PROJECT SUMMARY Metabolic diseases, such as obesity and type 2 diabetes (T2D), are characterized by perturbations of glucose tolerance, pancreatic beta cell function, energy imbalance, appetite regulation, and other unknown pathways. Clinical and genetic studies in humans and animal experiments have also implicated gut microbiota and products derived from their metabolism of dietary nutrients as important mediators of metabolic risk. In this regard, we have observed protective associations between plasma levels of indole-3-propionic acid (IPA) – a metabolite generated entirely by gut bacteria from dietary tryptophan – and insulin resistance traits in humans and mice. We have also identified 2 loci for IPA levels on chromosomes 2 and 16 in humans, which harbor genes encoding lactase (LCT) and members of the medium-chain fatty acid acyl-CoA synthetases (ACSM1-5), respectively. These observations point to host genetic factors that modulate IPA levels through both its production by gut bacteria (LCT) and endogenous metabolism (ACSMs). This notion is consistent with our gnotobiotic studies in germ-free mice that increasing Bifidobacterium abundance, which is reproducibly associated with the LCT locus in humans, elevated plasma levels of IPA and attenuated high fat diet-induced (HFD) insulin resistance. In parallel studies, IPA supplementation studies in mice also protected against metabolic disturbances, at least in part, through maintenance of intestinal barrier function, activation of arylhydrocarbon receptor (Ahr), suppression of nicotinamide N-methyl transferase (Nnmt), and elevation of tissue nicotinamide adenine dinucleotide (NAD+) levels. Despite these observations, we still only have a poor understanding of the genetic architecture of IPA metabolism in the host, through either main effects or interactions with diet/gut microbes; the interplay between gut bacterial species that metabolize tryptophan to IPA and its precursors; and the mechanisms underlying the tis