Glucagon-like peptide-1 (GLP-1) has gained significant attention in recent years for its role in metabolic health. Pharmaceutical GLP-1 receptor agonists (GLP-1 RAs) have demonstrated notable effects on appetite regulation, glycemic control, and body weight. However, far less clinical focus has been placed on the body’s natural ability to produce GLP-1 endogenously, a process that begins not in the pancreas, but in the gut.
This gut-based origin highlights the intricate relationship between GLP-1 and the gastrointestinal (GI) ecosystem. Notably, a growing body of research underscores the role of the gut microbiota in modulating GLP-1 secretion through short-chain fatty acids (SCFAs) like butyrate and propionate, and through bile acid signaling pathways involving TGR5 and FXR receptors.
These insights offer a powerful clinical implication: GLP-1 secretion is not fixed, it is influenced by microbial diversity, mucosal function, and immune activity. For practitioners, this means that stool-based, non-invasive gut microbiome functional wellness testing may provide valuable clues to assess and promote healthy GLP-1 physiology.
Physiology of Endogenous GLP-1 Production
GLP-1 is synthesized and secreted by enteroendocrine L-cells, primarily located in the distal ileum and colon, in response to nutrient intake, microbial metabolites, and gut-immune signals. While macronutrient intake, particularly carbohydrates, proteins, and dietary fats, serves as a primary stimulus for GLP-1 release, L-cell activity is also shaped by the metabolic byproducts of microbial fermentation, bile acid signaling, gut epithelial integrity, and immune tone. SCFA production and bile acid signaling represent two of the most well-characterized ways in which the gut microbiota influences GLP-1 secretion through receptor-mediated pathways and mucosal interactions.
Microbial Mechanisms Modulating GLP-1
SCFA Signaling
Short-chain fatty acids, particularly butyrate and propionate, are generated through the fermentation of dietary fibers and resistant starches by specific colonic bacteria. These SCFAs help promote and activate GLP-1 secretion by binding to free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41) located on L-cells. In addition to promoting GLP-1 physiology, SCFAs support appetite regulation, metabolic signaling, and gut-brain communication. Thus, reduced SCFA-producing microbes, often observed in individuals with low microbial diversity or diets lacking fermentable fiber, may influence GLP-1 signaling and reduce microbial support for enteroendocrine function.
Butyrate also serves as a key energy source for colonic epithelial cells and supports epithelial barrier integrity by promoting tight junction protein expression and modulating local immune signaling. These actions contribute to the gut’s ability to support healthy GLP-1 signaling.
Bile Acid/L-Cell Crosstalk
In addition to SCFAs, secondary bile acids play a complementary role in modulating GLP-1 secretion. When gut microbes convert primary bile acids into secondary forms such as deoxycholic acid and lithocholic acid, these metabolites can activate the bile acid receptors TGR5 and FXR expressed on L-cells. TGR5 activation, in particular, has been shown to enhance GLP-1 release and improve glucose homeostasis.
The efficiency of this signaling process is dependent on the presence of bile acid-modifying microbes, including certain species within the Clostridium and Bacteroides genera. Disruptions in bile acid metabolism, often associated with microbial dysbiosis or insufficient bile flow, may therefore compromise GLP-1 stimulation via this pathway.
Interaction with L-Cells in the Gut
The density of L-cells increases along the GI tract, with the highest concentrations found in the distal ileum and colon. These are the same regions most heavily colonized by butyrate-producing microbes and bile acid-converting bacteria. This spatial relationship between microbial metabolic activity and L-cell abundance reinforces the concept that the gut microbiome plays an integral role in supporting healthy GLP-1 physiology.
In addition to nutrient and microbial stimuli, L-cell function is sensitive to immune signals and epithelial integrity. Intestinal immune activation, elevated lipopolysaccharide (LPS), or mucosal disruption may influence L-cell density and GLP-1 output. This underscores the importance of maintaining gut immune balance and barrier function in supporting hormone regulation.
Gut Microbiome Functional Testing: Markers Relevant to GLP-1
Functional microbiome testing provides clinicians with a systems-level view of the GI ecosystem. These stool-based assays typically assess a range of domains, including microbial diversity, SCFA production potential, mucosal immune activity, digestive efficiency, and inflammatory response burden. While they are not direct measures of GLP-1 output, several of these markers can offer insight into a patient’s capacity for healthy GLP-1 secretion and gut hormone responsiveness.
Keystone Diversity
Microbial richness and keystone species diversity are foundational to gut ecosystem resilience. Reduced alpha diversity has been associated with insulin resistance, elevated body weight, and impaired enteroendocrine signaling. A robust and diverse microbiome fosters metabolic crosstalk among taxa, enhances SCFA production, and supports anti-inflammatory signaling, all of which influence GLP-1 dynamics.
Keystone species such as Faecalibacterium prausnitzii, Roseburia spp., Anaerostipes spp., and Akkermansia muciniphila are especially important in maintaining mucosal health, producing fermentative metabolites, and stabilizing gut barrier function.
SCFA-Producing Flora
Key SCFA-producing bacteria include Faecalibacterium, Roseburia, and Anaerostipes. Reduced abundance of these organisms may correspond to diminished fermentation capacity and lower support for GLP-1 physiology. Testing that quantifies or semi-quantifies these organisms can help determine whether targeted dietary strategies or next-generation probiotics may be warranted.
Akkermansia and Anaerostipes: Notable Keystone Strains
Akkermansia muciniphila is a mucin-degrading bacterium that contributes to gut barrier integrity, helps regulate normal inflammatory responses, and modulates host metabolism. Human and preclinical studies have shown that even pasteurized, non-viable forms of Akkermansia can promote healthy insulin metabolism and enhance GLP-1 secretion via TGR5-mediated signaling. Its presence in the microbiome is considered a strong marker of mucosal health and metabolic flexibility.
Anaerostipes spp. are lactate- and acetate-utilizing bacteria that convert these substrates into butyrate, often in concert with other keystone species. This cross-feeding behavior allows Anaerostipes to play a critical role in butyrate homeostasis and barrier protection, particularly in fiber-fed or postbiotic-supported microbiomes. Although not widely available as a probiotic at present, clinical interest in Anaerostipes is growing as a precursor microbe involved with further butyrate production. Butyrate’s direct effects on glycemic regulation and the promotion of microbial diversity further explain why Anaerostipes may support healthy GLP-1 production.
Dysbiosis and LPS Burden
Overrepresentation of opportunistic or potentially pathogenic organisms (such as Klebsiella, Citrobacter, Clostridium difficile, and Candida spp.) can drive intestinal inflammation and increase luminal LPS exposure. LPS is known to suppress GLP-1 secretion by impairing gut barrier integrity and triggering systemic inflammatory responses. Functional testing that identifies overgrowth patterns can help guide the rebalancing of the microbiome.
Barrier and Immune Markers
Markers such as secretory IgA (SIgA), calprotectin, and beta-glucuronidase provide insight into gut mucosal health and immune activity. Elevated calprotectin or low SIgA may indicate active inflammation or immune suppression, both of which can reduce L-cell viability and GLP-1 output. These markers, when evaluated alongside microbial profiles, offer a fuller picture of the intestinal environment and its capacity to support hormone signaling.
Clinical Applications: Translating Stool Testing into GLP-1-Supportive Care
Functional microbiome testing offers practitioners a valuable lens into the gut environment. When interpreted with GLP-1 physiology in mind, test results can guide highly personalized strategies to support endogenous GLP-1 production. Interventions can be organized across three primary domains: diet, lifestyle, and targeted supplementation. Each intervention should be selected based on an individual’s functional stool profile, clinical presentation, and clinical timeline.
Dietary Interventions
Nutritional strategies that enhance microbial fermentation, support SCFA production, and promote bile acid metabolism can directly influence L-cell signaling. Practitioners may consider the following:
Lifestyle Strategies
Behavioral interventions can amplify the effects of dietary changes by supporting circadian rhythm alignment, gut-brain signaling, and microbial resilience:
Targeted Supplementation
In cases where test results indicate low microbial fermentation capacity, dysbiosis, or bile acid signaling disruption, targeted nutraceuticals may play a supportive role:
Conclusion
Supporting normal endogenous GLP-1 production through microbiome support reflects an emerging paradigm in personalized nutrition and GI health. The body’s ability to produce GLP-1 is shaped by factors such as SCFA production, bile acid transformation, gut barrier status, and microbial diversity.
Functional gut microbiome testing offers practitioners a valuable opportunity to assess these factors in a clinically meaningful way. By analyzing specific microbial patterns, inflammatory markers, and digestive signatures, providers can identify underlying contributors to impaired GLP-1 signaling and implement targeted interventions that support gut hormone physiology.
To learn more about dietary, botanical, and lifestyle interventions in incretin health:
Foundations of GLP-1 Support: Nutritional and Lifestyle Strategies for Healthy Glucose Metabolism
GLP-1s and Hydration: What You Need to Know
Two Next-Generation Probiotics You Should Know About: Anaerostipes and Akkermansia
4 Surprising Botanicals to Promote Normal GLP-1 Production
By Rachel B. Johnson, MS, CNS, LDN
Designs for Health has been dedicated to being the most trusted source for superior quality, science-based nutritional products for nearly three decades. We’re committed to maximizing successful health outcomes by providing healthcare practitioners with comprehensive support through our extensive product line, ongoing clinical education, and practice development programs. The blogs we publish here cover a range of topics, including new and original approaches to diet and healthcare, analyses of the latest cutting-edge research, deep-dives into specific nutrients, botanicals, nutraceuticals and more, all fully referenced for those who want to dig deeper into the primary literature.
