My laboratory is broadly interested in the molecular mechanisms by which chemical signals modulate host-microbe interactions in physiology and disease. These chemical signals (metabolites) may be derived from host metabolism (endogenous metabolites) or the environment (microbes, diet, therapeutics) and can significantly affect host susceptibility to infection (Fig. 1). To dissect the chemical mechanisms that govern host-microbe interactions, we have developed chemical methods to characterize direct metabolite-protein interactions in cells (Fig. 2) and employed key animal models to discover novel protective factors from beneficial microbiota species (Fig. 3). These studies have revealed unpredicted metabolite-protein interactions, evolutionarily conserved mechanisms of host-microbe interactions and afforded new targets and leads for therapeutic development.