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

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.

Modulation of JNK-1/ β-catenin signaling byLactobacillus casei, inulin and their combination in 1,2-dimethylhydrazine-induced colon cancer in mice

“…Fecal pellets were collected from each animal, the collected samples within the same group were, pooled and kept at À80 C freezer until DNA extraction. 33,34 The DNA extraction was done using the homogenized pooled samples and using the GeneJet Genomic DNA purication Kit (Thermo Scientic, cat. no.…”

Gut microbiota in non‐alcoholic fatty liver disease and alcohol‐related liver disease: Current concepts and perspectives

“…Additionally, FXR modulates the gut–vascular barrier by regulating the entry sites for bacterial translocation . In the setting of NAFLD and ALD, both altered BA metabolism and changes in microbiota composition have been found, which potentially promotes disease development . Recent studies have explored the effects of ursodeoxycholic acid (UDCA) on gut microbiome composition in healthy individuals and also in individuals with liver dysfunction .…”

Role of the Gut–Liver Axis in Liver Inflammation, Fibrosis, and Cancer: A Special Focus on the Gut Microbiota Relationship

“…COX‐2 overexpression and excessive PGE2 production were detected in HSCs of human noncirrhotic NASH, indicating that a similar mechanism could function in humans . A recent report showed that DCA also promotes HCC progression by activating the mammalian target of rapamycin pathway . It was found that a new class of a steatohepatitis‐inducing HFD, STHD‐01, could promote HCC without chemical carcinogen administration …”

“…A recent report showed that DCA also promotes HCC progression by activating the mammalian target of rapamycin pathway . It was found that a new class of a steatohepatitis‐inducing HFD, STHD‐01, could promote HCC without chemical carcinogen administration …”