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)nega-tive feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeosta-sis 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 lina-gliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemother-apeutics 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.