Intestinal virome signature associated with severity of nonalcoholic fatty liver disease

1. The gut virome among patients with severe NAFLD was found to be different than those with milder NAFLD. #2. Adding viral diversity to clinical models used to predict NAFLD severity significantly increased diagnostic accuracy.

Evidence Level Rating: 2 (Good)

Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the world’s population, significantly increasing the risk of hepatocellular carcinoma and liver-related mortality. Research until now has focused almost exclusively on how NAFLD alters the gut bacterial microbiome, though the virome too is affected, with alterations described in other pathologies such as inflammatory bowel disease and colorectal cancer. The purpose of this prospective, cross-sectional observational study was to characterize the gut virome among 73 patients (mean [range] age = 55.6 [20.2-79.6] years, 51% female) with NAFLD and explore associations with different stages of NAFLD. Liver biopsies were obtained to assign a NAFLD activity score (NAS), as well as to stage the degree of fibrosis, both of which are associated with an increased risk of liver pathologies. Viral nucleic acid was extracted from fecal samples, yielding a total of 420 unique viral species. Patients with NAS 5-8 exhibited significantly lower viral diversity than those with NAS 0-4 (p = 0.005) as well as a significantly lower proportion of phages (p = 0.046). Patients with F2-F4 fibrosis also had a significantly lower proportion of phages compared with patients with minimal fibrosis (p < 0.001). Specifically, the relative abundance of the Lactococcus phage was found to be significantly lower in patients with F2-F4 fibrosis compared to those with F0-F1 fibrosis (p = 0.047); a similar association, though not significant, was seen when comparing patients with NAS 5-8 to those with NAS 0-4 (p = 0.063). When adding viral diversity into a model based on age and AST to predict NAS 5-8, diagnostic accuracy was significantly improved (AUC 0.95, 95% CI 0.91 to 0.99, likelihood ratio p value < 0.001). Likewise, for the detection of F2-F4 fibrosis, adding viral diversity to a model based on age, AST, and platelet counts significantly improved diagnostic accuracy (AUC 0.88, 95% CI 0.80 to 0.95, likelihood ratio p value = 0.001). Taken together, these data suggest that specific alterations in the gut virome are associated with a higher NAS and degree of fibrosis. Such findings could be instrumental in developing a non-invasive biomarker to predict NAFLD severity.

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