The Interplay Between GLP-1-Based Therapies, the Gut Microbiome, and MASLD/MASH in Type 2 Diabetes Mellitus: A Narrative Review.

GLP-1-based drugs are approved for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 60% of patients with T2DM, and the gut microbiome plays a critical role in its pathogenesis. The gut-liver axis represents a key mechanistic link between dysbiosis and hepatic steatosis. A narrative literature review was conducted using PubMed, Scopus, and ClinicalTrials.gov (2015-2026). Search terms included "GLP-1 receptor agonist," "microbiome," "MASLD," "MASH," "NAFLD," "NASH," "liraglutide," "semaglutide," "tirzepatide," "dulaglutide," and "exenatide." Of 363 identified articles, 330 were excluded due to duplication or non-relevant study design; 33 studies (18 preclinical, 15 clinical) were included. In preclinical models, liraglutide demonstrated normalization of the / ratio and increased and spp., while tirzepatide significantly reduced hepatic steatosis and increased abundance in diabetic mice. Semaglutide improved gut barrier integrity, increased and , and ameliorated MASLD in murine models. In clinical studies, tirzepatide achieved MASH resolution in 44-62% of patients in the phase 2 SYNERGY-NASH trial. In August 2025, the FDA approved semaglutide for MASH with fibrosis based on the Phase 3 ESSENCE trial. A recent longitudinal study in T2DM patients showed that baseline microbiome composition predicted glycemic response to semaglutide, without significant changes in microbiome diversity. In conclusion, GLP-1-based therapies demonstrate consistent preclinical associations with gut microbiome modulation and reduction in hepatic steatosis. Baseline microbiome composition has been suggested as a potential predictor of treatment response, supporting a personalized approach to MASLD management and warranting future clinical studies.