Tryptophan wasting and disease activity as a systems phenomenon in inflammation - an analysis across 13 chronic inflammatory diseases.

Chronic inflammatory diseases (CID) are systems disorders affecting various organs including the intestine, joint and skin. The essential amino acid tryptophan (Trp) is not only used for protein synthesis but can also be catabolized to various bioactive derivatives that are important for cellular energy metabolism and immune regulation. Increased Trp catabolism via the kynurenine pathway is seen across individual CID entities1-5. Here, we assessed the levels of Trp and tryptophan derivatives across 13 CID to investigate the extent and nature of Trp wasting as a systems phenomenon in CID. We found reduced serum Trp levels across the majority of CID and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Increases in the kynurenine-to-Trp ratio (Kyn:Trp) indicate that the kynurenine pathway is a major route for CID-related Trp wasting. However, the extent of Trp depletion and its relationship with disease activity varies by disease, indicating potential differences in Trp metabolism. In addition, we find that amino acid catabolism in chronic inflammation is specific to tryptophan wasting, whereas other proteinogenic amino acids are not affected. Hence, our results suggest that increased Trp catabolism is a common metabolic occurrence in CID that may directly affect systemic immunity. Grant supportThis work was supported by the DFG Cluster of Excellence 1261 "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), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings ("Taxonomy, Treatments, Targets and Remission", No. 831434, "ImmUniverse", grant agreement No. 853995, "BIOMAP", grant agreement No. 821511).