Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

초록

Targeting the aryl hydrocarbon receptor (AhR) isan emerging therapeutic strategy for multiple diseases (e.g.,inflammatory bowel disease).Thermosporothrix hazakensismicro-bial metabolite 2-(1 ' H-indole-3 '-carbonyl)-thiazole-4-carboxylicacid methyl ester (ITE) is a putative AhR endogenous ligand.To improve the chemical stability, we synthesized a series of ITEchemical mimics. Using a series of in vitro assays, we identified 2-(1H-indole-3-carbonyl)-N-methyl thiazole-4-carboxamide (ITE-CONHCH3) as a highly potent (EC50= 1.6 nM) AhR agonistwith high affinity (Ki= 88 nM). ITE-CONHCH3triggered AhRnuclear translocation and dimerization of AhR-ARNT, enhancedAhR binding in the CYP1A1 promoter, and induced AhR-regulated genes in an AhR-dependent manner. The metabolic stability of ITE-CONHCH3in a cell culture was 10 times higherthan that of ITE. Finally, we observed protective effects of ITE-CONHCH3in mice with DSS-induced colitis. Overall, wedemonstrate and validate a concept of microbial metabolite mimicry in the therapeutic targeting of AhR

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