Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)−kynurenine (KYN)−kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)−indoleamine 2,3-dioxygenase 1 (IDO1)−aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.

化学疗法引起的肠毒性已成为中断治疗和撤回批准药物的重要原因。在这项研究中，我们证明了化疗药物引起的肠道损伤通常以色氨酸（Trp）-犬尿氨酸（KYN）-犬尿酸（KA）轴代谢的急剧上调为特征。从机理上讲，化学疗法诱导的肠损伤触发了白介素6（IL-6）-吲哚胺2,3-二加氧酶1（IDO1）-芳烃受体（AHR）阳性反馈回路的形成，从而加速了肠道犬尿氨酸途径的代谢。此外，AHR和G蛋白偶联受体35（GPR35）的负反馈可通过逐渐检测肠道和巨噬细胞中的犬尿酸水平来调节肠道损伤和炎症，从而维持肠道完整性和体内稳态。分别。此外，基于虚拟筛选和生物学验证，从2388种批准的药物中分别发现了伐地那非和利拉列汀作为GPR35和AHR激动剂。重要的是，伐地那非和利那列汀显着减轻了化疗引起的肠道毒性体内研究表明，化学疗法与两者结合可以成为临床上针对癌症患者的一种有前途的治疗策略。这项工作强调了GPR35和AHR是犬尿氨酸途径代谢的守卫者，也是抵抗肠道损害的防御反应的核心组成部分。