PR001820 (Project)

Description:The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates gene expression upon activation by small molecules. It plays a significant role in the innate immune recognition of bacteria and response to exogenous molecules in the human host. By stimulating host immune cells with microbiota metabolites, the AhR signaling enables microbiota-dependent induction, training, and function of the host immune system. AhR is a potential target for developing therapeutics to treat myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, and aging-related diseases. A variety of bioactive molecules can act as AhR agonists, including the metabolites and derivatives of indole and tryptophan. However, given the ligand-binding versatility of AhR, new methods are needed to discover novel AhR agonists. Herein, we report an analytical workflow for the deep discovery of AhR agonists from the secreted metabolome of bacteria. We also describe a method of targeted discovery of AhR-activating metabolites and report a correlation analysis of the AhR activity with the concentration of endogenous metabolites that identified significant common AhR activators shared by different strains of bacteria in the human microbiome. Principal component analysis of relative concentrations of indole compounds clusters different bacteria species, providing a possible means for evaluating the regulation of the bacteria indole pathway.