Many circulating indole and phenol metabolites are host derived.

Indole and phenol metabolites are typically thought to be products of bacterial digestion of tryptophan (indoles) and phenylalanine or tyrosine (phenols). Interest in controlling gut microbial production of these metabolites has continually grown as they have important physiological impacts, with indoles agonizing AhR signaling, and phenols being associated with healthy body weight. While there is a growing wealth of research into which bacteria produce these metabolites, host contribution to their circulating pools has not been adequately characterized. Here, through stable isotope tracing in cell culture and mice, we show that mammalian cells can make aryl-pyruvates, -lactates, -acetates, and -carboxylic acids. Levels of these metabolites in mice and human patients are insensitive to perturbations of the microbiome. In contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol, and cresol. Overall, we show that host metabolism is a primary contributor to circulating indole and phenol metabolite pools.