Commensal bacteria make GPCR ligands that mimic human signalling molecules

Louis J. Cohen, Daria Esterhazy, Seong-Hwan Kim, Christophe Lemetre, Rhiannon R. Aguilar, Emma A. Gordon, Amanda J. Pickard, Justin R. Cross, Ana B. Emiliano, Sun M. Han, John Chu, Xavier Vila-Farres, Jeremy Kaplitt, Aneta Rogoz, Paula Y. Calle, Craig Hunter, J. Kipchirchir Bitok and Sean F. Brady ()
Additional contact information
Louis J. Cohen: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Daria Esterhazy: Laboratory of Mucosal Immunology, Rockefeller University
Seong-Hwan Kim: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Christophe Lemetre: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Rhiannon R. Aguilar: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Emma A. Gordon: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Amanda J. Pickard: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center
Justin R. Cross: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center
Ana B. Emiliano: Laboratory of Molecular Genetics, Rockefeller University
Sun M. Han: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
John Chu: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Xavier Vila-Farres: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Jeremy Kaplitt: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Aneta Rogoz: Laboratory of Mucosal Immunology, Rockefeller University
Paula Y. Calle: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Craig Hunter: Comparative Biosciences Center, Rockefeller University
J. Kipchirchir Bitok: Laboratory of Genetically Encoded Small Molecules, Rockefeller University
Sean F. Brady: Laboratory of Genetically Encoded Small Molecules, Rockefeller University

Nature, 2017, vol. 549, issue 7670, 48-53

Abstract: 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).

Date: 2017
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DOI: 10.1038/nature23874

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