• A Corrigendum to this article was published on 04 April 2018

This article has been updated

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).

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Change history

  • 04 April 2018

    Please see accompanying Corrigendum (http://doi.org/10.1038/nature25997).The description in the Methods of the human stool samples used for the analysis presented in Extended Data Figure 9 has been corrected, with patient age, gender and transplant indication provided in the table now added to Extended Data Fig. 9. The Reporting Summary has been updated. The original Article has been corrected online.

References

  1. 1.

    & Exploring and understanding the biochemical diversity of the human microbiota. Cell Chem. Biol. 23, 18–30 (2016)

  2. 2.

    & Chemical ecology in retrospect and prospect. Proc. Natl Acad. Sci. USA 105, 4539–4540 (2008)

  3. 3.

    et al. Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist. Proc. Natl Acad. Sci. USA 112, E4825–E4834 (2015)

  4. 4.

    et al. Endocannabinoids — at the crossroads between the gut microbiota and host metabolism. Nat. Rev. Endocrinol. 12, 133–143 (2016)

  5. 5.

    & Modulating the endocannabinoid system in human health and disease—successes and failures. FEBS J. 280, 1918–1943 (2013)

  6. 6.

    et al. Lysine and novel hydroxylysine lipids in soil bacteria: amino acid membrane lipid response to temperature and pH in Pseudopedobacter saltans. Front. Microbiol. 6, 637 (2015)

  7. 7.

    , , & Amino acid-containing membrane lipids in bacteria. Prog. Lipid Res. 49, 46–60 (2010)

  8. 8.

    , & Characterization of ornithine and glutamine lipids extracted from cell membranes of Rhodobacter sphaeroides. J. Am. Soc. Mass Spectrom. 20, 198–212 (2009)

  9. 9.

    , , & GPR119 regulates murine glucose homeostasis through incretin receptor-dependent and independent mechanisms. Endocrinology 152, 374–383 (2011)

  10. 10.

    et al. Sphingosine-1-phospate receptor 4 (S1P4) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model. FASEB J. 25, 4024–4036 (2011)

  11. 11.

    et al. Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 14, 561–571 (2001)

  12. 12.

    , , & E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol. Ther. 138, 485–502 (2013)

  13. 13.

    et al. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J. Clin. Invest. 109, 883–893 (2002)

  14. 14.

    et al. Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis. J. Clin. Invest. 125, 3606–3618 (2015)

  15. 15.

    et al. 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J. Clin. Endocrinol. Metab. 96, E1409–E1417 (2011)

  16. 16.

    et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 3, 167–175 (2006)

  17. 17.

    et al. Lysophosphatidylcholines activate G2A inducing Gαi−1-/Gαq/11- Ca2+ flux, Gβγ-Hck activation and clathrin/β-arrestin-1/GRK6 recruitment in PMNs. Biochem. J. 432, 35–45 (2010)

  18. 18.

    G2A and LPC: regulatory functions in immunity. Prostaglandins Other Lipid Mediat. 89, 73–81 (2009)

  19. 19.

    et al. N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons. Mol. Pharmacol. 74, 213–224 (2008)

  20. 20.

    , , , & G protein-coupled receptor 119 (GPR119) agonists for the treatment of diabetes: recent progress and prevailing challenges. J. Med. Chem. 59, 3579–3592 (2016)

  21. 21.

    et al. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies. PLoS ONE 9, e92494 (2014)

  22. 22.

    et al. Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus. Arch. Pharm. Res. 37, 671–678 (2014)

  23. 23.

    et al. Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes. Diabetes Obes. Metab. 14, 709–716 (2012)

  24. 24.

    et al. A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 148, 2601–2609 (2007)

  25. 25.

    et al. A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release. Endocrinology 149, 2038–2047 (2008)

  26. 26.

    , & GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes 58, 1058–1066 (2009)

  27. 27.

    et al. Oleoylethanolamide: effects on hypothalamic transmitters and gut peptides regulating food intake. Neuropharmacology 60, 593–601 (2011)

  28. 28.

    et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α. Nature 425, 90–93 (2003)

  29. 29.

    et al. GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis. J. Endocrinol. 201, 219–230 (2009)

  30. 30.

    , & GPR119: “double-dipping” for better glycemic control. Endocrinology 149, 2035–2037 (2008)

  31. 31.

    et al. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity. J. Clin. Invest. 124, 3391–3406 (2014)

  32. 32.

    , & Programming a human commensal bacterium, Bacteroides thetaiotaomicron, to sense and respond to stimuli in the murine gut microbiota. Cell Syst. 1, 62–71 (2015)

  33. 33.

    Molecular evolution of GPCRs: What we know and what the future holds. J. Mol. Endocrinol. 52, E1–E2 (2014)

  34. 34.

    , , & Molecular evolution of GPCRs: CRH/CRH receptors. J. Mol. Endocrinol. 52, T43–T60 (2014)

  35. 35.

    Genomic insights into mediator lipidomics. Prostaglandins Other Lipid Mediat. 77, 197–209 (2005)

  36. 36.

    et al. Production of α-galactosylceramide by a prominent member of the human gut microbiota. PLoS Biol. 11, e1001610 (2013)

  37. 37.

    et al. Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease. Am. J. Gastroenterol. 104, 3058–3067 (2009)

  38. 38.

    Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012)

  39. 39.

    et al. Relating the metatranscriptome and metagenome of the human gut. Proc. Natl Acad. Sci. USA 111, E2329–2338 (2014)

  40. 40.

    et al. Functional expression of dental plaque microbiota. Front. Cell. Infect. Microbiol. 4, 108 (2014)

  41. 41.

    , , , & Functional analysis of endogenous β-adrenergic receptor through fluorimetric monitoring of cyclic nucleotide-gated ion channel. Anal. Biochem. 360, 303–305 (2007)

  42. 42.

    & FeeM, an N-acyl amino acid synthase from an uncultured soil microbe: structure, mechanism, and acyl carrier protein binding. Structure 14, 1425–1435 (2006)

  43. 43.

    et al. Dysbiosis of small intestinal microbiota in liver cirrhosis and its association with etiology. Sci. Rep. 6, 34055 (2016)

  44. 44.

    et al. Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease. BMC Gastroenterol. 13, 113 (2013)

Download references

Acknowledgements

We thank the High-Throughput and Spectroscopy Resource Center, Center for Clinical and Translational Science and the Comparative Bioscience Center at Rockefeller University for the use of their facilities; members of the Mangelsdorf laboratory at UT Southwestern and D. Drucker at Mount Sinai Hospital, Toronto for the use of the GLUTag cell line; A. Milshteyn, A. Estrela and J. Craig for their critical review of the manuscript. This work was supported in part by a grant from the Robertson Foundation, the Center for Basic and Translational Research on Disorders of the Digestive System, the Leona M. and Harry B. Helmsley Charitable Trust, Rainin Foundation, U01 GM110714-1A1 (S.F.B.), GM122559-01 (S.F.B.), the Crohn’s and Colitis Foundation Career Development Award (L.J.C.) and NIDDK K08 DK109287-01 (L.J.C.).

Author information

Affiliations

  1. Laboratory of Genetically Encoded Small Molecules, Rockefeller University, New York, New York 10065, USA

    • Louis J. Cohen
    • , Seong-Hwan Kim
    • , Christophe Lemetre
    • , Rhiannon R. Aguilar
    • , Emma A. Gordon
    • , Sun M. Han
    • , John Chu
    • , Xavier Vila-Farres
    • , Jeremy Kaplitt
    • , Paula Y. Calle
    • , J. Kipchirchir Bitok
    •  & Sean F. Brady
  2. Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA

    • Louis J. Cohen
  3. Laboratory of Mucosal Immunology, Rockefeller University, New York, New York 10065, USA

    • Daria Esterhazy
    •  & Aneta Rogoz
  4. Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

    • Amanda J. Pickard
    •  & Justin R. Cross
  5. Laboratory of Molecular Genetics, Rockefeller University, New York, New York 10065, USA

    • Ana B. Emiliano
  6. Comparative Biosciences Center, Rockefeller University, New York, New York 10065, USA

    • Craig Hunter

Authors

  1. Search for Louis J. Cohen in:

  2. Search for Daria Esterhazy in:

  3. Search for Seong-Hwan Kim in:

  4. Search for Christophe Lemetre in:

  5. Search for Rhiannon R. Aguilar in:

  6. Search for Emma A. Gordon in:

  7. Search for Amanda J. Pickard in:

  8. Search for Justin R. Cross in:

  9. Search for Ana B. Emiliano in:

  10. Search for Sun M. Han in:

  11. Search for John Chu in:

  12. Search for Xavier Vila-Farres in:

  13. Search for Jeremy Kaplitt in:

  14. Search for Aneta Rogoz in:

  15. Search for Paula Y. Calle in:

  16. Search for Craig Hunter in:

  17. Search for J. Kipchirchir Bitok in:

  18. Search for Sean F. Brady in:

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 and mouse samples; L.J.C. and C.L. analysed data; L.J.C. and S.F.B. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sean F. Brady.

Reviewer Information Nature thanks D. J. Drucker and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains a Supplementary Discussion, Supplementary Figures and Data, Supplementary Tables 1-3 and an additional reference.

  2. 2.

    Reporting Summary

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature23874

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.