Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology

The intestine and liver are thought to metabolize dietary nutrients and regulate host nutrient homeostasis. Here, we find that the gut microbiota also reshapes the host amino acid (aa) landscape via efficiently metabolizing intestinal aa. To identify the responsible microbes/genes, we developed a metabolomics-based assay to screen 104 commensals and identified candidates that efficiently utilize aa. Using genetics, we identified multiple responsible metabolic genes in phylogenetically diverse microbes. By colonizing germ-free mice with the wild-type strain and their isogenic mutant deficient in individual aa-metabolizing genes, we found that these genes regulate the availability of gut and circulatory aa. Notably, microbiota genes for branched-chain amino acids (BCAAs) and tryptophan metabolism indirectly affect host glucose homeostasis via peripheral serotonin. Collectively, at single-gene level, this work characterizes a microbiota-encoded metabolic activity that affects host nutrient homeostasis and provides a roadmap to interrogate microbiota-dependent activity to improve human health. [Display omitted] •Identification of gut microbes that efficiently deplete amino acids (aa)•Identification of gut microbial metabolic genes that deplete aa•Microbiota genes that deplete aa affect host aa homeostasis•Microbiota genes that deplete aa affect host glucose tolerance via peripheral serotonin Li et al. identify gut microbes and their metabolic genes that efficiently deplete amino acids. These microbes and their metabolic genes for amino acid utilization affect host amino acid homeostasis. Moreover, microbiota genes involved in branched-chain amino acid and tryptophan depletion regulate host glucose tolerance via peripheral serotonin.