randomized placebo-controlled studies to reduce up to 20% of excessive body weight and – as long as you take them – maintain their effectiveness. Further flaming the public interest, recent preclinical and clinical research suggests that the same drugs which were originally developed as diabetes medications, may lower the risk of heart disease, such as heart failure, stroke and kidney disease.

“Obesity is a chronic disease that results in substantial global morbidity and mortality.”

According to the CDC, 40% of Americans are obese, and 32% are overweight. Soaring obesity rates make the United States the fattest country within The Organization for Economic Co-Operation and Development (OECD), a group made up of 38 countries in Europe, Asia and South America. Overweight and obesity rates have increased steadily since the 1980s in both men and women, and continue to grow, despite various behavioral, pharmacological and even surgical treatment approaches. Three out of four people are projected by the OECD to be overweight or obese within 10 years.

“Many previously tried interventions have failed due to side effects or lack of effectiveness.”

Dietary and behavioral approaches are often successful in the short term, but a large number of patients regain their weight after successful diet-induced weight loss (often overshooting their pre-diet body weight, a phenomenon referred to as the Yo-yo effect). However, there are exceptions to this gloomy assessment. A study of over 4,000 people who lost weight as part of a structured weight loss program identified behaviors that dieters have used successfully to maintain their weight loss for more than three years. The reported behaviors included eating nutrient-dense foods, monitoring food intake, engaging in physical activity, goal setting and celebrating small achievements.

While obesity for many individuals can be a serious cosmetic and social problem, compromising job opportunities and relationships, and often leading to discrimination (“fat shaming”), obesity also plays a major role in the worldwide epidemic of chronic, non-communicable diseases, which include metabolic syndrome, type-II diabetes, cardiovascular diseases, neurodegenerative diseases and liver disease.

“…it is surprising that there are only few well designed studies characterizing the effect of GLP-1 agonists on the gut microbiome.”

Given the wealth of scientific evidence implicating alterations in the gut microbiome as a risk factor for this chronic disease epidemic, it is surprising that there are only few well-designed studies characterizing the effect of GLP-1 agonists on the gut microbiome, and linking such microbial effects with the clinical effectiveness of the drug. A closer look at the reported effects of semaglutide, the molecule marketed as Ozempic, makes this lack of studies even more surprising.

GLP-1 (glucagon-like peptide-1) is an incretin hormone which is produced, stored and released by a class of endocrine or hormone producing cells (L cells) which are interspersed in the lining of the small intestine. These enteroendocrine cells produce some 40 different hormones which are released upon stimulation into the gut, onto nearby receptors on vagal nerve endings and on the pancreas to coordinate the optimal response of our digestive and metabolic system to food intake and regulate our appetite.

“GLP-1 plays a crucial role in glucose metabolism, appetite regulation, and insulin secretion…”

GLP-1 plays a crucial role in glucose metabolism, appetite regulation and insulin secretion. A wide range of food components and nutrients are known to stimulate the release of GLP-1, including soluble dietary fiber found in foods like oats, barley, fruits and legumes; short-chain fatty acids (SCFAs) like butyrate produced by the fermentation of dietary fibers by gut microbiota, dietary protein and certain amino acids contained in foods rich in proteins like eggs, dairy, meat and fish; fatty acids especially medium-chain fatty acids; complex carbohydrates including resistant starches contained in whole grains, legumes and starchy vegetables; large molecular polyphenols, found in fruits, vegetables, tea, coffee and wine, such as flavonoids, phenolic acids and bile acids which are released in response to dietary fat.

While these various food components can stimulate GLP-1 release directly, metabolites produced from complex carbohydrates by butyrate-producing microbes can also interact with GLP-1 receptors on these cells directly. In a healthy individual (with a healthy gut microbiome), a diet rich in these components, in particular complex carbohydrates, soluble fiber and polyphenols can help regulate GLP-1 levels and contribute to optimal metabolic health. Unfortunately, our modern diet has not only compromised our gut microbiome, but has damaged the intricate regulation of the gut’s hormonal system.

“[GLP-1 agonists] can have various effects on the gut microbiome.”

Even though not mentioned often in the ongoing public discussions about semaglutide, the drug like other GLP-1 receptor agonists, can have various effects on the gut microbiome. While research is still ongoing, here are some potential ways in which semaglutide might influence the gut microbiome:

  1. Altered regional gut motility, resulting in changes in the transit time of food through the digestive system. This can alter the habitat in which gut bacteria thrive, affecting their composition and activity. Slower movement of food through the intestines may allow for different bacterial populations to flourish compared to a faster transit time.
  2. Reduced appetite and caloric intake: Through its effect on satiety regions in the brain, semaglutide typically leads to decreased appetite and lower food intake. Changes in diet composition, food preferences and calorie consumption can have significant effects on the gut microbiome, as different bacteria preferentially feed on different nutrients.
  3. GLP-1 receptor agonists can influence the secretion and composition of bile acids, which play a crucial role in shaping the gut microbiome. Bile acids can have antimicrobial properties and affect bacterial growth and diversity.
  4. Possible direct modulation. There is emerging evidence that GLP-1 receptor agonists released into the gut lumen might directly interact with receptors on gut bacteria changing their functions and interactions with the gut. However, such direct microbial mechanisms are incompletely understood.

“…GLP-1 receptor agonists can increase the abundance of beneficial bacterial species…”

There is emerging scientific evidence suggesting that GLP-1 receptor agonists can increase the abundance of beneficial bacterial species, in particular the genera Akkermansia mucinophila, Fecalibacterium prausnitzi and Bifidobacterium Adolescentis (Actinobacteria), and decrease the abundance of harmful ones. Akkermansia play a crucial role in maintaining the integrity of the intestinal barrier, Fecalibacteria are anti-inflammatory butyrate producers and both Actinobacteria and Fecalibacteria increase insulin sensitivity. Interestingly, similar beneficial gut microbial changes have been observed in patients undergoing weight loss surgery, suggesting a shared mechanism.

When viewed together, the reported changes in the gut microbiome composition might contribute to the overall metabolic benefits of semaglutide, including improved insulin sensitivity, improved intestinal barrier function and reduced inflammation.

“…Combined pharmacological, dietary and microbiome targeted treatment approach to obesity…”

While the precise effects of semaglutide on the gut microbiome are still being studied, it is clear that it can influence the microbiome through multiple pathways. These changes in the gut microbiome might play a role in the medication’s overall efficacy, and the health benefits observed in patients using semaglutide. However, further research is needed to fully understand these interactions and their clinical implications. For example, a combined therapeutic strategy involving GLP-1 agonists, dietary recommendations and microbiome-targeted therapies may increase the effectiveness, and possibly enable patients to go off the medication once they have normalized their body weight.

Emeran Mayer, MD 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.