Akkermansia muciniphila HHAKKα Prevents High-Fat Diet-Induced Obesity in Mice via Gut Microbiota Modulation and Regulation of Hepatic Lipid Metabolism.

Obesity and its associated metabolic disorders pose significant global health challenges. This study investigated the anti-obesity effects of Akkermansia muciniphila HHAKKα in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were administered HHAKKα orally for 8 weeks while maintained on HFD. Results demonstrated that HHAKKα significantly inhibited weight gain (5.76 g vs. 10.79 g in HFD group), with efficacy comparable to orlistat. HHAKKα intervention effectively maintained glucose homeostasis, decreased serum triglycerides and LDL-cholesterol levels, and elevated adiponectin and GLP-1 levels. Furthermore, HHAKKα significantly reduced pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) and alleviated hepatic steatosis and adipocyte hypertrophy. Mechanistically, HHAKKα modulated gut microbiota composition, increasing beneficial bacteria (Akkermansia, Roseburia, Eubacterium) while decreasing the Bacillota/Bacteroidota ratio by 55.35%. Notably, the HHAKKα intervention significantly enhanced fecal short-chain fatty acids (SCFAs) production-particularly butyrate, which was restored to approximately 1.5 times its normal level-and this effect correlated negatively with serum lipid levels and inflammatory markers. Molecular analysis revealed that HHAKKα regulated hepatic lipid metabolism by inhibiting FASN expression and upregulating PGC-1α. These findings suggest that A. muciniphila HHAKKα ameliorates HFD-induced obesity through a multi-faceted mechanism involving gut microbiota modulation, SCFA production enhancement, inflammation suppression, and hepatic lipid metabolism regulation, highlighting its therapeutic potential for obesity management.