A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites

• Published in: Nature (London) Vol. 551; no. 7682; pp. 648 - 652
• Main Authors: Dodd, Dylan, Spitzer, Matthew H, Van Treuren, William, Merrill, Bryan D, Hryckowian, Andrew J, Higginbottom, Steven K, Le, Anthony, Cowan, Tina M, Nolan, Garry P, Fischbach, Michael A, Sonnenburg, Justin L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 30.11.2017
• Subjects: Amino acids; Amino Acids, Aromatic - blood; Amino Acids, Aromatic - metabolism; Animals; Bacteria; Blood Chemical Analysis; Closterium - genetics; Closterium - metabolism; Clostridium; Digestive system; Digestive tract; Enzymes; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - physiology; Genetic engineering; Genetics; Germ-Free Life; Gnotobiotic; Humans; Immunity; Indoles - blood; Indoles - metabolism; Intestinal microflora; Intestinal Mucosa - metabolism; Intestine; Male; Metabolic Networks and Pathways - genetics; Metabolic pathways; Metabolism; Metabolites; Metabolome - physiology; Metabolomics; Mice; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Multigene Family - genetics; Mutagenesis; Permeability; Phenylalanine; Phenylalanine - metabolism; Physiological aspects; Reductases; Serum - chemistry; Serum - metabolism; Serum levels; Substrates; Tryptophan; Tryptophan - metabolism; Tyrosine; Tyrosine - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature24661

The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream, where they can have systemic effects on the host. Although these small molecules commonly reach concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community.