Background The kynurenine pathway is upregulated in inflammatory bowel disease (IBD) in a disease-activity induced manner. This route of tryptophan (Trp) degradation leads to a variety of bioactive compounds, including several with anti-inflammatory (e.g., kynurenic acid (Kyna), xanthurenic acid (Xana)) or cytotoxic (quinolinic acid (Quin)) effects. Our aim was to stratify patients with IBD into distinct subgroups based on their Trp metabolic profiles (Trp metabotypes) and to assess their prognostic capacity regarding disease progression. Methods We measured 16 Trp-related metabolites with particular attention to kynurenine pathway metabolites in the serum of a longitudinal German cohort (hypothesis generation) of 82 Ulcerative Colitis (UC) and 52 Crohn’s Disease (CD) patients. We used unsupervised k-means clustering to identify distinct clusters of patients based on their metabolite profiles and employed regression analysis to identify associations between the metabotypes and disease activity and progression. The analysis was expanded to three independent prospective validation cohorts recruited in France (n = 281 UC, 788 CD), the USA (n = 329 controls, 470 UC, 374 CD) and an inception cohort in Norway (n = 179 UC, 340 CD). Results We found four highly stable metabotypes within the discovery cohort (Fig 1A). Strong signals from the anti-inflammatory compounds Kyna and Xana characterized the first two metabotypes (High/Low Kyna metabotypes), which exhibited opposing associations with clinical, biochemical, and endoscopic disease activity. The third is characterized by high Quin levels and increased disease activity, while the fourth is metabolically heterogeneous and has lower disease activity (Fig 1B). These metabotypes were present in both UC and CD, albeit with differing proportions. Associations with disease activity were confirmed in three validation cohorts. Furthermore, we found differential probabilities between the metabotypes regarding future escalation to biologic therapies, requirement for steroid courses, IBD-related hospitalization and surgery. This was particularly evident when comparing individuals in the Low Kyna group with the lower incidence rates observed in the High Kyna group (Fig. 1C). Conclusion A distinct pattern of Trp degradation occurs in a subset of IBD patients that is strongly and consistently linked with disease activity and longitudinal outcomes of disease progression across multiple recruitment sites spanning two continents. Further work will focus on metabolic characterization of the metabotypes to understand the physiological processes driving the differentiation. This work may lead to the design of new therapeutic modalities targeting Trp metabolism in distinct patient groups.