GLP-1 and GIP Receptor Agonists and the Gut Microbiota: Mechanisms, Microbial Changes and Therapeutic Implications

Glucagon-like peptide-1 (GLP-1) receptor agonists are established therapies for type 2 diabetes mellitus and obesity, while dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonism, exemplified by tirzepatide, has expanded incretin-based treatment. The gut microbiota is increasingly recognized as a potential regulator of incretin secretion, microbial metabolite production, intestinal barrier integrity and metabolic inflammation. This mini-review summarizes evidence published from 2021 to 2026 concerning interactions between GLP-1/GIP receptor agonists and the gut microbiota, with separate consideration of human and preclinical findings. Human studies show heterogeneous effects of GLP-1 receptor agonists on microbial diversity and composition; some identify treatment-associated taxa or metabolomic changes, whereas others report no major compositional alterations. Preclinical studies provide stronger mechanistic evidence, including effects involving short-chain fatty acids, bile acid signalling, intestinal immune responses and microbiota manipulation. Baseline microbial features may also contribute to interindividual differences in glycaemic response, although no validated predictive microbiome signature currently exists. Evidence for tirzepatide remains predominantly preclinical and suggests changes in microbial communities and bile acid metabolism, but the independent contribution of microbiota to its clinical effects is not established. Overall, the relationship between incretin therapy and the gut microbiota appears complex, bidirectional and context-dependent. Future longitudinal, controlled and mechanistic human studies integrating metagenomics, metabolomics and host metabolic measures are required to distinguish direct pharmacological effects from changes related to weight loss, diet, caloric intake and concomitant medication.