Sonja Lang1, Münevver Demir2, Anna Martin3, Lu Jiang4, Xinlian Zhang5, Yi Duan4, Bei Gao6, Hilmar Wisplinghoff7, Philipp Kasper3, Christoph Roderburg2, Frank Tacke2, Hans-Michael Steffen3, Tobias Goeser3, Juan G Abraldes8, Xin M Tu5, Rohit Loomba6, Peter Stärkel9, David Pride10, Derrick E Fouts11, Bernd Schnabl12. 1. Department of Medicine, University of California San Diego, La Jolla, California; University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany. 2. Department of Hepatology and Gastroenterology, Campus Virchow Clinic, Charité University Medicine, Berlin, Germany. 3. University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany. 4. Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California. 5. Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California. 6. Department of Medicine, University of California San Diego, La Jolla, California. 7. Wisplinghoff Laboratories, Cologne, Germany; Institute for Virology and Medical Microbiology, University Witten/Herdecke, Witten, Germany; University of Cologne, Faculty of Medicine, Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany. 8. Division of Gastroenterology (Liver Unit). Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 9. St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. 10. Department of Medicine, University of California San Diego, La Jolla, California; Department of Pathology, University of California San Diego, La Jolla, California; Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, California. 11. J. Craig Venter Institute, Rockville, Maryland. 12. Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California; Center for Innovative Phage Applications and Therapeutics, University of California San Diego, La Jolla, California. Electronic address: beschnabl@ucsd.edu.
Abstract
BACKGROUND & AIMS: Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. METHODS: In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. RESULTS: Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. CONCLUSIONS: In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data. Published by Elsevier Inc.
BACKGROUND & AIMS: Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). Previous studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD. METHODS: In a prospective, cross-sectional, observational study, we extracted RNA and DNA virus-like particles from fecal samples from 73 patients with NAFLD: 29 patients had an NAFLD Activity Score (NAS) of 0-4, 44 patients had an NAS of 5-8 or liver cirrhosis (LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 individuals without liver disease and 13 patients with mild primary biliary cholangitis were included in the analysis. We performed shotgun metagenomic sequencing of virus-like particles. RESULTS:Patients with NAFLD and NAS 5-8/LCI had a significant decrease in intestinal viral diversity compared with patients with NAFLD and NAS 0-4 or control individuals. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages compared with other intestinal viruses. Using multivariate logistic regression analysis with leave-1-out cross validation, we developed a model, including a viral diversity index and simple clinical variables, that identified patients with NAS 5-8/LCI with an area under the curve of 0.95 (95% confidence interval, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% confidence interval, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity. CONCLUSIONS: In a study of fecal viromes from patients with NAFLD and control individuals, we associated histologic markers of NAFLD severity with significant decreases in viral diversity and proportion of bacteriophages. We developed a model based on fecal viral diversity and clinical data that identifies patients with severe NAFLD and fibrosis more accurately than models based only on clinical or bacterial data. Published by Elsevier Inc.
Authors: Fatemeh Adiliaghdam; Hajera Amatullah; Sreehaas Digumarthi; Tahnee L Saunders; Raza-Ur Rahman; Lai Ping Wong; Ruslan Sadreyev; Lindsay Droit; Jean Paquette; Philippe Goyette; John D Rioux; Richard Hodin; Kathie A Mihindukulasuriya; Scott A Handley; Kate L Jeffrey Journal: Sci Immunol Date: 2022-04-08