DSS-induced colitis activates the kynurenine pathway in serum and brain by affecting IDO-1 and gut microbiota

• Published in: Frontiers in immunology 2023-01, Vol.13, p.1089200-1089200
• Main Authors: Zhao, Li-Ping, Wu, Jian, Quan, Wei, Zhou, Yu, Hong, Hui, Niu, Gu-Yu, Li, Ting, Huang, Shu-Bing, Qiao, Chen-Meng, Zhao, Wei-Jiang, Cui, Chun, Shen, Yan-Qin
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Colitis - metabolism; DSS-induced colitis; Gastrointestinal Microbiome; gut microbiota; Immunology; indoleamine-2,3-dioxygenase (IDO); Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Inflammatory Bowel Diseases; Kynurenine - metabolism; kynurenine pathway (KP); Mice; Mice, Inbred C57BL; RNA, Ribosomal, 16S; Tryptophan - metabolism; Tryptophan Oxygenase - metabolism
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.1089200

Accumulative studies suggest that inflammatory bowel disease (IBD) may cause multiple central nervous system (CNS) pathologies. Studies have found that indoleamine-2,3-dioxygenase (IDO, rate-limiting enzyme of the kynurenine (Kyn) pathway) deficient mice were protected from endotoxin induced cognitive impairment, and Kyn administration induced cognitive memory deficits in both control and IDO-deficient mice. However, there is no investigation of the brain Kyn pathway in IBD, thus we investigated whether dextran sulfate sodium (DSS)-induced colitis could cause dysregulation of Kyn pathway in brain, and also in serum. C57BL/6J mice were given drinking water with 2% DSS for 10 consecutive days to induce colitis. In serum, we found significant increase in Kyn and kynurenic acid (Kyna) level, which was regulated by IDO-1 and KAT2 (rate-limiting enzymes of Trp-Kyn-Kyna pathway). Similarly, by analyzing GEO datasets, higher IDO-1 levels in peripheral blood monocytes and colon of UC patients was found. Furthermore, the Kyn pathway was significantly upregulated in the cerebral cortex under the action of IDO-1 after DSS treatment, which ultimately induced the neurotoxic phenotype of astrocytes. To investigate whether gut microbiota is involved in IBD-induced Kyn pathway dysregulation, we performed intestinal flora 16S rRNA sequencing and found that DSS-induced colitis significantly altered the composition and diversity of the gut microbiota. Metabolic function analysis also showed that Tryptophan metabolism, NOD-like receptor signaling pathway and MAPK signaling pathway were significantly up-regulated in the 2% DSS group. A significant association between intestinal flora and Trp metabolism (both in serum and brain) was found by correlation analysis. Overall, this study revealed that DSS-induced colitis causes dysregulation of the Kyn pathway in serum and brain by affecting rate-limiting enzymes and intestinal flora.