Original articles
Di Wang, Danting Li, Yuxin Zhang, Jie Chen, Ying Zhang, Chuyao Liao, Siyuan Qin, Yuan Tian, Zunjian Zhang, Fengguo Xu. Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 763-780

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage
Di Wanga, Danting Lia, Yuxin Zhangb, Jie Chena, Ying Zhanga, Chuyao Liaoa, Siyuan Qina, Yuan Tiana, Zunjian Zhanga, Fengguo Xua
a Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China;
b Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
Abstract:
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.
Key words:    Intestinal toxicity    Kynurenine pathway    Gradually sensing    AHR    GPR35   
Received: 2020-05-06     Revised: 2020-07-14
DOI: 10.1016/j.apsb.2020.07.017
Funds: The authors thank Doudou Xu, Xien Zhang, and Bei Tan from China Pharmaceutical University (Nanjing, China) for the help of animal drug administration and tissue samples collection. The authors also thank Dr. Zhihong Liu from Sun Yat-sen University (Guangzhou, China) for providing fore-mentioned modeling software and Wecomput Technology Co., Ltd. (Beijing, China) for providing computation consulting. This work was supported by the National Nature Science Foundation of China (NSFC Nos. 81773861 and 81773682), National Science and Technology Major Project (2017ZX09101001, China), Jiangsu Provincial National Science Foundation for Distinguished Young Scholars (No. BK20180027, China), Double First-Class University Project, the Program for Jiangsu province Innovative Research Team and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, China).
Corresponding author: Zunjian Zhang, Fengguo Xu     Email:fengguoxu@cpu.edu.cn;zunjianzhangcpu@hotmail.com
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Di Wang
Danting Li
Yuxin Zhang
Jie Chen
Ying Zhang
Chuyao Liao
Siyuan Qin
Yuan Tian
Zunjian Zhang
Fengguo Xu

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