脂肪肝
肝细胞癌
细胞凋亡
内科学
双歧杆菌
代谢物
生物
肝细胞
酒精性肝病
肝癌
转录组
癌症研究
内分泌学
医学
肝硬化
疾病
生物化学
乳酸菌
基因表达
发酵
体外
基因
作者
Qian Song,Xiang Zhang,Weixin Liu,Yunfei Zhou,Fenfen Ji,Qing X. Li,Yanqiang Ding,Yan Zhang,Yasi Pan,Jun Yu
标识
DOI:10.1136/gutjnl-2022-iddf.8
摘要
Background
Gut microbiome and its metabolites may play roles in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). We aimed to investigate the specific beneficial bacteria species as novel prophylaxis for NAFLD-HCC. Methods
The effect of Bifidobacterium pseudolongum was assessed in two NAFLD-HCC mouse models induced by diethylnitrosamine (DEN) with high-fat/high-cholesterol diet (HFHCD) for 24 weeks or with choline-deficient/high-fat diet (CDHFD) for 25 weeks. Germ-free mice were gavaged with B. pseudolongum for one month. Stool, portal vein, and liver tissue samples were collected from all mouse models. Targeted metabolomic profiles and transcriptome sequencing were performed to elucidate functional metabolites of B. pseudolongum. Conditioned medium of B. pseudolongum (B.p CM, 10%) or candidate metabolite were co-cultured with human NAFLD-HCC cell lines (HKCI2, HKCI10) and normal hepatocyte LO2. Results
B. pseudolongum was the top-depleted bacteria in the NAFLD-HCC mouse model. Oral gavage of B. pseudolongum reduced tumor number (P<0.01), maximum tumor diameter (P<0.01), and tumor load (P<0.05) in the DEN+HFHCD mouse model, which was further validated in the DEN+CDHFD mouse model. HKCI2 and HKCI10 cells co-incubation with B.p CM significantly suppressed cell viability, and cell migration, but induced cell cycle arrest and apoptosis. This effect was not observed in normal hepatocyte LO2 cells. Acetate was identified as the critical metabolite generated from B. pseudolongum by integrative analyses of targeted metabolomics from B.p CM, portal vein, stool and liver tissues of germ-free mice. Acetate significantly inhibited proliferation and migration in two NAFLD-HCC cell lines. Acetate also suppressed NAFLD-HCC tumor growth in vivo. Moreover, B. pseudolongum restored healthy microbiome composition and gut barrier function. Mechanistically, B. pseudolongum-produced acetate entered the portal vein to reach the liver and interact with G coupled-protein receptor 43 (GPR43) in hepatocytes. The activation of GPR43 further suppressed the IL-6/JAK1/STAT3 signaling pathway, thereby preventing NAFLD-HCC progression. Conclusions
B. pseudolongum is protected against NAFLD-HCC by secreting anti-tumor metabolite acetate through the gut-liver axis. B. pseudolongum is a potential probiotic for the prevention of NAFLD-HCC.
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