title: 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.
authors.affiliation: 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.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Xie
authors.affiliation: E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201204, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhao
authors.affiliation: E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yan
authors.affiliation: University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
authors.forename: Wenlian
authors.initials: W
authors.lastname: Chen
authors.affiliation: University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.affiliation: University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
authors.forename: Junfang
authors.initials: J
authors.lastname: Ji
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Yunjing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Lei
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Ge
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Xiaojiao
authors.initials: X
authors.lastname: Zheng
authors.affiliation: University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Rajani
authors.affiliation: Department of Oceanography, University of Hawaii at Mānoa, Honolulu, Hawaii 96822, USA.
authors.forename: Rosanna A
authors.initials: RA
authors.lastname: Alegado
authors.affiliation: Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Jiajian
authors.initials: J
authors.lastname: Liu
authors.affiliation: E-institute of Shanghai Municipal Education Committee, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.|Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201204, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London SW7 2AZ, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nicholson
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
mesh_terms: D000818:Animals; D001419:Bacteria / Q000145:classification*; D001647:Bile Acids and Salts / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology*; D002792:Cholestyramine Resin / Q000494:pharmacology / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015994:Incidence; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000382:microbiology*; D008297:Male; D056186:Metagenomics / Q000379:methods*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000382:microbiology*; D012737:Sex Factors; D013311:Streptozocin / Q000009:adverse effects*
chemical_list: D001647:Bile Acids and Salts; D035683:MicroRNAs; D002792:Cholestyramine Resin; D013311:Streptozocin