Combination of GLP-1 receptor agonist and Akkermansia muciniphila Akk11 reduces adiposity and ameliorates MASLD in T2D mice.

AIMS/HYPOTHESIS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease globally and is closely associated with type 2 diabetes (T2D) and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer partial therapeutic benefits in MASLD, but their efficacy is often limited in advanced insulin-resistant states, highlighting the need for adjunctive strategies to improve treatment responsiveness. METHODS: We investigated the metabolic and mechanistic effects of combining semaglutide (GLP-1RA) with Akkermansia muciniphila 11 (Akk11) in db/db mice, a model of T2D-associated MASLD. Mice were treated with semaglutide alone or in combination with Akk11. Metabolic parameters, hepatic and adipose tissue morphology, gut microbiota composition, transcriptomic profiles, and inflammatory signaling were evaluated. RESULTS: GLP-1RA monotherapy elicited only modest improvements in glycemia and hepatic lipid accumulation, with effects waning over time. However, Akk11 supplementation significantly enhanced semaglutide therapeutic effects, leading to reduced subcutaneous and visceral fat, improved liver histology, and decreased serum triglycerides. Mechanistically, combination treatment suppressed fatty acid synthesis, promoted mitochondrial function, and remodeled the gut microbiota. Notably, both GLP-1RA and AKK attenuated intestinal pyroptosis pathways, and the combination further suppressed pro-inflammatory markers in the liver and intestine. CONCLUSIONS/INTERPRETATION: Our findings highlight a synergistic interaction between GLP-1RA and Akk11, likely mediated through microbiota remodeling and parallel improvements in lipid metabolism across intestinal, hepatic, and adipose compartments. This study supports the development of microbiota-guided strategies to enhance therapies for MASLD and other metabolic diseases.