RESEARCH HIGHLIGHTS Nature Reviews Gastroenterology & Hepatology | Published online 13 Sep 2017; doi:10.1038/nrgastro.2017.131
G U T M I C R O B I O TA
N-acyl synthase gene expression was enriched in gut bacteria
A new study has found that gut bacteria produce metabolites — N-acyl amides — that interact with G protein-coupled receptors (GPCRs) and mimic human GPCR ligands, providing clues to how microbial metabolites might regulate host physiology. The links between the gut microbiota and human health are now well known, but the exact mechanisms by which this relationship occurs are poorly understood. “Much of the research into the human microbiome to date has involved the characterization of bacterial populations by DNA sequencing with less attention to specific bacterial functions encoded in bacterial DNA,” explain authors Louis Cohen and Sean Brady. Previous work had identified N-acyl amides as a class of microbiota-synthesized GPCR-active signalling molecules. Moreover, in humans, N-acyl amides are an important class of signalling molecules that regulate host physiology. As such, the researchers combined bioinformatic analysis and synthetic biology to further investigate host–microbe interactions and the potential function of
these bacterial metabolites in host physiology. A large data-set of human microbial genomes was searched for N-acyl synthase genes, which showed that N-acyl synthase gene expression was enriched in gut bacteria (in stool samples) versus bacteria from other body sites (such as the subgingival plaque). Crucially, the N-acyl amides interacted with gastrointestinal GPCRs in assays and the gut-microbiota-encoded N-acyl amides had structural similarity to endogenous human GPCR ligands. One of the clearest observations of overlap between bacterial and human GPCR-active ligands was for the endocannabinoid receptor GPR119. On a functional level, experiments in mouse and cell models demonstrated that a microbial agonist (N-acyl serinol) of GPR119 regulated metabolic hormones and glucose homeostasis as effectively as human ligands. Glucagon-like peptide 1 secretion was induced in vitro to the same degree by bacterial and human GPCR ligands in mouse enteroendocrine GLUTag cells. Furthermore, when challenged with an oral glucose tolerance test,
substantial decreases in blood glucose levels were observed in gnotobiotic mice colonized with bacteria that were engineered to produce N-acyl serinols compared with those colonized with Escherichia coli that expressed an empty vector. “Bacteria and humans may share a conserved chemical language that helps them to function as a single system in the human microbiome,” note Cohen and Brady. More research is needed to better understand the in vivo role of N-acyl amides in humans and their potential as therapeutic targets. “Diseases associated with the human microbiome might be treated by manipulating endogenous systems already present in the microbiome (human microbiome biosynthetic gene therapy),” they postulate.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY
Katrina Ray ORIGINAL ARTICLE Cohen, L. J. et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature http://dx.doi.org/ 10.1038/nature23874 (2017)
www.nature.com/nrgastro
Laura Marshall/Macmillan Publishers Limited
Microbial metabolites as mimickers of human molecules
. d e v r e s e r s t h g i r l l A . e r u t a N r e g n i r p S f o t r a p , d e t i m i L s r e h s i l b u P n a l l i m c a M 7 1 0 2 ©
G U T M I C R O B I O TA
N-acyl synthase gene expression was enriched in gut bacteria
A new study has found that gut bacteria produce metabolites — N-acyl amides — that interact with G protein-coupled receptors (GPCRs) and mimic human GPCR ligands, providing clues to how microbial metabolites might regulate host physiology. The links between the gut microbiota and human health are now well known, but the exact mechanisms by which this relationship occurs are poorly understood. “Much of the research into the human microbiome to date has involved the characterization of bacterial populations by DNA sequencing with less attention to specific bacterial functions encoded in bacterial DNA,” explain authors Louis Cohen and Sean Brady. Previous work had identified N-acyl amides as a class of microbiota-synthesized GPCR-active signalling molecules. Moreover, in humans, N-acyl amides are an important class of signalling molecules that regulate host physiology. As such, the researchers combined bioinformatic analysis and synthetic biology to further investigate host–microbe interactions and the potential function of
these bacterial metabolites in host physiology. A large data-set of human microbial genomes was searched for N-acyl synthase genes, which showed that N-acyl synthase gene expression was enriched in gut bacteria (in stool samples) versus bacteria from other body sites (such as the subgingival plaque). Crucially, the N-acyl amides interacted with gastrointestinal GPCRs in assays and the gut-microbiota-encoded N-acyl amides had structural similarity to endogenous human GPCR ligands. One of the clearest observations of overlap between bacterial and human GPCR-active ligands was for the endocannabinoid receptor GPR119. On a functional level, experiments in mouse and cell models demonstrated that a microbial agonist (N-acyl serinol) of GPR119 regulated metabolic hormones and glucose homeostasis as effectively as human ligands. Glucagon-like peptide 1 secretion was induced in vitro to the same degree by bacterial and human GPCR ligands in mouse enteroendocrine GLUTag cells. Furthermore, when challenged with an oral glucose tolerance test,
substantial decreases in blood glucose levels were observed in gnotobiotic mice colonized with bacteria that were engineered to produce N-acyl serinols compared with those colonized with Escherichia coli that expressed an empty vector. “Bacteria and humans may share a conserved chemical language that helps them to function as a single system in the human microbiome,” note Cohen and Brady. More research is needed to better understand the in vivo role of N-acyl amides in humans and their potential as therapeutic targets. “Diseases associated with the human microbiome might be treated by manipulating endogenous systems already present in the microbiome (human microbiome biosynthetic gene therapy),” they postulate.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY
Katrina Ray ORIGINAL ARTICLE Cohen, L. J. et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature http://dx.doi.org/ 10.1038/nature23874 (2017)
www.nature.com/nrgastro
Laura Marshall/Macmillan Publishers Limited
Microbial metabolites as mimickers of human molecules
. d e v r e s e r s t h g i r l l A . e r u t a N r e g n i r p S f o t r a p , d e t i m i L s r e h s i l b u P n a l l i m c a M 7 1 0 2 ©
