A Distinct Tryptophan Metabolic Phenotype Marks Severe Fatigue in Quiescent Crohn's Disease

ABSTRACT Background Fatigue is a common and debilitating symptom in inflammatory bowel disease (IBD), but its underlying mechanisms remain unclear. Altered tryptophan metabolism may contribute to fatigue. Tryptophan is metabolized through the kynurenine, serotonin, and indole pathway, involving host and microbial processes. We aimed to explore the link between tryptophan metabolism and fatigue, which could lead to the identification of potential biomarkers and therapeutic targets. Methods Plasma levels of 20 tryptophan metabolites were quantified by liquid chromatography‐tandem mass spectrometry in 38 Crohn's disease (CD), 26 ulcerative colitis (UC) patients and 10 healthy controls. Patients were stratified by disease activity and fatigue severity using the Multidimensional Fatigue Inventory (MFI), and data were evaluated with random forest and ROC analyses. Results In CD patients, severe fatigue (defined as MFI ≥ 80) was associated with elevated serotonin and reduced kynurenine pathway metabolite levels such as kynurenine, kynurenic acid, and quinolinic acid. These alterations became even more pronounced in quiescent CD. ROC analyses identified kynurenine (AUC = 0.96), kynurenine/tryptophan (AUC = 0.94) and serotonin/kynurenine (AUC = 0.88) as the top discriminators of severe fatigue in quiescent CD. In UC and CD patients with less severe fatigue, these metabolic signatures remained unchanged. Conclusions Severe fatigue in CD, particularly in quiescent disease, is associated with differences in tryptophan metabolites with low kynurenine pathway metabolite levels and high serotonin levels, which was not observed in UC, suggesting CD‐specific mechanisms. Tryptophan metabolites show potential as biomarkers for severe fatigue and might reveal mechanistic insights relevant for fatigue management in CD.