化疗药物引起的肠毒性已成为中断治疗和停用已批准药物的重要原因。在这项研究中,我们证明,化疗药物引起的肠道损伤通常以色氨酸(Trp)-犬尿氨酸(KYN)-犬尿氨酸(KA)轴代谢的急剧上调为特征。机械上,化疗引起的肠道损伤引发了白细胞介素-6(IL-6)-吲哚胺2,3-双加氧酶1(IDO1)-芳烃受体(AHR)正反馈环的形成,加速犬尿氨酸途径在肠道中的代谢。此外,AHR和G蛋白偶联受体35(GPR35)负反馈通过逐渐感知肠道和巨噬细胞中的犬尿氨酸水平来调节肠道损伤和炎症,以维持肠道完整性和体内平衡。分别。此外,基于虚拟筛选和生物验证,从2388种批准的药物中发现了分别作为GPR35和AHR激动剂的伐地那非和利格列汀。重要的是,伐地那非和利格列汀在体内显著减轻化疗诱导的肠道毒性的结果表明,二者联合使用的化疗药物在临床上可能是一种有希望的癌症患者治疗策略.这项工作强调了GPR35和AHR作为犬尿氨酸途径代谢的守护者和针对肠道损伤的防御反应的核心组成部分。
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.