The incidence of atopic diseases is increasing rapidly in industrialized countries. While diet, pollution, and the microbiota are known to play a role in their development, the mechanisms by which these factors interact with one another and the host, remain to be determined. We hypothesized that the gut microbiota from individuals with atopic diseases encodes metabolic pathways that can influence activation of atopic responses in the host. Using cell-free supernatants from gut microbiota strains, we identified bacterial species that produce metabolites that activate primary mast cells. Mast cells were selectively activated by metabolites from specific gut microbiota species in a dose-responsive manner while maintaining cell viability. Biochemical and analytical methods are being used to further investigate and identify the bioactive metabolites within the supernatants. And while this analysis is ongoing, results so far support the involvement of a small, polar molecule driving mast cell activation and exacerbating mast cell-mediated, IgE-dependent allergic responses. Immunological analysis has ruled out the involvement of common pattern recognition receptors on the mast cells. Ongoing work is focused on further characterization of the bioactive metabolites and the biosynthetic genes involved in their production, the mechanisms by which these metabolites activate type 2 immune cells, and their potential to regulate allergic responses in vivo. Identifying novel metabolic pathways encoded by the gut microbiota that activate type 2 immune cells provides potential novel therapeutic targets for small molecule inhibitors to prevent or treat atopic diseases.