DUF6383-domain containing protein from Parabacteroides distasonis predicts survival in patients with alcohol-associated hepatitis

Intestinal dysbiosis is a hallmark of alcohol-associated liver disease (ALD) characterized by a higher abundance of unfavorable species and a reduction of beneficial species. In this study, we aimed to analyze the bacterial proteome of stool samples from patients with alcohol-associated hepatitis (AH) (n = 80), alcohol use disorder (AUD; n = 20), and controls (n = 19) from an international multicenter cohort using quantitative tandem mass tag (TMT)-based metaproteomic profiling. We validated our results in an independent multicenter cohort of 72 patients with AH at the genomic level using qPCR. We detected 2,364 bacterial proteins and identified distinct metaproteomic signatures separating controls, patients with AUD, and AH. Patients with AUD and AH were characterized by depletion of Firmicutes-derived proteins and enrichment of proteins from Bacteroidetes, Proteobacteria, and Actinobacteria. Eighteen bacterial proteins increased with disease severity, many with multifunctional “moonlighting” roles, including enolase and hexokinase. DUF6383 domain-containing protein from Parabacteroides distasonis is correlated with histological injury, inflammatory cell infiltration, and is linked to neutrophil degranulation in the host. Patients with a high abundance of DUF6383 domain-containing protein had significantly lower 90-day survival, and this association was validated by qPCR at the genomic level in a second cohort. Our findings show that microbial proteins are associated with disease severity and progression, and that DUF6383 domain-containing protein from P. distasonis is a potential prognostic biomarker for AH.