Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice
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Shoji Yamada1, Yoko Takashina2, Mitsuhiro Watanabe2, Ryogo Nagamine1, Yoshimasa Saito1,3, Nobuhiko Kamada4 and Hidetsugu Saito1,3
1Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan
2Graduate School of Media and Governance, Keio University, Fujisawa, Kanagawa 252-0882, Japan
3Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan
4Division of Gastroenterology, Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, 48109, USA
Hidetsugu Saito, email: [email protected]
Keywords: deoxycholic acid; bile acid metabolites; mTOR; hepatocellular carcinoma
Received: April 28, 2017 Accepted: November 20, 2017 Published: January 06, 2018
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.
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