The gut microbiota as a potential determinant of response to GLP-1 receptor agonists: a narrative review

Interindividual variability in clinical response to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represents a significant challenge in the management of obesity and type 2 diabetes (T2D). In recent years, growing interest has focused on the potential role of the gut microbiota as a biological modifier of incretin-based therapy. This narrative review synthesizes current preclinical and human evidence on the bidirectional interactions between GLP-1 RAs and the intestinal microbial ecosystem, with particular attention to microbial composition, metabolite production (including short-chain fatty acids and bile acids), intestinal barrier integrity, and inflammatory signaling. Experimental models consistently demonstrate that GLP-1 RAs can remodel gut microbial communities and influence metabolite profiles. In human studies, GLP-1 RA therapy has been associated with changes in microbial diversity and enrichment of specific taxa; however, most available data remain observational and associative. Small exploratory cohorts suggest that baseline microbiota composition may correlate with differential metabolic response, giving rise to the responder/non-responder framework. Nevertheless, definitions of response are heterogeneous, study populations are limited in size, and mechanistic causality has not been established. Importantly, microbiota changes observed during GLP-1 RA therapy may be influenced by confounding factors such as weight loss magnitude, dietary modifications, and concomitant treatments, particularly metformin. Functional pathway inferences frequently rely on 16S rRNA-based predictions rather than direct metabolomic measurements, warranting cautious interpretation. Overall, current evidence supports the hypothesis that host-microbiome interactions may contribute to therapeutic heterogeneity, but robust longitudinal and interventional human studies are required before microbiome-informed stratification or adjunctive microbiota-targeted interventions can be considered for clinical implementation. Elucidating these interactions may ultimately refine precision approaches to incretin-based therapy in metabolic disease.