Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice.
Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice.
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DOI：
10.18632/oncotarget.24066
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发表时间：
2018-02-09
期刊：
影响因子：
--
通讯作者：
Saito H
中科院分区：
文献类型：
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作者：
Yamada S;Takashina Y;Watanabe M;Nagamine R;Saito Y;Kamada N;Saito H
肠道微生物群在非酒精性脂肪性肝炎（NASH）患者肝细胞癌（HCC）的发展中起着重要作用。然而，对这一过程的确切机制的理解仍然不完整。一类新的脂肪性肝炎诱导高脂肪饮食（HFD），即STHD-01，可以在不使用化学致癌物质的情况下促进HCC的发展。利用这种饮食，我们全面分析了NASH HCC发展过程中肠道微生物群及其代谢功能的变化。喂食STHD-01的小鼠在9周内出现NASH。41周时NASH进一步发展为HCC。抗生素治疗显著减轻了肝脏病理，抑制了肿瘤的发展，表明肠道微生物群在该模型中肿瘤发展中的关键作用。给小鼠喂食STHD-01后，肝脏和粪便中胆固醇和胆汁酸的积累增加。抗生素治疗不能逆转这些表型。相比之下，抗生素治疗后，次级胆汁酸的积累显著减少，这表明肠道微生物群在初级胆汁酸向次级胆汁酸的转化中起着关键作用。次级胆汁酸如脱氧胆酸激活肝细胞中的mTOR通路。在STHD-01小鼠的肝脏中观察到mTOR的活化，而在抗生素处理小鼠时，mTOR的活化降低。总的来说，肠道微生物群的胆汁酸代谢促进了sthd -01诱导的NASH中HCC的发展。
Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01-induced NASH.