Circulating bacterial peptides and linked metabolomic signatures are indicative of early mortality in Paediatric Cirrhosis

Introduction: Paediatric Cirrhosis-Sepsis (PC-S) patients attain early mortality. Plasma bacterial composition, the cognate metabolites and their contribution in the deterioration of PC-S patients to early mortality in unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating PC-S patients predisposed to early mortality using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using Machine learning (ML) algorithms. Methods: We enrolled 160 patients with liver diseases [Cirrhosis-Sepsis/Nonsepsis (n=110); Non-cirrhosis (n=50)] and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis; n=70 and Non-cirrhosis; n=40). The candidate predictors were validated on two test cohorts - T1 (Plasma test cohort) & T2 (one drop blood test cohort). Both T1 & T2 had 120 patients each, of which 70 were from the training cohort. Results: Increased levels of tryptophan metabolites, Salmonella enterica and Escherichia coli associated peptides segregated cirrhotic patients. Increased levels of Deoxyribose-1-phosphate, N5-Citryl-D-ornithine and Herbinix hemicellulolytic and Leifsonia xyli segregated PC-S patients. MMCN based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S Non-survivors. Increased Indican, Staphylobillin, Glucose-6-phosphate, 2-Octenoylcarnitine, Palmitic acid and Guanidoacetic acid along with Leifsonia xyli, Mycoplasma genitalium and Hungateiclostridium thermocellumsegregated PC-S Non-survivors and superseded the liver disease severity indices with high accuracy, sensitivity & specificity for mortality prediction using random forest ML algorithm. Conclusions: Our study reveals a novel metabolite signature panel capable of segregating PC-S patients predisposed to early mortality using as low as one drop blood.