Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease

Yi Duan, Cristina Llorente, Sonja Lang, Katharina Brandl, Huikuan Chu, Lu Jiang, Richard C. White, Thomas H. Clarke, Kevin Nguyen, Manolito Torralba, Yan Shao, Jinyuan Liu, Adriana Hernandez-Morales, Lauren Lessor, Imran R. Rahman, Yukiko Miyamoto, Melissa Ly, Bei Gao, Weizhong Sun, Roman Kiesel, Felix Hutmacher, Suhan Lee, Meritxell Ventura-Cots, Francisco Bosques-Padilla, Elizabeth C. Verna, Juan G. Abraldes, Robert S. Brown, Victor Vargas, Jose Altamirano, Juan Caballería, Debbie L. Shawcross, Samuel B. Ho, Alexandre Louvet, Michael R. Lucey, Philippe Mathurin, Guadalupe Garcia-Tsao, Ramon Bataller, Xin M. Tu, Lars Eckmann, Wilfred A. van der Donk, Ry Young, Trevor D. Lawley, Peter Stärkel, David Pride, Derrick E. Fouts and Bernd Schnabl ()
Additional contact information
Yi Duan: University of California San Diego
Cristina Llorente: University of California San Diego
Sonja Lang: University of California San Diego
Katharina Brandl: University of California San Diego
Huikuan Chu: University of California San Diego
Lu Jiang: University of California San Diego
Richard C. White: J. Craig Venter Institute
Thomas H. Clarke: J. Craig Venter Institute
Kevin Nguyen: J. Craig Venter Institute
Manolito Torralba: J. Craig Venter Institute
Yan Shao: Wellcome Sanger Institute
Jinyuan Liu: University of California San Diego
Adriana Hernandez-Morales: Texas A & M University
Lauren Lessor: Texas A & M AgriLife Research and Texas A & M University
Imran R. Rahman: University of Illinois at Urbana-Champaign
Yukiko Miyamoto: University of California San Diego
Melissa Ly: University of California San Diego
Bei Gao: University of California San Diego
Weizhong Sun: University of California San Diego
Roman Kiesel: University of California San Diego
Felix Hutmacher: University of California San Diego
Suhan Lee: University of California San Diego
Meritxell Ventura-Cots: University of Pittsburgh Medical Center, Pittsburgh Liver Research Center
Francisco Bosques-Padilla: Universidad Autonoma de Nuevo Leon
Elizabeth C. Verna: Columbia University College of Physicians and Surgeons
Juan G. Abraldes: University of Alberta
Robert S. Brown: Weill Cornell Medical College
Victor Vargas: Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona
Jose Altamirano: Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona
Juan Caballería: Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
Debbie L. Shawcross: King’s College London
Samuel B. Ho: University of California San Diego
Alexandre Louvet: Service des Maladies de L’appareil Digestif et Unité INSERM, Hôpital Huriez
Michael R. Lucey: University of Wisconsin School of Medicine and Public Health
Philippe Mathurin: Service des Maladies de L’appareil Digestif et Unité INSERM, Hôpital Huriez
Guadalupe Garcia-Tsao: Yale University School of Medicine
Ramon Bataller: University of Pittsburgh Medical Center, Pittsburgh Liver Research Center
Xin M. Tu: University of California San Diego
Lars Eckmann: University of California San Diego
Wilfred A. van der Donk: University of Illinois at Urbana-Champaign
Ry Young: Texas A & M University
Trevor D. Lawley: Wellcome Sanger Institute
Peter Stärkel: Université Catholique de Louvain
David Pride: University of California San Diego
Derrick E. Fouts: J. Craig Venter Institute
Bernd Schnabl: University of California San Diego

Nature, 2019, vol. 575, issue 7783, 505-511

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1742-x

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