Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma

作者：Qian Song, Xiang Zhang, Weixin Liu, Hong Wei, Wei Liang, Yunfei Zhou, Yanqiang Ding, Fenfen Ji, Alvin H.K. Cheung, Nathalie Wong, Jun Yu · 发表于：Journal of Hepatology · 年份：2023 · DOI：10.1016/j.jhep.2023.07.005 · 被引用次数：276 · 研究领域：Gut microbiota and health、Cancer Research and Treatments、Probiotics and Fermented Foods

BACKGROUND & AIMS: Recent studies have highlighted the role of the gut microbiota and their metabolites in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). We aimed to identify specific beneficial bacterial species that could be used prophylactically to prevent NAFLD-HCC. METHODS: The role of Bifidobacterium pseudolongum was assessed in two mouse models of NAFLD-HCC: diethylnitrosamine + a high-fat/high-cholesterol diet or + a choline-deficient/high-fat diet. Germ-free mice were used for the metabolic study of B. pseudolongum. Stool, portal vein and liver tissues were collected from mice for non-targeted and targeted metabolomic profiles. Two human NAFLD-HCC cell lines (HKCI2 and HKCI10) were co-cultured with B. pseudolongum-conditioned media (B.p CM) or candidate metabolites. RESULTS: B. pseudolongum was the top depleted bacterium in mice with NAFLD-HCC. Oral gavage of B. pseudolongum significantly suppressed NAFLD-HCC formation in two mouse models (p < 0.01). Incubation of NAFLD-HCC cells with B.p CM significantly suppressed cell proliferation, inhibited the G1/S phase transition and induced apoptosis. Acetate was identified as the critical metabolite generated from B. pseudolongum in B.p CM, an observation that was confirmed in germ-free mice. Acetate inhibited cell proliferation and induced cell apoptosis in NAFLD-HCC cell lines and suppressed NAFLD-HCC tumor formation in vivo. B. pseudolongum restored heathy gut microbiome composition an...