HHS Public Access Author manuscript Nature. Author manuscript; available in PMC 2018 February 28 Published in final edited form as Nature.2017 September07,549(767048-53.doi:10.1038/ nature23874 Commensal bacteria produce GPCR ligands that mimic human signaling molecules Louis J. Cohen, 2, Daria Esterhazy, Seong-Hwan Kim, Christophe Lemetre', Rhiannon R. Aguilar', Emma A Gordon1, Amanda J. Pickard, Justin R Cross, Ana B. Emiliano4, Sun M. Han, John Chu, Xavier Vila-Farres', Jeremy Kaplitt, Aneta Rogoz, Paula Y. Calle Craig Hunter, J Kipchirchir Bitok', and Sean F. Brady Laboratory of Genetically Encoded Small Molecules, Rockefeller University Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai lAboratory of Mucosal Immunology, Rockefeller University 4Laboratory of Molecular Genetics, Rockefeller University cOmparative Biosciences Center, Rockefeller University 6Donald B. and Catherine C Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center Summary Statement Commensal bacteria are believed to play important roles in human health. The mechanisms by which they affect mammalian physiology are poorly understood; however, 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 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 al though future studies are needed to define their potential physiologic role in humans. This work suggests that chemical mimicry of eukaryotic signaling molecules may be common among commensal bacteria and download text and data.mine the content in such documents for the academic research, subjectalwaystothefullConditionsofusehttp://www.nature.com/authors/editorialpolicies/license.htmlterms Correspondence and requests for materials should be addressed to s.F. B. (sbrady(@rockefeller. edu). Contact: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, New York, 10065 Author Contributions: L.J.C. and S F B designed research, L.J.C. assisted with all experiments;, S.H. K. assisted with molecule characterization, E.A.G P.Y. C., J.K. B, and R.R.A. assisted with gene cloning:, D E, A B E, S M.H C H. and A.R. assisted with mouse experiments; J.C. X V-F, J K. assisted with molecule synthesis; A.J.P. and J. R C assisted with metabolite analysis in human/mouse samples; L.J.C. and C L analyzed data, LJ. C. and S.F.B. wrote the paper methods, figures and tables related to the structural determination of compound Competing Financial Interest Statement The authors of this study have no competing financial interests to declareCommensal bacteria produce GPCR ligands that mimic human signaling molecules Louis J. Cohen1,2, Daria Esterhazy3, Seong-Hwan Kim1, Christophe Lemetre1, Rhiannon R. Aguilar1, Emma A. Gordon1, Amanda J. Pickard6, Justin R. Cross6, Ana B. Emiliano4, Sun M. Han1, John Chu1, Xavier Vila-Farres1, Jeremy Kaplitt1, Aneta Rogoz3, Paula Y. Calle1, Craig Hunter5, J. Kipchirchir Bitok1, and Sean F. Brady1 1Laboratory of Genetically Encoded Small Molecules, Rockefeller University 2Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai 3Laboratory of Mucosal Immunology, Rockefeller University 4Laboratory of Molecular Genetics, Rockefeller University 5Comparative Biosciences Center, Rockefeller University 6Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center Summary Statement Commensal bacteria are believed to play important roles in human health. The mechanisms by which they affect mammalian physiology are poorly understood; however, 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 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 physiologic role in humans. This work suggests that chemical mimicry of eukaryotic signaling molecules may be common among commensal bacteria Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence and requests for materials should be addressed to S.F.B. (sbrady@rockefeller.edu). Contact: Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, New York, 10065. Author Contributions: L.J.C. and S.F.B. designed research; L.J.C. assisted with all experiments; S-H.K. assisted with molecule characterization; E.A.G., P.Y.C., J.K.B., and R.R.A. assisted with gene cloning; D.E., A.B.E., S.M.H., C.H. and A.R. assisted with mouse experiments; J.C., X.V-F., J.K. assisted with molecule synthesis; A.J.P. and J.R.C. assisted with metabolite analysis in human/mouse samples; L.J.C. and C.L. analyzed data; L.J.C. and S.F.B. wrote the paper Supplementary Information Extended data figures and tables are provided to accompany the main text and methods. Supplementary information contains the methods, figures and tables related to the structural determination of compounds. Competing Financial Interest Statement The authors of this study have no competing financial interests to declare. HHS Public Access Author manuscript Nature. Author manuscript; available in PMC 2018 February 28. Published in final edited form as: Nature. 2017 September 07; 549(7670): 48–53. doi:10.1038/nature23874. Author Manuscript Author Manuscript Author Manuscript Author Manuscript