Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease

ABSTRACT: Summary Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogeneic stem cell transplantation (alloSCT). A driver of fibrosis is the kynurenine (Kyn) pathway, and Kyn metabolism patterns and cytokines may influence cGVHD severity and manifestation (fibrosing versus gastrointestinal [GI] cGVHD). Using a liquid chromatography-tandem mass spectrometry approach on sera obtained from 425 patients with allografts, we identified high CXCL9, high indoleamine-2,3-dioxygenase (IDO) activity, and an activated Kyn pathway as common characteristics in all cGVHD subtypes. Specific Kyn metabolism patterns could be identified for non-severe cGVHD, severe GI cGVHD, and fibrosing cGVHD, respectively. Specifically, fibrosing cGVHD was associated with a distinct pathway shift toward anthranilic and kynurenic acid, correlating with reduced activity of the vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGVHD and provides a rationale for translational trials on prophylactic vitamin B2/B6 supplementation for cGVHD prevention. Graphical abstract Highlights High IDO activity and an activated Kyn pathway are common in all cGVHD subtypes Specific Kyn metabolism patterns were identified for gastrointestinal and fibrosing cGVHD A pathway shift toward anthranilic and kynurenic acid was found in fibrosing cGVHD A rationale for vitamin B2/B6 adjustment for cGVHD prevention is presented Orsatti et al. show that severe cGVHD is a debilitating complication after alloSCT. The authors demonstrate that cytokines/chemokines that associate with cGVHD also correlate with metabolic alterations in the kynurenine pathway and the composition of metabolites known to influence fibrosis. Vitamin B2/B6 deficiencies are possibly involved and may be adjusted.

SUBMITTER: Orsatti L 

PROVIDER: S-EPMC8561165 | biostudies-literature |

REPOSITORIES: biostudies-literature