Targeting the aryl hydrocarbon receptor (AhR) is an emerging therapeutic strategy for multiple diseases (e.g., inflammatory bowel disease). <i>Thermosporothrix hazakensis</i> microbial metabolite 2-(1'<i>H</i>-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is a putative AhR endogenous ligand. To improve the chemical stability, we synthesized a series of ITE chemical mimics. Using a series of in vitro assays, we identified 2-(1<i>H</i>-indole-3-carbonyl)-<i>N</i>-methyl thiazole-4-carboxamide (ITE-CONHCH<sub>3</sub>) as a highly potent (EC<sub>50</sub> = 1.6 nM) AhR agonist with high affinity (<i>K</i><sub>i</sub> = 88 nM). ITE-CONHCH<sub>3</sub> triggered AhR nuclear translocation and dimerization of AhR-ARNT, enhanced AhR binding in the CYP1A1 promoter, and induced AhR-regulated genes in an AhR-dependent manner. The metabolic stability of ITE-CONHCH<sub>3</sub> in a cell culture was 10 times higher than that of ITE. Finally, we observed protective effects of ITE-CONHCH<sub>3</sub> in mice with DSS-induced colitis. Overall, we demonstrate and validate a concept of microbial metabolite mimicry in the therapeutic targeting of AhR.