Intestinal MiR194 Regulates Hepatic Bile Acids through Intestinal FXR‐FGF15 Pathway in Alcoholic Liver Disease in Mice

Abstract

BackgroundAlcoholic liver disease (ALD) is characterized by gut dysbiosis, higher hepatic and circulating levels of bile acids (BAs) and intestinal epithelial dysfunction. BA homeostasis is modulated by hepatic and intestinal nuclear farnesoid X receptor (FXR, Nr1h4), a ligand activated transcription factor, through regulating key genes involved in bile acid synthesis and metabolism. BA synthesis regulation by intestinal FXR is through induction of fibroblast growth factor 15 (FGF15) that inhibits hepatic Cyp7a1, the key gene in BA de novo synthesis. Previous studies showed that FXR expression is suppressed miR194 in various tissues. In this study, we investigated the regulation of FXR by miR194 in intestinal tissues in mice with ALD.MethodsC57BL6 and intestinal specific FXR knockout (FXRΔIEC) mice were subjected to the Lieber DeCarli liquid diet containing 5% alcohol for 10 days, and one bonus of alcohol (5 g/kg) was gavaged on last day 9 hours before tissue collecting. Control mice were fed isocaloric maltose dextrin. A group of mice was supplemented with Lactobacillus rhamnosus GG (LGG) at a dose of 109 CFU/day for 10 days before alcohol exposure.ResultsAlcohol feeding significantly increased hepatic fat accumulation and serum ALT and AST levels. Interestingly, the alcohol‐induced effects were associated with an increased expression of miR194 and a decreased expression of FXR and FGF15 in the intestine, and with an upregulation of hepatic Cyp7a1 and BA concentration. When the mice were supplemented with probiotic LGG, intestinal miR194 expression was suppressed, FXR‐FGF15 signaling pathway was upregulated, and hepatic BA levels were decreased. Alcohol induced hepatic steatosis and injury were markedly prevented by LGG. More importantly, the beneficial effects of LGG on hepatic BA homeostasis in ALD mice were diminished when the intestinal epithelial FXR was deleted. In vitro study showed that alcohol treatment increased miR194 and decreased FXR mRNA, and inhibition of miR194 attenuated the suppression of FXR mRNA by alcohol.ConclusionsTaken together, our results demonstrate that intestinal FXR‐FGF15 signaling plays a pivotal role in maintaining hepatic BA homeostasis in ALD mice and probiotic LGG protects against ALD through maintaining BA homeostasis regulated by intestinal miR194‐FXR‐FGF15‐mediated signaling pathways.Support or Funding InformationSupported by grants from NIH.