Gut metagenome-derived signature predicts hepatic decompensation and mortality in NAFLD-related cirrhosis

There are limited data on the diagnostic accuracy of gut microbial signatures for predicting hepatic decompensation in patients with cirrhosis.To determine whether a stool metagenome-derived signature accurately detects hepatic decompensation and mortality risk in cirrhosis secondary to non-alcoholic fatty liver disease (NAFLD) METHODS: Shotgun metagenomic sequencing was performed on faecal samples collected at study entry from a prospective cohort of adults with NAFLD-related cirrhosis. A Random Forest machine learning algorithm was utilised to identify a metagenomic signature of decompensated cirrhosis (defined by ascites, hepatic encephalopathy or variceal haemorrhage) and subsequently validated in an external cohort. A Cox proportional hazards regression model was used to examine predictors of all-cause mortality.In all, 25 adults with NAFLD-related cirrhosis (training cohort) were included. Among the 16 participants with decompensated cirrhosis, 33% had ascites, 56% had hepatic encephalopathy and 22% had experienced a variceal haemorrhage (not mutually exclusive). We identified a stool metagenomic signature comprising 13 discriminatory species that reliably distinguished decompensated NAFLD-related cirrhosis (diagnostic accuracy, 0.97, 95% confidence interval [CI] 0.96-0.99). Diagnostic accuracy of the 13-species signature remained high after adjustment for lactulose (area under the curve [AUC] 0.99) and rifaximin use (AUC 0.93). The discriminative ability of 13-species metagenomic signature was robust in an independent test cohort (AUC 0.95, 95% CI 0.81-1.00). The 13-species metagenomic signature (hazard ratio [HR] 1.54, 95% CI 1.10-2.15, p = 0.01) was a stronger predictor of mortality than the Model for End-Stage Liver Disease score (HR 1.25, 95% CI 1.03-1.53, p = 0.03).This study provides evidence for a gut metagenome-derived signature with high diagnostic accuracy for hepatic decompensation that predicts risk of mortality in NAFLD-related cirrhosis.