Tryptophan degradation as a systems phenomenon in inflammation - an analysis across 13 chronic inflammatory diseases.

Background: Chronic inflammatory diseases (CIDs) are systems disorders that affect diverse organs including the intestine, joints and skin. The essential amino acid tryptophan (Trp) can be broken down to various bioactive derivatives important for immune regulation. Increased Trp catabolism has been observed in some CIDs, so we aimed to characterise the specificity and extent of Trp degradation as a systems phenomenon across CIDs.

Methods: We used high performance liquid chromatography and targeted mass spectrometry to assess the serum and stool levels of Trp and Trp derivatives. Our retrospective study incorporates both cross-sectional and longitudinal components, as we have included a healthy population as a reference and there are also multiple observations per patient over time.

Findings: We found reduced serum Trp levels across the majority of CIDs, and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Notably, serum Trp was low in several CIDs even in the absence of measurable systemic inflammation. Increases in the kynurenine-to-Trp ratio (Kyn:Trp) suggest that these changes result from increased degradation along the kynurenine pathway.

Interpretation: Increases in Kyn:Trp indicate the kynurenine pathway as a major route for CID-related Trp metabolism disruption and the specificity of the network changes indicates excessive Trp degradation relative to other proteogenic amino acids. Our results suggest that increased Trp catabolism is a common metabolic occurrence in CIDs that may directly affect systemic immunity.

Funding: This work was supported by the DFG Cluster of Excellence 2167 "Precision medicine in chronic inflammation" (KA, SSchr, PR, BH, SWa), the BMBF (e:Med Juniorverbund "Try-IBD" 01ZX1915A and 01ZX2215, the e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), EKFS (2020_EKCS.11, KA), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings ("Taxonomy, Treatments, Targets and Remission", 831434, "ImmUniverse", 853995, "BIOMAP", 821511).

Competing Interests: Declaration of interests The authors declare no competing interests related to the conception and results of this study. Financial disclosures: F.T. received speaker's fees from Abbvie, Bristol-Myers-Squibb, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Janssen, and funding from Sanofi/Regeneron. K.A. received speaker's fees from Abbvie, Dr Falk Pharma, Eli Lilly, Janssen, Takeda and Galapagos. S.S. received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion Healthcare, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos/Gilead Sciences, Genentech/Roche, GlaxoSmithKline, IMAB Biopharma, MSD, Pfizer, Shire, and Takeda. M.S. received speaker's fees from AbbVie, Affibody AB, Akari Therapeutics Plc, Almirall-Hermal, Amgen, Argenx BV, AstraZeneca AB, Biogen Idec, Bioskin, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Dermira, Eli Lilly, Foamix, Forward Pharma, Galderma, Hexal AG, Incyte Inc., Janssen-Cilag, Johnson & Johnson, Klinge Pharma, Kymab, Leo Pharma, Medac, MSD, Novartis, Pfizer, Regeneron Pharmaceutical, Sandoz Biopharmaceuticals, Sanofi-Aventis, Trevi Therapeutics, UCB Pharma. S.We. received research grants from Leo Pharma, Pfizer, and Sanofi and consulting fees from AbbVie, Almirall, Boehringer, Eli Lilly, Galderma, Pfizer, Sanofi, and Regeneron, honoraria for lectures or presentations from AbbVie, Almirall, Eli Lilly, Pfizer, Sanofi, Regeneron, and support for attending meetings from AbbVie and Sanofi. M.S. received speaker's fees from AbbVie, Almirall-Hermal, Eli Lilly, Sanofi-Aventis and travel support from AbbVie, Almirall-Hermal, Eli Lilly, Sanofi-Aventis and Amgen. D.H. received a travel grant from United European Gastroenterology. H.G. received conference travel support from Abbvie. D.T. received research grants from AbbVie, and Novartis, consulting fees from AbbVie, Almirall, Celltrion, Eli Lilly, Janssen-Cilag, Novartis, Samsung and UCB, honoraria for lectures and presentations from AbbVie, Amgen, Biogen, Eli Lilly, New-Bridge, Novartis, Samsung, Sandoz and UCB, and participates on data safety monitoring or advisory boards for AbbVie, Eli Lilly, Novartis and UCB. All other authors have no conflicts of interest to declare.

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