Abstract
BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) exhibit distinct shifts in circulating metabolite levels linked to disease activity and phenotype, but associations with disease progression remain unexplored. Our aim was to investigate relationships between circulating metabolites and metabolic pathways with disease progression risk in patients with IBD. METHODS: We performed an observational cohort study using the Mount Sinai Crohn's and Colitis Registry. Follow-up data were retrieved from longitudinal electronic health records. Untargeted metabolomic analysis was performed on baseline serum. Disease progression was defined as new systemic steroid or biological prescriptions, IBD-related hospitalization, or surgery. We used multivariable Cox proportional hazards (CoxPH) regression, L1-regularized CoxPH, and Random Survival Forest models to analyze metabolite associations with disease progression risk. RESULTS: We studied 1292 metabolites in 277 patients with ulcerative colitis (UC) and 375 patients with Crohn's disease (CD). Over a median follow-up of 2 years, 57.5% experienced disease progression. In CD, 151 metabolites correlated with disease progression (false discovery rate [FDR] < 0.1): 81 (53.6%) associated with higher risk (enriched in amino acids, purine/pyrimidine metabolism, and bile acids) and 70 (46.4%) with lower risk (enriched in fatty acid oxidation, steroid biosynthesis, tryptophan, and antioxidants). In UC, 84 metabolites associated with disease progression (FDR < 0.1): 29 (34.5%) with increased risk (enriched in sphingolipids, hydrogen sulfide, and tyrosine metabolism) and 55 (65.5%) with decreased risk (enriched in steroid biosynthesis, histidine, and phenylalanine metabolism). Survival models incorporating a combination of metabolomic data and clinical parameters outperformed those based solely on clinical variables, including age, sex, disease location, disease behavior, disease extent, current and prior use of biologics, endoscopic disease activity, surgical history, and perianal disease. CONCLUSIONS: Specific metabolites and pathways are associated with disease progression in IBD, highlighting potential prognostic biomarkers and relevant pathways.