Mus musculus isolate:Liver Transcriptome or Gene expression

The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to alcoholic liver disease. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an overrepresentation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates intestinal bile acids. Targeted metabolomics confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower FXR activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (CYP7)-A1 protein expression and bile acid levels. Depletion of the commensal microbiota with non-absorbable antibiotics decreased hepatic CYP7A1 expression and reduced alcoholic liver disease in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal farnesoid x receptor (FXR) activity, we used a pharmacological intervention with the intestine-restricted FXR agonist Fexaramine, which protected mice from ethanol-induced liver injury. While bile acid metabolism was only minimally altered, Fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial lipid metabolic effect to FGF15, a non-tumorigenic FGF19 variant – a human FGF15 ortholog – was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions restore bile acid signaling and reduce ethanol-induced liver disease in mice.