Indole-3-propionic Acid Is an Endogenous Agonist of TAS2R38

Bitter taste receptor 38 (TAS2R38) is increasingly recognized for its extra-oral roles in metabolic and immune regulation but remains incompletely understood due to limited endogenous ligands. Therefore, we aimed to discover a novel TAS2R38 agonist from food- and microbiota-derived metabolites of aromatic amino acids. Using AI-based molecular modeling, a promising ligand-binding pocket and key interactions for TAS2R38 activation, including π–π stacking via aromatic rings and hydrogen bonding via polar head groups, were characterized. Guided by these features, indole-3-propionic acid (IPA)─a gut microbiota-derived tryptophan metabolite─was identified and validated by cell-based assays as a potent TAS2R38 agonist. IPA significantly suppressed forskolin-induced intracellular cAMP accumulation in TAS2R38-expressing HEK293T cells (IC₅₀ = 1.06 μM), comparable to that of the well-known strong agonist phenylthiocarbamide (PTC). Structure–activity analyses of IPA analogs further validated the proposed binding mechanism. This study provides a new molecular framework for designing functional food ingredients targeting extra-oral TAS2Rs.