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.
Keywords: 1-MT, 1-methyl-tryptophan; AG, AG490; AHR; AHR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; BCA, bicinchoninic acid; BSA, bovine serum albumin; CH, CH223191; CPT-11, irinotecan; CYP1A1, cytochrome P450 1A1; DAI, disease activity index; DMSO, dimethyl sulfoxide; DPP-4, dipeptidyl peptidase-4; DRE, dioxin response elements; DSS, dextran sulphate sodium; Dens-Cl, N-diethyl-amino naphthalene-1-sulfonyl chloride; Dns-Cl, N-dimethyl-amino naphthalene-1-sulfonyl chloride; ECL, enhanced chemiluminescence; ELISA, enzyme-linked immunosorbent assay; ERK1/2, extracellular regulated protein kinases 1/2; ESI, electrospray ionization; FBS, fetal bovine serum; GE, gastric emptying; GFP, green fluorescence protein; GI, gastrointestinal transit; GPR35; GPR35, G protein-coupled receptor 35; Gradually sensing; HE, hematoxylin and eosin; HRP, horseradish peroxi-dase; IBD, inflammatory bowel disease; IDO1, indoleamine 2,3-dioxygenase 1; IL-6, interleukin-6; IS, internal standard; Intestinal toxicity; JAK2, janus kinase 2; KA, kynurenic acid; KAT, kynurenine aminotransferase; KYN, kynurenine; Kynurenine pathway; LC–MS, liquid chromatography–mass spectrometry; LPS, lipopolysaccharides; Linag, linagliptin; MOE, molecular operating environment; MOI, multiplicity of infection; MRM, multiple-reaction monitoring; MTT, thiazolyl blue tetrazolium bromide; PBS, phosphate buffer saline; PDB, protein data bank; PDE5, phosphodiesterase type-5; PF, PF-04859989; PMA, phorbol 12-myristate 13-acetate; PMSF, phenylmethylsulfonyl fluoride; RIPA, radioimmunoprecipitation; RPKM, reads per kilobase per million mapped reads; RPMI 1640, Roswell Park Memorial Institute 1640; RT-PCR, real-time polymerase chain reaction; STAT3, signal transducer and activator of transcription 3; Trp, tryptophan; VCR, vincristine; Vard, vardenafil.
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