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Observational Study
. 2025 Jun 4;19(6):jjaf082.
doi: 10.1093/ecco-jcc/jjaf082.

Distinct perturbances in metabolic pathways associate with disease progression in inflammatory bowel disease

Arno R Bourgonje  1 , Susanne Ibing  2   3   4 , Alexandra E Livanos  1 , Danielle Y Ganjian  1 , Carmen Argmann  5 , Bruce E Sands  1 , Marla C Dubinsky  1 , Drew S Helmus  1 , Henrik A Jacobsen  6   7 , Lone Larsen  6   7 , Tine Jess  6   7 , Mayte Suarez-Fariñas  8 , Bernhard Y Renard  2   3   4 , Jean-Frédéric Colombel  1 , Ryan C Ungaro  1
Affiliations
Observational Study

Distinct perturbances in metabolic pathways associate with disease progression in inflammatory bowel disease

Arno R Bourgonje et al. J Crohns Colitis. .

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.

Keywords: disease progression; inflammatory bowel disease; metabolomics.

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Conflict of interest statement

The corresponding author confirms on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. A.R.B. reports receiving research grants from Janssen Pharmaceuticals and speaker’s fees from AbbVie and Ferring. R.C.U. has served as a consultant or received speaker’s fees from AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Takeda, and received research support from AbbVie, Boehringer Ingelheim, Lilly, and Pfizer. J.-F.C. reports receiving research grants from AbbVie, Janssen Pharmaceuticals, Takeda, and Bristol Myers Squibb; receiving payment for lectures from AbbVie and Takeda; receiving consulting fees from AbbVie, Amgen, AnaptysBio, Allergan, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Genentech (Roche), Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Invea, Iterative Scopes, Merck, Landos, Microba Life Science, Novartis, Nautilus, Otsuka Pharmaceutical, Pfizer, Protagonist Therapeutics, Prometheus, Sanofi, Seres, Takeda, Teva, TiGenix, and Vifor; and hold stock options in Intestinal Biotech Development. B.Y.R. has served as a consultant and/or holds intellectual property rights commercialized by Seqstant, BioNTech, and Genentech (Roche). B.E.S. reports personal fees and nonfinancial support from AbbVie; personal fees and nonfinancial support from Abivax; personal fees from Adiso Therapeutics; personal fees from Agomab; personal fees from Alimentiv; personal fees from Amgen; personal fees from AnaptysBio; personal fees and nonfinancial support from AstraZeneca; personal fees from Biolojic Design; personal fees from Biora Therapeutics; personal fees from Boehringer Ingelheim; grants, personal fees, and nonfinancial support from Bristol Myers Squibb; personal fees and nonfinancial support from Celltrion; personal fees from Ensho Therapeutics; personal fees from Equillium; personal fees from Enthera; personal fees from Enveda Biosciences; personal fees from Evommune; personal fees from Ferring; personal fees from Fzata; personal fees from Galapagos; personal fees from Genentech; personal fees from Gilead Sciences; personal fees from Glaxo SmithKline; personal fees from Gossamer Bio; personal fees from Imhotex; personal fees from Index Pharmaceuticals; personal fees from Innovation Pharmaceuticals; grants, personal fees, and nonfinancial support from Janssen; personal fees and nonfinancial support from Johnson & Johnson; personal fees from Kaleido; personal fees from Kallyope; personal fees and nonfinancial support from Lilly; personal fees and nonfinancial support from Merck; personal fees from Microba; personal fees from Microbiotica; personal fees from Mitsubishi Tanabe Pharma; personal fees from Mobius Care; personal fees from Morphic Therapeutics; personal fees from MRM Health; personal fees from Nexus Therapeutics; personal fees from Immunyx Therapeutics; personal fees from Nimbus Discovery; personal fees from Odyssey Therapeutics; personal fees from Palisade Bio; personal fees and nonfinancial support from Pfizer; personal fees from Progenity; personal fees and nonfinancial support from Prometheus Biosciences; personal fees from Prometheus Laboratories; personal fees from Protagonist Therapeutics; personal fees from Q32 Bio; personal fees from Rasayana Therapeutics; personal fees from Recludix Therapeutics; personal fees from Reistone Biotherapeutics; personal fees from Sorriso Pharmaceuticals; personal fees from Spyre Therapeutics; personal fees from Surrozen; personal fees from Target RWE; personal fees and nonfinancial support from Takeda; personal fees from Teva; personal fees from Theravance Biopharma; personal fees from TLL Pharmaceutical; personal fees from TR1X; personal fees from Union Therapeutics; personal fees, stock, and stock options and nonfinancial support from Ventyx Biosciences, all outside the submitted work. T.J. reports consultancy for Ferring and Pfizer. H.A.J. reports receiving payment for lectures from Tillotts Pharma. The remaining authors disclose no conflicts.

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