A new—and costly—category of weight loss drugs has burst into the market, targeting the nearly 40% of the world’s population who are overweight or obese. Considered by some experts to be a game changer in obesity, GLP-1 (glucagon-like peptide-1) receptor agonists are in such high demand that some people with diabetes (the original indication) are being confronted with shortages.
Drugs like semaglutide (marketed as Ozempic and Wegovy) and tirzepatide (Zepbound) assist in blood sugar control and promote weight loss by replicating the function of natural hormones called incretins. Semaglutide focuses on GLP-1 whereas tirzepatide mimics GLP-1 and another incretin named glucose-dependent insulinotropic peptide (GIP).
Recent research suggests that the clinical benefits of GLP-1 RAs may be mediated by modulation of gut microbiota. This IPA blog will explore the evidence for a relationship and its implications.
GLP-1 receptor agonists, in brief
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine cells after food ingestion which leads to pancreatic insulin release, suppression of glucagon, and delays in gastric emptying.
To increase the beneficial effects of incretins, GLP-1 receptor agonists (GLP-1 RAs) are formulated to mimic the GLP-1 hormone to regulate blood sugar. In 2005, a compound called exenatide became the first GLP-1 RA to win FDA approval for the treatment of Type 2 diabetes mellitus (T2DM). The use of GLP-1 RAs in individuals with T2DM not only enhances glycemic control but also demonstrates benefits such as weight loss, positive impacts on blood pressure and cholesterol levels, and a reduction in cardiovascular morbidity and mortality.
Other drug compounds for T2DM treatment followed, including liraglutide (Saxenda) and semaglutide (Ozempic) which researchers discovered also caused weight loss. The latter with its weekly injection induced a higher percentage of weight loss (15%). A higher dose of semaglutide (Wegovy) was FDA-approved for weight loss in 2021. And in November of 2023, the FDA approved tirzepatide (Zepbound) via weekly injection to treat overweight and obesity. It activates both GLP-1 and GIP hormone receptors. Note that while GIP regulates blood sugar by a similar action as GLP-1 on insulin secretion, it also promotes fat deposition in adipose tissue which makes its exact mechanism of action in promoting weight loss inconclusive.
The dramatic weight loss potential with these drugs is certainly welcome news for all who have struggled with obesity. However, side effects should not be discounted. Common side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation, while rare but serious effects may include pancreatitis, thyroid cancer, and others.
GLP-1 RAs and gut microbiota
Evidence suggests that some of the beneficial effects of GLP-1 RAs may be attributed to the modulation of gut microbiota.
Change in composition and diversity
It is well established that animals and humans with obesity exhibit reduced gut microbial diversity. There is a decrease in the Bacteroidetes population and an increase in the Firmicutes population, resulting in a reduced Bacteroidetes to Firmicutes ratio. Additionally, a notable characteristic is the decreased abundance of Akkermansia muciniphila.
These microbiota changes are linked to obesity, insulin resistance, and diabetes. This connection is likely due to the microbes’ capacity to extract energy from the diet, affect fatty acid metabolism in adipose tissue and the liver, influence gut hormones, activate toll-like receptors, and impact intestinal barrier integrity.
The new weight loss drugs impact the gut microbiota. GLP-1 RAs have demonstrated an association with reduced dysbiosis, specifically an elevation in the Bacteroidetes to Firmicutes ratio, a decline in microbiota phenotypes related to obesity, an augmentation in microbiota phenotypes associated with leanness, and an increased abundance of A. muciniphila. Notably, A. muciniphila is inversely associated with obesity and other metabolic diseases. It was recently found to increase the endogenous production of GLP-1 in high-fat-fed mice models.
Microbiota compositional changes may be the result of GLP-1 RA impacts: delayed gastric emptying rate and timing, as well as effects on the gut lumen’s internal environment, including pH levels and nutrient availability.
Short-chain fatty acid production
The higher Bacteroidetes to Firmicutes ratio induced by the GLP-1 RAs can increase the quantity of short-chain fatty acids (SCFAs) specifically butyrate, acetate, and propionate. SCFAs increase endogenous GLP-1 secretion from the intestinal L-cells which can impact insulin release and hunger signals.
Probiotics may act similarly. In one study with mouse models, an eight-strain probiotic combination led to a suppression of weight gain and insulin resistance by altering the gut microbiota. This probiotic combination specifically decreased Firmicutes and increased Bacteroidetes, a change which led to a higher butyrate production which in turn increased the secretion of GLP-1 from the intestinal L-cells.
Intestinal barrier function
Research has demonstrated that GLP-1 therapies in obese and diabetic mice led to improved intestinal barrier function by reducing intestinal inflammation and promoting mucosal healing.
A shift in beneficial bacteria may be one explanation. A. muciniphilawasfound in increased abundance after GLP-1 therapy and plays a crucial role in gut barrier function.
Gut-brain axis
The gut-brain axis serves as a complex bidirectional communication system, playing a crucial role in regulating glucose homeostasis and appetite. Enteroendocrine cells in the intestines release hormones like GLP-1 and others, influencing appetite and metabolism but also contributing to the efficacy of therapeutic interventions for conditions like T2DM and obesity.
Takeaway
The emergence of GLP-1 receptor agonists, such as semaglutide and tirzepatide, represents a promising breakthrough in the field of weight loss drugs, offering a potential therapeutic option for the nearly 40% of the global population struggling with obesity. Their function of regulating blood sugar and promoting weight loss may be mediated by modulation of the gut microbiota, influencing factors like microbial diversity, short-chain fatty acid production, and intestinal barrier function.
This information provides a context for stakeholders in the biotics field to explore new avenues for research, product development, and collaborative initiatives aimed at addressing the complex challenges of obesity and related health issues.
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