Host metabolism can produce many indoles and phenols independently of the microbiome.

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 because they have important physiological impacts, with indoles agonizing aryl hydrocarbon receptor signalling and phenols being associated with healthy body weight. Although there is a growing body of research on which bacteria produce these metabolites, the host contribution to their circulating pools has not been characterized. Here, through stable isotope tracing in cell culture, mice and rats, we show that mammalian cells can make aryl-pyruvates, aryl-lactates, aryl-acetates and aryl-carboxylic acids independently of the microbiome. We demonstrate that circulating levels of these metabolites in mice and human patients are robust to perturbations of the microbiome. By contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol and p-cresol. Overall, these results suggest that host metabolism is a major contributor to circulating indole and phenol metabolite pools.