Obesity-induced gut microbiota transplantation promotes the occurrence and development of hepatocellular carcinoma.

OBJECTIVE: Obesity is a recognized risk factor for hepatocellular carcinoma (HCC), yet the causal role of obesity-remodeled gut microbiota remains poorly defined. This study aims to investigate the direct impact of obesity-related gut microbiota on the development of hepatocellular carcinoma. METHODS: C57BL/6J mice were fed a high-fat diet (HFD) to establish obesity. Fecal microbiota from HFD or normal-chow diet (NCD) mice was transplanted into DEN-initiated recipients. Tumor burden was assessed by incidence, multiplicity, and size. Histomorphology and biochemical methods were employed to assess liver injury, inflammation, fibrosis, lipid metabolism, and the potential signaling pathways involved in these events. RESULTS: The gut microbiota of obese mice significantly promoted the incidence of HCC, and increased tumor number, and size spectrum. Specifically, obesity-related gut microbiota significantly aggravated hepatocarcinogenesis (increasing GPC3, GP73, AFP, and N-cadherin, and decreasing E-cadherin), pro-inflammatory cytokine surge (increasing IL-6, IL-1β, IL-17, and TNF-α), and fibrotic activation (increasing α-SMA, TGF-β, and Col1a1) were observed. Mechanistically, obesity-FMT dysregulated lipid metabolism (increasing free fatty acids, total cholesterol, and triglycerides) and activated TLR4-NF-κB and mTOR pathways. CONCLUSION: Our findings suggest that gut microbiota from obese donors directly promotes HCC progression via TLR4-NF-κB/mTOR-driven inflammation, fibrosis, and metabolic dysregulation, offering novel targets for microbiota-based interventions in obesity-associated liver cancer.