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Sci Rep ; 7: 45232, 2017 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-28345673

RESUMEN

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.


Asunto(s)
Bacterias/clasificación , Carcinoma Hepatocelular/microbiología , Dieta Alta en Grasa/efectos adversos , Neoplasias Hepáticas/microbiología , Metagenómica/métodos , Enfermedad del Hígado Graso no Alcohólico/microbiología , Estreptozocina/efectos adversos , Animales , Ácidos y Sales Biliares/metabolismo , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Resina de Colestiramina/farmacología , Resina de Colestiramina/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Incidencia , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/genética , Masculino , Ratones , MicroARNs/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Factores Sexuales
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