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Journal Club

Ryan Lingerak
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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"Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease "

Nature | Vol 575 | 21 November 2019 | 505

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1–3. 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 faecalis5,6—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 Duan1,2,29, Cristina Llorente1,2,29, Sonja Lang1, Katharina Brandl3, Huikuan Chu1, Lu Jiang1,2, Richard C. White4, Thomas H. Clarke4, Kevin Nguyen4, Manolito Torralba5, Yan Shao6, Jinyuan Liu7, 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 Vargas17,18, Jose Altamirano17, Juan Caballería18,19, Debbie L. Shawcross20, Samuel B. Ho1,2, Alexandre Louvet21, Michael R. Lucey22, Philippe Mathurin21, Guadalupe Garcia-Tsao23,24, Ramon Bataller12, Xin M. Tu7, Lars Eckmann1, Wilfred A. van der Donk10,25,26, Ry Young8,9, Trevor D. Lawley6, Peter Stärkel27, David Pride1,11,28, Derrick E. Fouts4 & Bernd Schnabl1,2,28*