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

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

Automated summary

By synthesizing a series of ITE chemical mimics, we identified ITE-CONHCH3 as a highly potent AhR agonist with high affinity and metabolic stability. ITE-CONHCH3 can induce nuclear translocation and dimerization of AhR, enhance AhR binding, and induce AhR-regulated gene expression in an AhR-dependent manner. Additionally, ITE-CONHCH3 exhibited protective effects in a mouse colitis model.