Tryptophan pathway metabotypes associate with disease activity and immune-metabolic dysfunction in inflammatory bowel disease

Background: Tryptophan (Trp) metabolism is a central immunometabolic axis in inflammatory bowel disease (IBD), yet its clinical utility unclear. We aimed to identify biologically and clinically relevant Trp-related metabolic subtypes (metabotypes) in IBD and assess their association with disease activity, outcomes, and early pathogenesis. Methods: We applied unsupervised clustering to 16 serum Trp-related metabolites in a discovery cohort of IBD patients undergoing biologic induction (52 Crohns disease [CD], 82 ulcerative colitis [UC]). The resulting metabotypes were validated in three independent IBD cohorts (Suivitheque: 788 CD, 281 UC, 50 non-IBD; MSCCR: 470 CD, 374 UC, 329 non-IBD; Ibsen III: 179 CD, 340 UC, 26 IBD-U, 209 symptomatic non-IBD controls), a healthy reference population, and a prospective pre-disease cohort of CD relatives. Associations with clinical indices, outcomes, and metabolic pathway shifts were assessed using multivariable models and pathway enrichment analysis. Results: Four reproducible metabotypes were identified and are described based on dominant metabolites in their metabolite profiles Low Kynureninic acid (Kyna), High Kyna, High Quinolinic acid (Quin), and Balanced. Low Kyna and High Quin were associated with elevated disease activity across all cohorts, yet exhibited differential metabolic perturbations when assessed by pathway enrichment analysis. A pre-disease cluster resembling Low Kyna and High Quin was enriched for inflammatory markers and future CD diagnosis. Conclusion: Trp-linked metabotypes define distinct immunometabolic states in IBD that associate with inflammation and may precede disease onset. These findings provide a framework for metabolic stratification in mechanistic studies and clinical trials targeting nutrient pathways.