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

By Dylan Dodd, M. Spitzer, William W. Van Treuren, Bryan D. Merrill, A. J. Hryckowian, S. Higginbottom, Anthony T. Le, T. Cowan, Garry P. Nolan, Michael A. Fischbach and 1 more. Nature, 2017

1,219 citations recorded by the source corpus.

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.

Subfields: Food Science, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0b70d761c2ff5753ab3dad36bfb097c70093490a

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In Food Science

1. A. Valdes
2. Ana Nogal
3. David S. Wishart
4. C. Menni

In Molecular Biology

1. A. Valdes
2. Harry Sokol
3. Ana Nogal
4. David S. Wishart
5. C. Menni
6. Jianguo Xia
7. Jasmine Chong
8. Beomsoo Han

Citations in the corpus

• Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. (2018, positive): “In addition, oxidative and reductive pathways have also been described in this species and lead to the production of indoleacetic acid (IAA) and indolepropionic acid (IPA), two Trp metabolites known to affect intestinal permeability and host immunity (Dodd et al., 2017; Galligan, 2018; Lamas et al.,”
• The Human Gut Microbiome: From Association to Modulation. (2018, neutral): “…several compounds that accumulate in the host’s blood 561 serum, that the replacement of wild type C. sporogenes with a genetically engineered strain in 562 gnotobiotic mice decreased serum levels of these metabolites, and affected gut permeability 563 and host immune response (Dodd et al., 2017).”
• Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites (2020, background): “…and potentially, those of other enriched bile acids to the pathogenesis of cholesterol-induced NAFLD–HCC. Additionally, IPA, which is exclusively produced by commensal gut microbes, 41 42 was depleted in both HFHC-fed conventional mice and germ-free mice transplanted with stools from HFHC-fed mice.”
• The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health (2021, background): “Indoleproprionic acid is a compound synthetized from tryptophan by a reduced number of bacterial strains.(62) Circulating levels of indoleproprionic acid are negatively correlated with different metabolic syndrome parameters,(51) and higher levels of this compound have been also associated with a lo”
• Metabolomics for Investigating Physiological and Pathophysiological Processes. (2019, background): “The data from a variety of urinary metabolite/microbe associative studies are summarized in TABLE 5, as well as in several papers (118, 148, 157, 290, 388).”
• Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019, neutral): “Furthermore, changes in the microbiome often result in altered metabolic profiles, impacting the availability and diversity of nutrients and microbial metabolites (Dodd et al., 2017; Melnik et al., 2017; Sharon et al., 2014; Wikoff et al., 2009).”