Friday, April 19, 2024
4/19/2024
Project Summary Alcohol abuse and alcohol-related diseases are a major medical burden in industrialized countries. Chronic alcoholism is associated with changes in the intestinal microbiota, increases in intestinal permeability, and elevated systemic levels of bacterial products. We demonstrated that Enterococcus faecalis (E. faecalis) is sufficient to cause mild steatotic liver disease and to exacerbate ethanol-induced liver disease in mice. We identified cytolysin, a two-subunit exotoxin secreted by E. faecalis, to cause hepatocyte death and liver injury. Compared with controls, patients with alcohol use disorder or alcoholic hepatitis have increased fecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with liver disease severity and mortality in patients with alcoholic hepatitis. How chronic alcohol use results in increased intestinal and hepatic numbers of cytolysin-positive E. faecalis is not known. Results from our laboratory suggest that increased intestinal numbers of E. faecalis are facilitated by changes in the intestinal glycocalyx and in particular by reduced ¿(1,2)-fucosylation of glycoproteins on the apical membrane of intestinal epithelial cells. Alcohol- mediated suppression of Fucosyltransferase 2 (Fut2) allows intestinal colonization and bacterial translocation of E. faecalis. Furthermore, translocated E. faecalis is phagocytosed and eliminated by the complement receptor of the immunoglobulin superfamily (CRIg) on Kupffer cells. Patients with chronic alcoholic hepatitis have lower hepatic CRIg expression, which reduces E. faecalis elimination, prolongs exposure to E. faecalis and increases liver damage. Thus, ethanol associated changes in intestinal colonization and hepatic elimination of E. faecalis promotes alcohol-related liver disease. Our experimental approach is to use mouse models of ethanol feeding to investigate the role of Fut2 in limiting intestinal colonization of E. faecalis and reducing liver disease (Aim 1). We will also assess the functional contribution of the phagocytic protein CRIg to E. faecalis elimination and to liver disease (Aim 2). New strategies will be tested to prevent and ameliorate ethanol-induced liver disease in preclinical models. We believe these studies will provide novel insights into the contribution of the microbiota to alcohol-related liver disease.
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