Review Suggests Gut Microbiome Influences Response to GLP-1 Drugs

What if the reason some people lose more weight-or see better blood sugar control-on GLP-1 drugs lies in their gut bacteria? A new review published in the British Journal of Clinical Pharmacology explores the two-way relationship between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the gut microbiome, highlighting potential implications for metabolic health and personalized medicine.

More than 500 million people worldwide live with type 2 diabetes, and obesity rates continue to rise. GLP-1RAs such as liraglutide, semaglutide and dulaglutide have transformed treatment by improving insulin secretion, reducing appetite and lowering cardiovascular risk. Yet patient responses vary widely—prompting researchers to examine whether gut microbes play a role.

The review synthesizes findings from clinical and preclinical studies examining how gut bacteria regulate GLP-1 secretion and how GLP-1RAs, in turn, alter microbial composition. Gut microbes break down dietary fiber into short-chain fatty acids (SCFAs) like butyrate, acetate and propionate. These metabolites stimulate GLP-1 release from intestinal L-cells via G-protein-coupled receptors and intracellular signaling pathways. Butyrate may also enhance proglucagon gene expression, supporting sustained hormone production.

Bile acids—modified by intestinal bacteria—further regulate GLP-1 through receptors such as TGR5 and FXR, demonstrating a dynamic microbial-hormonal interaction. Conversely, dysbiosis can promote inflammation via lipopolysaccharide activation of TLR4 and NF-κB signaling, potentially impairing insulin and GLP-1 pathways.

Evidence also suggests GLP-1RAs reshape the microbiome. Studies report enrichment of beneficial species such as Akkermansia muciniphila and shifts in the Firmicutes-to-Bacteroidetes ratio, alongside reduced inflammatory markers. However, results are inconsistent, likely influenced by diet, weight loss, metformin use and study design differences.

Importantly, small pilot studies indicate that baseline microbial signatures may predict stronger HbA1c reductions. Early machine-learning models show promise in forecasting treatment response based on microbiome profiles.

While animal studies suggest microbial shifts may contribute to metabolic improvements, definitive human causal data remain limited. The authors conclude that controlled, longitudinal studies integrating diet standardization and multiomics tools are needed to clarify whether microbiome-guided therapy could enhance the precision and long-term effectiveness of GLP-1RA treatment in obesity and type 2 diabetes.

REFERENCE: Kamath S, Chan NSL, Joyce P. (2026). GLP-1 agonists and the gut microbiome: A bidirectional relationship. British Journal of Clinical Pharmacology, 1-17. DOI: 10.1002/bcp.70487, https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/bcp.70487