Global 
Deutschland Liver and Bile
Gut. 2024;74(1):103-115
Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis
Objective: Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils.
Design: In this study, the authors performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n = 19), patients with alcohol-use disorder (AUD; n = 20) and AH (n = 80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, they conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n = 70), who were recruited in a second and independent multicentre cohort (AlcHepNet). Result: Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p = 0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all 3 groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, the authors confirmed that faecal MPO levels can predict short-term survival at 60 days.
Conclusions: The authors found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with alcohol-associated hepatitis, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.