Recovery of <i>Bacteroides thetaiotaomicron</i> ameliorates hepatic steatosis in experimental alcohol-related liver disease

Abstract

Alcohol-related liver disease (ALD) is a major cause of liver disease and represents a global burden, as treatment options are scarce. Whereas 90% of ethanol abusers develop alcoholic fatty liver disease (AFLD), only a minority evolves to steatohepatitis and cirrhosis. Alcohol increases lipogenesis and suppresses lipid-oxidation implying steatosis, although the key role of intestinal barrier integrity and microbiota in ALD has recently emerged. <i>Bacteroides thetaiotaomicron</i> (<i>Bt</i>) is a prominent member of human and murine intestinal microbiota, and plays important functions in metabolism, gut immunity, and mucosal barrier. We aimed to investigate the role of <i>Bt</i> in the genesis of ethanol-induced liver steatosis. <i>Bt</i> DNA was measured in feces of wild-type mice receiving a Lieber-DeCarli diet supplemented with an increase in alcohol concentration. In a second step, ethanol-fed mice were orally treated with living <i>Bt</i>, followed by analysis of intestinal homeostasis and histological and biochemical alterations in the liver. Alcohol feeding reduced <i>Bt</i> abundance, which was preserved by <i>Bt</i> oral supplementation. <i>Bt</i>-treated mice displayed lower hepatic steatosis and triglyceride content. <i>Bt</i> restored mucosal barrier and reduced LPS translocation by enhancing mucus thickness and production of Mucin2. Furthermore, <i>Bt</i> up-regulated <i>Glucagon-like peptide-1</i> (GLP-1) expression and restored ethanol-induced <i>Fibroblast growth factor 15</i> (FGF15) down-regulation. Lipid metabolism was consequently affected as <i>Bt</i> administration reduced fatty acid synthesis (FA) and improved FA oxidation and lipid exportation. Moreover, treatment with <i>Bt</i> preserved the mitochondrial fitness and redox state in alcohol-fed mice. In conclusion, recovery of ethanol-induced <i>Bt</i> depletion by oral supplementation was associated with restored intestinal homeostasis and ameliorated experimental ALD. <i>Bt</i> could serve as a novel probiotic to treat ALD in the future.