Gut microbiota in conventionalized and humanized Cyp2c70 mice

Mice with deletion of Cyp2c70 have a human-like bile acid pool, display signs of hepatobiliary disease, and can be used as a model to study interactions between bile acids and the gut microbiota in cholestatic liver disease. In this study we rederived Cyp2c70 knockout mice as germ-free (GF) and colonized them with a human or a mouse microbiota to investigate if the presence of a microbiota can be protective in cholestatic liver disease. GF Cyp2c70-/- mice showed reduced neonatal survival, liver fibrosis and increased cholangiocyte proliferation. Colonization with a human or a mouse microbiota increased neonatal survival, and mice colonized with a mouse microbiota showed improved liver phenotype at 6-10 weeks of age. The improved liver phenotype in conventionalized (CD) Cyp2c70-/- mice was associated with increased levels of tauro-ursodeoxycholic acid (TUDCA) and UDCA resulting in a more hydrophilic bile acid profile compared with GF and humanized Cyp2c70-/- mice. The biliary hydrophobicity index of CD Cyp2c70-/- mice was associated with changes in the gut microbiota and improved liver phenotype. Hence, our results indicate that neonatal survival seems to depend on the establishment of a gut microbiota at birth, and the improved liver phenotype in CD Cyp2c70-/- mice may be mediated by increased levels of TUDCA/UDCA and/or by the presence of specific bacteria.