Tryptophan degradation as a systems phenomenon in inflammation – an analysis across 13 chronic inflammatory diseasesResearch in context
Danielle M.M. Harris,
Silke Szymczak,
Sven Schuchardt,
Johannes Labrenz,
Florian Tran,
Lina Welz,
Hanna Graßhoff,
Henner Zirpel,
Melike Sümbül,
Mhmd Oumari,
Nils Engelbogen,
Ralf Junker,
Claudio Conrad,
Diamant Thaçi,
Norbert Frey,
Andre Franke,
Stephan Weidinger,
Bimba Hoyer,
Philip Rosenstiel,
Silvio Waschina,
Stefan Schreiber,
Konrad Aden
Affiliations
Danielle M.M. Harris
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Institute for Human Nutrition and Food Science, Division Nutriinformatics, Kiel University, Kiel, Germany
Silke Szymczak
Institute of Medical Biometry and Statistics, University of Lübeck, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
Sven Schuchardt
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany
Johannes Labrenz
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Florian Tran
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Lina Welz
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Institute for Human Nutrition and Food Science, Division Nutriinformatics, Kiel University, Kiel, Germany
Hanna Graßhoff
Department of Rheumatology University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
Henner Zirpel
Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany
Melike Sümbül
Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Mhmd Oumari
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Nils Engelbogen
Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Ralf Junker
Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Claudio Conrad
Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Diamant Thaçi
Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany
Norbert Frey
Department of Medicine III: Cardiology, Angiology, and Pneumology, Heidelberg University, Heidelberg, Germany
Andre Franke
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Stephan Weidinger
Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Bimba Hoyer
Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Philip Rosenstiel
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Silvio Waschina
Institute for Human Nutrition and Food Science, Division Nutriinformatics, Kiel University, Kiel, Germany
Stefan Schreiber
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
Konrad Aden
Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, Kiel University and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Corresponding author. Department of Internal Medicine I, University Medical Center Schleswig Holstein, Rosalind Franklin Straße 11, 24105, Kiel, Germany.
Summary: 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).
