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

Abstract

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.

Alterations in tryptophan metabolism and de novo NAD+ biosynthesis within the microbiota-gut-brain axis in chronic intestinal inflammation

“…These findings are significant as the metabolism of tryptophan, via the kynurenine pathway, serves as a critical link between peripheral inflammation and central nervous system alterations ( 25 ). In contrast to our results, elevated kynurenine levels have been observed in humans with major depressive disorder ( 131 ), as well as in acute DSS-induced colitis mice ( 132 ). Acute inflammation in DSS-induced colitis stimulates the tryptophan-kynurenine-KYNA pathway in the brain ( 132 ); therefore, our findings suggest that chronic colitis in Winnie mice has a diminished impact on this pathway, given that neuroprotective KYNA concentration was reduced.…”

Psychiatric Comorbidities of Inflammatory Bowel Disease: It Is a Matter of Microglia’s Gut Feeling

“…In an inflammatory milieu, this augmented production of neurotoxic molecules, such as QUIN, 3-hydroxykynurenine (3-HK), and 3-hydroxy anthranilic acid (3-HAA), may potentially contribute to depressive symptoms by causing damage to hippocampal neurons [135]. DSS-induced colitis caused elevated KYN levels in the cerebral cortex, which were primarily a result of local synthesis mediated by the IDO-1, rather than transport from the bloodstream [136]. While there was no significant change in the pro/anti-inflammatory phenotypes transition of microglia cells in their response to colitis-induced KYN elevation, a neurotoxic neurotoxin subtype of astrocytes was observed.…”

“…While there was no significant change in the pro/anti-inflammatory phenotypes transition of microglia cells in their response to colitis-induced KYN elevation, a neurotoxic neurotoxin subtype of astrocytes was observed. In addition, the changes in the variety and composition of the gut microbiota resulted in increased TRP metabolism in serum and brain [136]. When subjected to various forms of stress, experimental animals exhibit elevated ratios of KYN/TRP in both the brain and the intestines, along with an upregulation of IDO expression [137].…”

Stress and the gut-brain axis: an inflammatory perspective

“…Enterochromaffin cells are responsible for 5-HT (5-hydroxytryptamine) production (Reigstad et al, 2015 ; Rao and Gershon, 2016 ; Malinova et al, 2018 ). Enteroendocrine cells modulate signaling between enteric glial cells and GVB (Dowling et al, 2022 ), release cholecystokinin or YY peptide (Hayashi et al, 2023 ), and partake in microbial metabolites conversion such as tryptophan, and further, kynurenine (Ye et al, 2021 ; Zhao et al, 2023 ). The ENS detects bacteria-derived LPS via highly abundant TLRs, especially TLR2 and TLR4 (Hyland and Cryan, 2016 ).…”