Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

Chronic liver disease due to alcohol use disorder contributes markedly to the global burden of disease and mortality(1–3). Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice(4), but little is known about microbial factors responsible for this process. We identified cytolysin, a two-subunit exotoxin secreted by Enterococcus faecalis (E. faecalis)(5,6), to cause hepatocyte death and liver injury. Compared with controls, patients with 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. Using humanized mice colonized with bacteria from feces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found these phages to decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolysin-positive E. faecalis with worse clinical outcomes and mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, providing a method to precisely edit the intestinal microbiota. A prospective clinical trial with a larger cohort is required to validate human relevance of our findings and to test whether this new therapeutic approach is effective for patients with alcoholic hepatitis.