Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed the management of type 2 diabetes mellitus (T2DM) and obesity, yet their interactions with the gut microbiome remain an emerging frontier in pharmacological and metabolic research. Mounting evidence suggests that the gut microbiota modulates GLP-1 secretion via microbial metabolites, including short-chain fatty acids and bile acid derivatives, while GLP-1 agonists reciprocally reshape microbial composition, influencing metabolic outcomes beyond their classical incretin functions. This bidirectional interplay has profound implications for precision medicine, as gut microbial signatures have been associated with variability in therapeutic response, raising the possibility that microbiome features could contribute to response stratification in future studies. Advances in pharmacomicrobiomics, multiomics integration and computational modelling now enable a more refined dissection of these interactions, illuminating potential microbial targets for intervention. Study discrepancies may arise from variations in host diet, baseline microbiome composition and genetic factors influencing GLP-1 signalling. Future studies should incorporate stratified analyses accounting for these confounders to understand causative mechanisms. This review collates current evidence on the microbiome-mediated modulation of GLP-1 dynamics, evaluates the pharmacomicrobiomic impact of GLP-1 agonists and outlines future research directions at the interface of gut microbiota and incretin biology. By unravelling the complexities of this host-microbe-drug axis, the field moves closer to a paradigm of personalized metabolic medicine, where future GLP-1 therapeutic strategies may consider host metabolic and microbial context, optimizing efficacy and minimizing variability in patient response.
