Circulating urobilinogen contributes to Inflammation, Intestinal Permeability and corticosteroid non-response in Severe Alcohol-associated Hepatitis.

Abstract

Severe alcohol-associated hepatitis (SAH) is a life-threatening condition with high mortality rates and poor response to prednisolone therapy. Identifying reliable early predictors of therapy response and survival is critical. Plasma metabolomics was conducted on 70 SAH patients (50 responders, 20 non-responders) to identify biomarkers for non-response and early mortality. These findings were validated in a cohort of 153 patients and an independent cohort of 245 using high resolution mass spectrometry, machine learning, and severity indices. Temporal metabolic changes indicated interactions between the host and microbiome, with a focus on inflammation and intestinal permeability. Plasma metabolomics revealed that non-responders had significantly higher urobilinogen levels (3.6-fold change). Additionally, a decrease in alpha/beta diversity and temporal metabolic inactivity characterized non-responders. Plasma urobilinogen levels predicted non-response (AUC>0.97) and identified non-survivors (AUC=0.94) with a threshold of >0.07 mg/ml. Urobilinogen levels correlated with bacterial peptides belonging to Firmicutes and Proteobacteria, neutrophil activation, oxidative stress, and pro-inflammatory cytokine production. These changes contributed to non-response by increasing glucocorticoid receptor β expression and compromising intestinal permeability. Fecal microbiota transplantation decreased urobilinogen levels by reducing bilirubin reductase gene-containing microbiota. Plasma urobilinogen >0.07 mg/ml could predict early mortality, and modulation of the gut microbiome may improve outcomes in SAH patients.