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Nature. 2019 Nov;575(7783):505-511. doi: 10.1038/s41586-019-1742-x. Epub 2019 Nov 13.

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Author information

1
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
2
Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
3
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
4
J. Craig Venter Institute, Rockville, MD, USA.
5
J. Craig Venter Institute, La Jolla, CA, USA.
6
Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, UK.
7
Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
8
Department of Biochemistry and Biophysics, Texas A & M University, College Station, TX, USA.
9
Center for Phage Technology, Texas A & M AgriLife Research and Texas A & M University, College Station, TX, USA.
10
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
11
Department of Pathology, University of California San Diego, La Jolla, CA, USA.
12
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh Liver Research Center, Pittsburgh, PA, USA.
13
Hospital Universitario, Departamento de Gastroenterología, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
14
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
15
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
16
Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
17
Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
18
Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
19
Liver Unit, Hospital Clinic, Barcelona, Spain.
20
Liver Sciences, Department of Inflammation Biology, School of Infectious Diseases and Microbial Sciences, King's College London, London, UK.
21
Service des Maladies de L'appareil Digestif et Unité INSERM, Hôpital Huriez, Lille, France.
22
Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
23
Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
24
Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, CT, USA.
25
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
26
Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
27
St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
28
Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA.
29
Department of Medicine, University of California San Diego, La Jolla, CA, USA. beschnabl@ucsd.edu.
30
Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. beschnabl@ucsd.edu.
31
Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA, USA. beschnabl@ucsd.edu.

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.

PMID:
31723265
PMCID:
PMC6872939
[Available on 2020-05-13]
DOI:
10.1038/s41586-019-1742-x

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