Glycine conjugates of indole-3-carboxylates are aryl hydrocarbon receptor ligands

Substituted indoles are conserved metabolites across all kingdoms of life and may function as a mediators of inter- and intra-species communication. Indole-3-carboxylates (indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA)) represent abundant tryptophan-derived aryl hydrocarbon receptor (AHR) agonists in human serum, potentially influencing AHR-dependent physiology. LC-MS analysis of mouse serum, urine and cecal/fecal contents reveals that both IAA and IPA undergo host and microbial mediated glycine conjugation to facilitate urinary elimination. Notably, at physiologically detectable human serum concentrations (μM), IAA-Glycine retains human AHR activation potential. Comparative in silico docking simulations corroborate IAA-Glycine as a direct ligand for the human AHR. In contrast to xenobiotic ligands such as TCDD and FICZ, the endogenous tryptophan metabolites examined here exhibited greater activation associated with human AHR relative to mouse AHR. These results underscore the role of microbial and host-derived amino acid conjugation in generating bioactive metabolites and position auxin chemistry within human physiology. Glycine conjugates of indole-3-acetic acid and indole-3-propionic acid made by the host and/or the microbiome are Ah receptor agonists.