Intestinal Virome Signature Associated With Severity of Nonalcoholic Fatty Liver Disease.

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Alterations in the gut microbiome have been associated with the severity of nonalcoholic fatty liver disease (NAFLD). These studies focused exclusively on the bacteria in the microbiome; we investigated changes in the viral microbiome (virome) in patients with NAFLD.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 a NAFLD activity score (NAS) of 0-4, 44 patients had a NAS of 5-8 or cirrhosis (NAS 5-8/LCI), 37 patients had F0-F1 fibrosis, and 36 patients had F2-F4 fibrosis. As controls, 9 subjects 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.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 controls. The presence of more advanced NAFLD was associated with a significant reduction in the proportion of bacteriophages (phages) 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% CI, 0.91-0.99) and F2-F4 fibrosis with an area under the curve of 0.88 (95% CI, 0.80-0.95). Addition of data on viral diversity significantly improved multivariate models, including those based on only clinical parameters or bacterial diversity.In a study of fecal viromes from patients with NAFLD and controls, 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.


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