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
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
Author description:
PDF(KB) Free
Di Wang
Danting Li
Yuxin Zhang
Jie Chen
Ying Zhang
Chuyao Liao
Siyuan Qin
Yuan Tian
Zunjian Zhang
Fengguo Xu

1. Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004;100:2026-46.
2. Mitchell EP. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol 2006;19:566-79.
3. Dore MP, Pes GM, Murino A, Quarta Colosso B, Pennazio M. Short article: small intestinal mucosal injury in patients taking chemotherapeutic agents for solid cancers. Eur J Gastroenterol Hepatol 2017;29: 568-71.
4. Grattagliano I, Ubaldi E, Portincasa P. Drug-induced enterocolitis: prevention and management in primary care. J Dig Dis 2018;19: 127-35.
5. Rodrigues D, Souza T, Jennen DG, Lemmens L, Kleinjans JC, de Kok TM. Drug-induced gene expression profile changes in relation to intestinal toxicity: state-of-the-art and new approaches. Canc Treat Rev 2019;77:57-66.
6. Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. J Am Med Assoc 2003; 289:1107-16.
7. Prisciandaro LD, Geier MS, Butler RN, Cummins AG, Howarth GS. Evidence supporting the use of probiotics for the prevention and treatment of chemotherapy-induced intestinal mucositis. Crit Rev Food Sci Nutr 2011;51:239-47.
8. Wardill HR, Bowen JM, Gibson RJ. New pharmacotherapy options for chemotherapy-induced alimentary mucositis. Expet Opin Biol Ther 2014;14:347-54.
9. Sullivan LB, Gui DY, Vander Heiden MG. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat Rev Canc 2016;16:680-93.
10. Wishart DS. Emerging applications of metabolomics in drug discovery and precision medicine. Nat Rev Drug Discov 2016;15:473-84.
11. Yao Y, Zhang P, Wang J, Chen J, Wang Y, Huang Y, et al. Dissecting target toxic tissue and tissue specific responses of irinotecan in rats using metabolomics approach. Front Pharmacol 2017;8:122.
12. Cui DN, Wang X, Chen JQ, Lv B, Zhang P, Zhang W, et al. Quantitative evaluation of the compatibility effects of huangqin decoction on the treatment of irinotecan-induced gastrointestinal toxicity using untargeted metabolomics. Front Pharmacol 2017;8:211.
13. Guo H, Jiao Y, Wang X, Lu T, Zhang Z, Xu F. Twins labeling-liquid chromatography/mass spectrometry based metabolomics for absolute quantification of tryptophan and its key metabolites. J Chromatogr A 2017;1504:83-90.
14. Kaluzna-Czaplinska J, Gatarek P, Chirumbolo S, Chartrand MS, Bjorklund G. How important is tryptophan in human health?. Crit Rev Food Sci Nutr 2019;59:72-88.
15. Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science 2017; 357:eaaf9794.
16. Platten M, Nollen EAA, Rohrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov 2019;18:379-401.
17. Jia Xin Yu, Vanessa M, Hubbard-Lucey, Tang J. Immuno-oncology drug development goes global. Nat Rev Drug Discov 2019;18:899-900.
18. Rohrig UF, Majjigapu SR, Vogel P, Zoete V, Michielin O. Challenges in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. J Med Chem 2015;58:9421-37.
19. Dounay AB, Tuttle JB, Verhoest PR. Challenges and opportunities in the discovery of new therapeutics targeting the kynurenine pathway. J Med Chem 2015;58:8762-82.
20. Lamas B, Natividad JM, Sokol H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol 2018;11:1024-38.
21. Metidji A, Omenetti S, Crotta S, Li Y, Nye E, Ross E, et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 2018;49:353-62.
22. Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 2019;19:184-97.
23. Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018;23: 716-24.
24. Husted AS, Trauelsen M, Rudenko O, Hjorth SA, Schwartz TW. GPCR-mediated signaling of metabolites. Cell Metabol 2017;25: 777-96.
25. Agudelo LZ, Ferreira DMS, Cervenka I, Bryzgalova G, Dadvar S, Jannig PR, et al. Kynurenic acid and Gpr35 regulate adipose tissue energy homeostasis and inflammation. Cell Metabol 2018;27:378-92.
26. Tan JK, McKenzie C, Marino E, Macia L, Mackay CR. Metabolitesensing g protein-coupled receptors-facilitators of diet-related immune regulation. Annu Rev Immunol 2017;35:371-402.
27. Coumailleau P, Poellinger L, Gustafsson JA, Whitelaw ML. Definition of a minimal domain of the dioxin receptor that is associated with HSP90 and maintains wild type ligand binding affinity and specificity. J Biol Chem 1995;270:25291-300.
28. MacKenzie AE, Caltabiano G, Kent TC, Jenkins L, McCallum JE, Hudson BD, et al. The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35. Mol Pharmacol 2014;85:91-104.
29. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 2004;1:337-41.
30. Guo HM, Chen JQ, Huang Y, Zhang W, Xu FG, Zhang ZJ. A pseudokinetics approach for time-series metabolomics investigations: more reliable and sensitive biomarkers revealed in vincristine-induced paralytic ileus rats. RSC Adv 2016;6:54471-8.
31. Reynell PC, Spray GH. The simultaneous measurement of absorption and transit in the gastro-intestinal tract of the rat. J Physiol 1956;131: 452-62.
32. Wang X, Cui DN, Dai XM, Wang J, Zhang W, Zhang ZJ, et al. HuangQin decoction attenuates CPT-11-induced gastrointestinal toxicity by regulating bile acids metabolism homeostasis. Front Pharmacol 2017;8:156.
33. Kurita A, Kado S, Kaneda N, Onoue M, Hashimoto S, Yokokura T. Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats. Cancer Chemother Pharmacol 2000;46:211-20.
34. Cooper HS, Murthy SN, Shah RS, Sedergran DJ. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 1993;69:238-49.
35. Jin BR, Chung KS, Cheon SY, Lee M, Hwang S, Noh Hwang S, et al. Rosmarinic acid suppresses colonic inflammation in dextran sulphate sodium (DSS)-induced mice via dual inhibition of NF-kB and STAT3 activation. Sci Rep 2017;7:46252.
36. Taleb S. Tryptophan dietary impacts gut barrier and metabolic diseases. Front Immunol 2019;10:2113.
37. Beischlag TV, Luis Morales J, Hollingshead BD, Perdew GH. The aryl hydrocarbon receptor complex and the control of gene expression. Crit Rev Eukaryot Gene Expr 2008;18:207-50.
38. Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P. Amplification of dopaminergic signaling by a positive feedback loop. Proc Natl Acad Sci U S A 2000;97:12840-5.
39. Damon LE, Cadman EC. Advances in rational combination chemotherapy. Canc Invest 1986;4:421-44.
40. Kern DH, Morgan CR, Hildebrand-Zanki SU. In vitro pharmacodynamics of 1-b-D-arabinofuranosylcytosine: synergy of antitumor activity with cis-diamminedichloroplatinum(II). Cancer Res 1988;48:117-21.
41. Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 2014;13:397-406.
42. Mackenzie AE, Milligan G. The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 2017;113: 661-71.
43. Zhao P, Sharir H, Kapur A, Cowan A, Geller EB, Adler MW, et al. Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and b-arrestin2 with antinociceptive activity. Mol Pharmacol 2010;78:560-8.
44. Widenmaier SB, Snyder NA, Nguyen TB, Arduini A, Lee GY, Arruda AP, et al. NRF1 is an ER membrane sensor that is central to cholesterol homeostasis. Cell 2017;171:1094-109.
45. Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature 2015;517:302-10.
46. Turski MP, Turska M, Paluszkiewicz P, Parada-Turska J, Oxenkrug GF. Kynurenic acid in the digestive system-new facts, new challenges. Int J Tryptophan Res 2013;6:47-55.
47. Divorty N, Mackenzie AE, Nicklin SA, Milligan G. G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease. Front Pharmacol 2015;6:41.
48. Milligan G. Orthologue selectivity and ligand bias: translating the pharmacology of GPR35. Trends Pharmacol Sci 2011;32:317-25.
49. Grada A, Otero-Vinas M, Prieto-Castrillo F, Obagi Z, Falanga V. Research techniques made simple: analysis of collective cell migration using the wound healing assay. J Invest Dermatol 2017;137:e11-6.
50. Headon D. Reversing stratification during wound healing. Nat Cell Biol 2017;19:595-7.
51. Gutierrez-Vazquez C, Quintana FJ. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 2018;48:19-33.
52. Collins SL, Patterson AD. The gut microbiome: an orchestrator of xenobiotic metabolism. Acta Pharm Sin B 2020;10:19-32.
53. Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl hydrocarbon receptor in combination with Stat 1 regulates LPS-induced inflammatory responses. J Exp Med 2009;206: 2027-35.
54. DiNatale BC, Schroeder JC, Perdew GH. Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines. Mol Carcinog 2011;50:173-83.
55. DiNatale BC, Schroeder JC, Francey LJ, Kusnadi A, Perdew GH. Mechanistic insights into the events that lead to synergistic induction of interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and inflammatory signaling. J Biol Chem 2010;285: 24388-97.
56. Pulley JM, Rhoads JP, Jerome RN, Challa AP, Erreger KB, Joly MM, et al. Using what we already have: uncovering new drug repurposing strategies in existing omics data. Annu Rev Pharmacol Toxicol 2019; 60:333-52.
Similar articles: