SummaryBackgroundThere are limited data on the diagnostic accuracy of gut microbial signatures for predicting hepatic decompensation in patients with cirrhosis.AimsTo determine whether a stool metagenome‐derived signature accurately detects hepatic decompensation and mortality risk in cirrhosis secondary to non‐alcoholic fatty liver disease (NAFLD)MethodsShotgun 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.ResultsIn 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).ConclusionsThis 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.
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