Multi-omics analysis provides clues in understanding diarrhea-predominant irritable bowel syndrome with concomitant nonerosive reflux disease

Diarrhea-predominant irritable bowel syndrome (IBS-D) and nonerosive reflux disease (NERD) frequently co-occur, but the molecular basis of this comorbidity remains poorly understood. We aimed to systematically characterize the multi-omics landscape of IBS-D patients with concomitant NERD and to identify shared pathophysiological pathways. Twenty patients with IBS-D overlapping NERD and 20 matched healthy controls were recruited. All participants underwent assessment of the short form-36 health survey and hospital anxiety and depression scale. Plasma samples were analyzed by untargeted LC-MS metabolomics and data-independent acquisition-based proteomics, while fecal microbiota were profiled by 16 S rRNA sequencing. Multi-omics integration was performed using Procrustes analysis, correlation networks, and random forest modeling. Patients with IBS-D and concomitant NERD exhibited normal physical function but severe deficits in role function, mental health, and overall health perception. Metabolic disruptions, immune-inflammatory system abnormalities, and gut dysbiosis were discovered using multi-omics analysis, which included 350 differential metabolites, 920 divergent proteins, opportunistic pathogen enrichment, and depletion of beneficial commensal populations. The microbiota-gut-brain axis was identified as a major hub by integrative pathway analysis, which included forkhead box O signaling, tryptophan metabolism, and neuroactive ligand-receptor interactions. Klebsiella abundance associated positively with monoamine oxidase A expression but adversely with serotonin pathway metabolites. Random forest analysis identified some metabolites as potential diagnostic biomarkers. Microbiota-gut-brain axis dysfunction is an important mechanism underlying the comorbidity of IBS-D and NERD.