Ryan Lingerak

Dec. 11, 2019 8:45 a.m. - 9:45 a.m.
School of Medicine E501 Mentor: Bing-Cheng Wang, PhD

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Nature | Vol 575 | 21 November 2019 | 505

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 mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin—a two-subunit exotoxin that is secreted by Enterococcus faecalis^5,6—as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

Yi Duan^1,2,29, Cristina Llorente^1,2,29, Sonja Lang^1, Katharina Brandl³, Huikuan Chu¹, Lu Jiang^1,2, Richard C. White⁴, Thomas H. Clarke⁴, Kevin Nguyen⁴, Manolito Torralba⁵, Yan Shao⁶, Jinyuan Liu^7, Adriana Hernandez-Morales⁸, Lauren Lessor⁹, Imran R. Rahman¹⁰, Yukiko Miyamoto¹, Melissa Ly¹¹, Bei Gao¹, Weizhong Sun¹, Roman Kiesel¹, Felix Hutmacher¹, Suhan Lee¹, Meritxell Ventura-Cots¹², Francisco Bosques-Padilla¹³, Elizabeth C. Verna¹⁴, Juan G. Abraldes¹⁵, Robert S. Brown Jr¹⁶, Victor Vargas^17,18, Jose Altamirano¹⁷, Juan Caballería^18,19, Debbie L. Shawcross²⁰, Samuel B. Ho^1,2, Alexandre Louvet²¹, Michael R. Lucey²², Philippe Mathurin²¹, Guadalupe Garcia-Tsao^23,24, Ramon Bataller¹², Xin M. Tu⁷, Lars Eckmann¹, Wilfred A. van der Donk^10,25,26, Ry Young^8,9, Trevor D. Lawley⁶, Peter Stärkel²⁷, David Pride^1,11,28, Derrick E. Fouts⁴ & Bernd Schnabl^1,2,28*