Sex-dependent effects on gut microbiota regulate hepatic carcinogenic outcomes

Abstract

Emerging evidence points to a strong association between sex and gut microbiota, bile acids (BAs), and gastrointestinal cancers. Here, we investigated the mechanistic link between microbiota and hepatocellular carcinogenesis using a streptozotocin-high fat diet (STZ-HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) murine model and compared results for both sexes. STZ-HFD feeding induced a much higher incidence of HCC in male mice with substantially increased intrahepatic retention of hydrophobic BAs and decreased hepatic expression of tumor-suppressive microRNAs. Metagenomic analysis showed differences in gut microbiota involved in BA metabolism between normal male and female mice, and such differences were amplified when mice of both sexes were exposed to STZ-HFD. Treating STZ-HFD male mice with 2% cholestyramine led to significant improvement of hepatic BA retention, tumor-suppressive microRNA expressions, microbial gut communities, and prevention of HCC. Additionally the sex-dependent differences in BA profiles in the murine model can be correlated to the differential BA profiles between men and women during the development of HCC. These results uncover distinct male and female profiles for gut microbiota, BAs, and microRNAs that may contribute to sex-based disparity in liver carcinogenesis, and suggest new possibilities for preventing and controlling human obesity-related gastrointestinal cancers that often exhibit sex differences.

Interactions between the MicroRNAs and Microbiota in Cancer Development: Roles and Therapeutic Opportunities

“…Recent studies demonstrated the relationship between microbiota and hepatocellular carcinogenesis [38]. The results established that sex-based disparity in liver carcinogenesis is connected with the gut microbiota and tumour-suppressive miRNAs, miRNA-22, miRNA-26a, miRNA-26a-1, miRNA-192, miRNA-122 and miRNA-125b.…”

“…Nevertheless, the controlling mechanism is uncertain. Increased concentrations of farnesoid X receptor (FXR), a bile acid nuclear receptor, in female animals may augment the expression of miRNA-26a, miRNA-26a-1 and miRNA-122 as the suppressors in HCC, probably causing a reduction of the risk of HCC in female mice [38]. Moreover, butyrate from microbiota increases programmed cell death via up-regulation of miRNA-22 expression and reduction of sirtuin1 expression in hepatic cells [39].…”

Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis

“…Multifaceted approaches that integrate metagenomic and metabolomic profiling from well-characterized gnotobiotic animal models will be essential in determining the role of microbiota-mediated alterations in bile acids in the development of gastrointestinal cancers. In addition, distinct profiles of gut microbiota and bile acids have been reported in males and females, and these might contribute to the sex-based disparity in liver carcinogenesis 202 . A better understanding of the hormonal actions of bile acids on their receptors will reveal opportunities for prevention and control of gastrointestinal cancers that often exhibit gender differences.…”

Microbiota and the liver

“…In particular, a higher abundance of Corynebacterium, Corynebacteriaceae, Rhodococcus, Nocardiaceae, Adlercreutzia, Bacillus, Bacillaceae, Staphylococcus, Desulfovibrio and Desulvibrionales, and Clostrodium were found in male mice in comparison to female mice. (81) This may result in altered microbial bile acid metabolism and a substantial increase of intrahepatic retention of hydrophobic bile acids in male mice more with decreased hepatic expression of tumor suppressive microRNAs.…”