Lu Jiang1,2, Sonja Lang1, Yi Duan1,2, Xinlian Zhang3, Bei Gao1, Jessica Chopyk4, Leila K Schwanemann4, Meritxell Ventura-Cots5, Ramon Bataller5, Francisco Bosques-Padilla6, Elizabeth C Verna7, Juan G Abraldes8, Robert S Brown9, Victor Vargas10,11, Jose Altamirano10, Juan Caballería11,12, Debbie L Shawcross13, Samuel B Ho1,2, Alexandre Louvet14, Michael R Lucey15, Philippe Mathurin14, Guadalupe Garcia-Tsao16,17, Tatiana Kisseleva1, David A Brenner1, Xin M Tu3, Peter Stärkel18, David Pride1,4,19, Derrick E Fouts20, Bernd Schnabl1,2,19. 1. Department of Medicine, University of California San Diego, La Jolla, CA. 2. Department of Medicine, VA San Diego Healthcare System, San Diego, CA. 3. Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA. 4. Department of Pathology, University of California San Diego, La Jolla, CA. 5. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA. 6. Department of Gastroenterology, University Hospital, Autonomous University of Nuevo LeonAutonomous University of Nuevo Leon, Monterrey, Mexico. 7. Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY. 8. Division of Gastroenterology (Liver Unit), Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 9. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY. 10. Liver Unit, University Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain. 11. Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain. 12. Liver Unit, Hospital Clinic, Barcelona, Spain. 13. Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, London, United Kingdom. 14. Department of Diseases of the Digestive System and INSERM Unit, Huriez Hospital, Lille, France. 15. Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI. 16. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT. 17. Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT. 18. St. Luc University Hospital, Catholic University of Louvain, Brussels, Belgium. 19. Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, CA. 20. J. Craig Venter Institute, Rockville, MD.
Abstract
BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.
BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.