Plasma multi-omics outlines association of urobilinogen with corticosteroid non-response, inflammation and leaky gut in Sever Alcoholic Hepatitis

• DOI: 10.1101/2023.03.06.23286831
• Publication Date: 2023-03-09T03:25:24Z
• Authors: Manisha Yadav; Babu Mathew; Sadam H Bhat; Neha Sharma; Jitender Kumar; Pushpa Yadav; Gaurav Tripathi; Vasundhra Bindal; Nupur Sharma; Sushmita Pandey; Ravinder Singh; Ashima Bhaskar; Ved Prakash Dwivedi; Nirupama Trehanpati; Shvetank Sharma; Shiv Kumar Sarin; Jaswinder Singh M...
• Keywords: Metabolome

ABSTRACT Background and Aims Severe alcoholic hepatitis (SAH) has a high mortality corticosteroid therapy is effective in 60% patients. Reliable indicators of response to SAH are needed. A total 223 patients, 70 derivative [50 responders (R) 20 non-responders (NR)] 153 validation cohort [136R, 17NR] were subjected plasma metabolic/meta-proteomic analysis using UHPLC-HRMS validated Machine-Learning (ML). Temporal metabolic changes assessed Weighted Metabolome Correlation Network Analysis (WMCNA). Functionality (inflammatory-nature, effect on membrane integrity glucocorticoid receptor) non-response indicator was in-vitro primary healthy neutrophils or mice enterocytes. Baseline metabolomics meta-proteomics clearly discriminated NR showed significant increase urobilinogen (3.6-fold), cholesterol sulfate (6.9-fold), Adenosine monophosphate (4.7-fold) others (p<0.05, FC>1.5, FDR<0.01). Increase alpha/beta diversity, biosynthesis secondary metabolites characteristic feature (p<0.05). metabolically inactive however R temporal change the metabolite expression post-corticosteroid Plasma predicted [AUC=0.94] with hazard-ratio 1.5(1.2-1.6) cut-off >0.07mg/ml segregated non-survivors (p<0.01) >98% accuracy ML. directly correlated circulating bacterial peptides linked bilirubin metabolising bacteria (r 2 >0.7;p<0.05). Urobilinogen induced neutrophil activation , oxidative-stress pro-inflammatory cytokine s (CXCR1, NGAL, NOXO1, NOX4, IL15, TNFα others, p<0.05), promoted resistance by increasing GR-Beta trans-repression genes under GR-alpha (inflammatory-NFkB, MAPK-MAP) reducing GR-alpha, transactivation (anti-inflammatory) gene levels. also leaky gut deregulating intestinal junction proteins. Conclusion metabolome/meta-proteome can stratify pre-therapy steroid response. pedals vicious cycle translocation inflammation