Commensal bacteria make GPCR ligands that mimic human signalling molecules.

TitleCommensal bacteria make GPCR ligands that mimic human signalling molecules.
Publication TypeJournal Article
Year of Publication2017
AuthorsCohen LJ, Esterhazy D, Kim S-H, Lemetre C, Aguilar RR, Gordon EA, Pickard AJ, Cross JR, Emiliano AB, Han SM, Chu J, Vila-Farres X, Kaplitt J, Rogoz A, Calle PY, Hunter C, J Bitok K, Brady SF
JournalNature
Volume549
Issue7670
Pagination48-53
Date Published2017 09 07
ISSN1476-4687
KeywordsAmides, Animals, Bacteria, Biological Mimicry, Blood Glucose, Female, Gastrointestinal Microbiome, Gastrointestinal Tract, HEK293 Cells, Homeostasis, Humans, Ligands, Male, Mice, Receptors, G-Protein-Coupled, Signal Transduction, Symbiosis
Abstract

Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy).

DOI10.1038/nature23874
Alternate JournalNature
PubMed ID28854168
PubMed Central IDPMC5777231
Grant ListT32 DK007792 / DK / NIDDK NIH HHS / United States
U01 GM110714 / GM / NIGMS NIH HHS / United States
K08 DK109287-01 / DK / NIDDK NIH HHS / United States
K08 DK109287 / DK / NIDDK NIH HHS / United States
R35 GM122559 / GM / NIGMS NIH HHS / United States

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