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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\u2010cause mortality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In all, 25 adults with NAFLD\u2010related 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\u2010related cirrhosis (diagnostic accuracy, 0.97, 95% confidence interval [CI] 0.96\u20130.99). Diagnostic accuracy of the 13\u2010species 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\u2010species metagenomic signature was robust in an independent test cohort (AUC 0.95, 95% CI 0.81\u20131.00). The 13\u2010species metagenomic signature (hazard ratio [HR] 1.54, 95% CI 1.10\u20132.15, <jats:italic>p<\/jats:italic>\u00a0=\u20090.01) was a stronger predictor of mortality than the Model for End\u2010Stage Liver Disease score (HR 1.25, 95% CI 1.03\u20131.53, <jats:italic>p<\/jats:italic>\u00a0=\u20090.03).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study provides evidence for a gut metagenome\u2010derived signature with high diagnostic accuracy for hepatic decompensation that predicts risk of mortality in NAFLD\u2010related cirrhosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.17236","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T05:19:47Z","timestamp":1664255987000},"page":"1475-1485","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Gut metagenome\u2010derived signature predicts hepatic decompensation and mortality in NAFLD\u2010related cirrhosis"],"prefix":"10.1111","volume":"56","author":[{"given":"Suzanne R.","family":"Sharpton","sequence":"first","affiliation":[{"name":"Division of Gastroenterology Department of Medicine University of California San Diego  La Jolla California USA"},{"name":"NAFLD Research Center, Department of Medicine University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Gyu","family":"Oh","sequence":"additional","affiliation":[{"name":"Gene Expression Laboratory Salk Institute for Biological Studies  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egbert","family":"Madamba","sequence":"additional","affiliation":[{"name":"NAFLD Research Center, Department of Medicine University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenjingyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Science, Department of Chemistry University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth T.","family":"Yu","sequence":"additional","affiliation":[{"name":"Gene Expression Laboratory Salk Institute for Biological Studies  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette R.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Gene Expression Laboratory Salk Institute for Biological Studies  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Huan","sequence":"additional","affiliation":[{"name":"Faculty of Science, Department of Chemistry University of British Columbia  Vancouver 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