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Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage

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Acta Pharmaceutica Sinica B 2021年第3期11卷 763-780页

作者： Di Wang Danting Li Yuxin Zhang Jie Chen Ying Zhang Chuyao Liao Siyuan Qin Yuan Tian Zunjian Zhang Fengguo Xu Key Laboratory of Drug Quality Control and Pharmacovigilance(Ministry of Education) State Key Laboratory of Natural MedicineChina Pharmaceutical UniversityNanjing 210009China Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical SchoolNanjing 210008China

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)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl 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 *** work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.

关键词： Intestinal toxicity Kynurenine pathway gradually sensing AHR GPR35

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