Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice.

Shoji Yamada,Hidetsugu Saito,Yoshimasa Saito,Mitsuhiro Watanabe,Yoko Takashina,Ryogo Nagamine,Nobuhiko Kamada

doi:10.18632/oncotarget.24066

Abstract

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.

Highlights

The number of patients with non-alcoholic fatty liver disease (NAFLD) has been increasing in the recent years [1]
Activation of mammalian target of rapamycin (mTOR) was observed in the liver of mice fed steatohepatitis-inducing HFD (STHD)-01, and the activation was reduced when mice were treated with antibiotics
The liver injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and the transcription of pro-inflammatory cytokines such as tumor nuclear factor (Tnf)-α and interleukin (Il)-1β increased significantly in the STHD-01 group, and these effects were dramatically suppressed by antibiotic treatment (Figure 2B)

Summary

Introduction

The number of patients with non-alcoholic fatty liver disease (NAFLD) has been increasing in the recent years [1]. In patients with NAFLD, dysregulation of adipokines, insulin resistance, and dyslipidemia lead to fat accumulation in the liver [2,3,4]. Activation of Kupffer cells and hepatic stellate cells in NAFLD patients elicits inflammation and fibrogenesis in the liver, leading to the development of non-alcoholic steatohepatitis (NASH). Around 10% of NASH patient further develop liver cirrhosis and hepatocellular carcinoma (HCC) [5,6,7]. The prevalence of NASH-associated HCC has been gradually increasing in the recent years [8,9,10,11]. HCC is the fifth most common malignant tumor in the world, the precise mechanisms by which NASH causes HCC are not entirely understood [1,2,3,4,5,6,7,8,9,10,11,12,13]

Methods

Results

Conclusion