What question did this study set out to answer?

The research investigates how tryptophan metabolism might relate to fatigue severity in Crohn’s Disease.

January 23, 2026

P0058Altered tryptophan metabolism is associated with severe fatigue in quiescent Crohn’s Disease

Key Points

The research investigates how tryptophan metabolism might relate to fatigue severity in Crohn’s Disease.
Quantified 20 tryptophan metabolites using liquid chromatography-tandem mass spectrometry.
Analyzed plasma samples from Crohn’s Disease, Ulcerative Colitis, and healthy controls.
Used the Multidimensional Fatigue Inventory to stratify patients by fatigue severity.
Implemented random forest and ROC analyses to assess the data.
Severe fatigue in Crohn’s Disease correlates with increased serotonin and decreased kynurenine pathway metabolites.
Kynurenine (AUC = 0.96) and kynurenine/tryptophan ratios (AUC = 0.94) are strong predictors of severe fatigue.
These metabolic shifts are particularly distinct in quiescent Crohn’s Disease, unlike in Ulcerative Colitis.

Abstract

Abstract Background Fatigue is a common and debilitating symptom in Inflammatory Bowel Disease(1), but its underlying mechanisms remain unclear(2). Altered tryptophan metabolism may contribute to fatigue(3). 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. Plasma serotonin and kynurenine levels in the study cohort compared to controls and summarizing tree plots A dynamics of tryptophan metabolites in severely fatigued (MFI ≥80) compared to lesser fatigued (MFI 80) IBD, CD, and quiescent CD patients. Node size indicates the relative difference between MFI ≥80 and MFI 80. Node colors represent the direction of the association of each metabolite with fatigue, red for higher in fatigue, blue for lower, with darker colors indicating significance (raw p 0.05) B serotonin and C kynurenine levels in healthy controls (HCs) vs all IBD patients, all CD patients, and quiescent CD patients. Patients stratified by MFI score 80 vs ≥ 80. HC (n = 10), IBD 80 (n = 50), IBD ≥80 (n = 14), CD 80 (n = 30), CD ≥ 80 (n = 8), quiescent CD 80 (n = 17), quiescent CD ≥ 80 (n = 3). IAA: indole-3-acetic acid; I3Ad: indole-3-aldehyde; IAM: indole-3-acetamide; I3S: indole-3-sulfate; ILA: indole-3-lactic acid; NA: not applicable Conclusion Severe fatigue in CD, particularly in quiescent disease, is associated with a shift in tryptophan metabolism towards reduced kynurenine pathway metabolite levels and increased 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. References: (1) Schoefs E, Vermeire S, Ferrante M, et al. What are the Unmet Needs and Most Relevant Treatment Outcomes According to Patients with Inflammatory Bowel Disease? A Qualitative Patient Preference Study. J Crohns Colitis. Apr 3 2023;17(3):379–388. doi:10.1093/ecco-jcc/jjac145 (2) D’Silva A, Fox DE, Nasser Y, et al. Prevalence and Risk Factors for Fatigue in Adults With Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis. Clin Gastroenterol Hepatol. May 2022;20(5):995–1009 e7. doi:10.1016/j.cgh.2021.06.034 (3) Ghiboub M, Boneh RS, Sovran B, et al. Sustained Diet-Induced Remission in Pediatric Crohn’s Disease Is Associated With Kynurenine and Serotonin Pathways. Inflamm Bowel Dis. May 2 2023;29(5):684–694. doi:10.1093/ibd/izac262 Conflict of interest: Metselaar, Paula: None Van Der Hoff, Mees: None Wieser, Naomi: None Welting, Olaf: None Lefèvre, Antoine: None Dupuy, Camille: None Emond, Patrick: None Derikx, Joep: None De Jonge, Wouter: received grant support from Leona M and Harry B Helmsley Charitable Trust, TKI Health Holland, and the European Commission speaker fees from Janssen Cilag, Alimentiv, and IBD Canada and is scientific board member of the MDL fund D’Haens, Geert: Grant: Pfizer, BMS, Johnson and Johnson, Abbvie, Alimentiv BV, Eli Lilly, Takeda, Prometheus Laboratories Personal Fees: Abbvie, Abivax, Agomab, Alimentiv, Anaptys Bio, AstraZeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Glaxo Smith Kline, Dr Falk Pharma, Pfizer, Johnson and Johnson, Merck, Mirador, Polpharma, Procise Diagnostics, Prometheus Biosciences, Sorriso Pharma, Spyre, Takeda, Ventyx Velde, Anje: None Löwenberg, Mark: Has received consultancy/lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, and Tillotts and has received grants from Alfasigma, NFU, ZonMW, and TKI Ghiboub, Mohammed: was supported by the AGEM Talent Development Grant, the ECCO Grant and the Litwin Pioneers Initiative

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Metselaar et al. (Thu,) studied this question.

synapsesocial.com/papers/69731047c8125b09b0d1ff1f https://doi.org/https://doi.org/10.1093/ecco-jcc/jjaf231.239

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