Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
Sci Rep. 2017 Mar 27;7:45232. doi: 10.1038/srep45232.
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.
新出现的证据表明，性别与肠道微生物群、胆汁酸（BAs）和胃肠道癌症之间存在很强的关联。在这里，我们使用链脲佐菌素高脂肪饮食（STZ-HFD）诱导的非酒精性脂肪性肝炎-肝细胞癌（NASH-HCC）小鼠模型研究了微生物群与肝细胞癌发生之间的机制联系，并比较了两种性别的结果。STZ-HFD 喂养在雄性小鼠中诱导 HCC 的发生率要高得多，其肝内疏水性 BAs 的保留显著增加，而肿瘤抑制性 microRNA 的肝表达减少。宏基因组分析显示，正常雄性和雌性小鼠之间涉及 BA 代谢的肠道微生物群存在差异，当雌雄小鼠都暴露于 STZ-HFD 时，这种差异会放大。用 2%考来烯胺治疗 STZ-HFD 雄性小鼠可显著改善肝 BA 保留、肿瘤抑制性 microRNA 表达、微生物肠道群落，并预防 HCC。此外，在小鼠模型中 BA 谱的性别依赖性差异可与男性和女性在 HCC 发展过程中 BA 谱的差异相关联。这些结果揭示了肠道微生物群、BAs 和 microRNA 的独特的男性和女性特征，这些特征可能有助于基于性别的肝脏癌变差异，并为预防和控制常表现出性别差异的人类肥胖相关胃肠道癌症提供了新的可能性。
