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. 2022 Nov;56(10):1475-1485.
doi: 10.1111/apt.17236. Epub 2022 Sep 26.

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

Suzanne R Sharpton  1   2 , Tae Gyu Oh  3 , Egbert Madamba  2 , Chenjingyi Wang  4 , Ruth T Yu  3 , Annette R Atkins  3 , Tao Huan  4 , Michael Downes  3 , Ronald M Evans  3 , Rohit Loomba  1   2   5
Affiliations

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

Suzanne R Sharpton et al. Aliment Pharmacol Ther. 2022 Nov.

Abstract

Background: There are limited data on the diagnostic accuracy of gut microbial signatures for predicting hepatic decompensation in patients with cirrhosis.

Aims: 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.

Results: 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).

Conclusions: 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.

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Conflict of interest statement

CONFLICTS OF INTEREST

SS has no conflicts of interest. TO has no conflicts of interest. EM has no conflicts of interest. CW has no conflicts of interest. RY has no conflicts of interest. AA has no conflicts of interest. TH has no conflicts of interest. MD has no conflicts of interest. RE has no conflicts of interest. RL serves as a consultant for Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89 bio and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer and Siemens. RL is also co-founder of Liponexus, Inc.

Figures

FIGURE 1
FIGURE 1
Metagenomic profiling in non-alcoholic fatty liver disease (NAFLD)-related cirrhosis, comparing compensated and decompensated cirrhosis. (A) Shannon α-diversity scores highlighted significant decreases in the richness of gut microbiota in the decompensated NAFLD cirrhosis group (n = 9) compared with the compensated NAFLD cirrhosis group (n = 16; p = 0.022). Grey dots represent values for individual participants. Boxes represent the interquartile range (IQR) between the first and third quartiles. Median values are represented by horizontal lines within the boxes. Notches represent 95% confidence intervals for the medians. Whiskers indicate the range from minimum (first quartile −1.5 × IQR) to maximum (third quartiles +1.5 × IQR). (B) Principal coordinate analysis of stool samples from decompensated and compensated NAFLD cirrhosis patients using weighted-UniFrac distances (PERMANOVA = 0.001). (C) Stacked bar plots depicting class-level differences in gut microbiome composition between decompensated NAFLD cirrhosis and compensated NAFLD cirrhosis. The ‘others’ subcategory includes rare species (<1%). (D) A metagenomic signature of 13 discriminatory species in decompensated NAFLD cirrhosis compared to compensated NAFLD cirrhosis. Species were chosen from the highest scores of Mean Decrease in Gini using Random Forest (RF) feature selection. Importance and log2FoldChange were presented by each species.
FIGURE 2
FIGURE 2
Diagnostic accuracy of faecal metagenome-derived signature for the detection of decompensated non-alcoholic fatty liver disease (NAFLD) cirrhosis. (A) Receiver operating characteristics (ROC) curve using Model for End-Stage Liver Disease (MELD) score for the prediction of decompensated NAFLD cirrhosis in the training cohort. (B) ROC curve of the Random Forest (RF) model using 13 discriminatory species for the prediction of decompensated NAFLD cirrhosis in the training cohort. (C) Comparison of area under the curve (AUC) values from 100 models of repeated RF outcome for decompensated NAFLD cirrhosis in the training cohort. (D) Validation of the RF model using MELD score in an external cohort. ROC curve for prediction of decompensated NAFLD cirrhosis. (E) Validation of the RF model using 13 discriminatory species in an external cohort. Tests demonstrated that the microbial signature had robust accuracy in independent cohorts (AUC 0.97 and AUC 0.95 in training and validation cohorts, respectively).
FIGURE 3
FIGURE 3
Correlation analysis of metagenomic and metabolomic features for decompensated non-alcoholic fatty liver disease (NAFLD) cirrhosis. (A) A flow chart shows study overview of correlating microbes and metabolites. Metabolite analysis with 23 matched serum or stool samples were correlated top 13-discriminatory species. (B) Correlation analysis identified significant association between serum metabolites and 13-species. The intensity values of bile acids, amino acids and other metabolites were correlated with 13-species abundance levels using Spearman’s correlation analysis. The colour range shows positive (yellow) or negative (light blue) correlation. The + symbol represents the significance of p-value (p < 0.05). (C) Using stool metabolites and 13-species, Spearman’s correlation analysis was performed. The colour range shows positive (yellow) or negative (light blue) correlation. The + symbol represents the significance of p-value (p < 0.05).
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