Objective The extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway. Design Targeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition. Results In mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models. Conclusion Our study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4+ T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT. Data are available on reasonable request.

中文翻译：

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重新改变色氨酸代谢作为炎症性肠病的新型治疗策略

目的 色氨酸（Trp）代谢改变在多大程度上解释或影响炎症性肠病（IBD）的结果仍不清楚。然而，一些色氨酸代谢终产物对于肠道稳态至关重要。在这里，我们研究了犬尿氨酸途径代谢物的作用。设计 在两个大型人类 IBD 队列（1069 名 IBD 患者）中进行了靶向定量代谢组学。右旋糖酐硫酸钠诱导小鼠结肠炎实验用于评估已鉴定代谢物的作用。体外、离体和体内实验被用来破译所涉及的机制。通过不同的方法评估对能量代谢的影响，包括通过分析抑制翻译来进行单细胞代谢。结果在小鼠和人类中，肠道炎症的严重程度与黄尿酸 (XANA) 和犬尿酸 (KYNA) 的量呈负相关。补充 XANA 或 KYNA 通过影响肠上皮细胞和 T 细胞，包括芳基碳氢化合物受体 (AhR) 激活和细胞能量代谢重新连接，降低结肠炎的严重程度。此外，使用负责生成 XANA 和 KYNA 的重组酶氨基己二酸转氨酶 (AADAT) 直接调节内源色氨酸代谢，在啮齿动物结肠炎模型中具有保护作用。结论 我们的研究发现了一种将色氨酸代谢与肠道炎症和 IBD 联系起来的新机制。恢复 XANA 和 KYNA 具有保护作用，涉及 AhR 以及肠上皮细胞和 CD4+ T 细胞能量代谢的重新布线。这项研究为新的治疗策略铺平了道路，旨在通过 AADAT 操纵内源性代谢途径，从药理学上纠正 IBD 的改变。可根据合理要求提供数据。