The kynurenine pathway (KP) is the principal metabolic route for the essential amino acid tryptophan (TRP). Recent advances have highlighted a pivotal role for several KP metabolites in inflammatory diseases, including ulcerative colitis (UC). However, the alterations of KP enzymes and their functional impact in UC remain poorly defined. Here, we focused on kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which serve as critical branching enzymes in the KP. We observed that dextran sodium sulfate (DSS)-induced colitis mice exhibited disturbed TRP metabolism along with KMO and KYNU upregulated. In patients with active UC, both the expression of KMO and KYNU were positively correlated with inflammatory factors TNF-α and IL-1β. Pharmacological blockade of KMO or genetic silencing of KYNU suppressed IL-1β-triggered proinflammatory cytokines expression in intestinal epithelial cells. Furthermore, blockage of KMO by selective inhibitor Ro 61-8048 alleviated the symptoms of DSS-induced colitis in mice, accompanied by an expanded NAD+ pool and redox balance restoration. The protective role of Ro 61-8048 may be partly due to its effect on KP regulation, particularly in enhancing kynurenic acid production. In summary, our study provides new evidence for the proinflammatory property of KMO and KYNU in intestinal inflammation, hinting at a promising therapeutic approach in UC through targeting these enzymes.
Keywords: Kynurenic acid; Kynureninase; Kynurenine 3-monooxygenase; Kynurenine pathway; NAD(+); Ulcerative colitis.
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