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Commensal bacteria make GPCR ligands that mimic human signalling molecules

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  • Louis J. Cohen

    (Laboratory of Genetically Encoded Small Molecules, Rockefeller University
    Icahn School of Medicine at Mount Sinai)

  • 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)

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).

Suggested Citation

  • 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 V, 2017. "Commensal bacteria make GPCR ligands that mimic human signalling molecules," Nature, Nature, vol. 549(7670), pages 48-53, September.
  • Handle: RePEc:nat:nature:v:549:y:2017:i:7670:d:10.1038_nature23874
    DOI: 10.1038/nature23874
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    Cited by:

    1. Javier Lopez-Simon & Marina Vila-Nistal & Aleksandra Rosenova & Daniele Corte & Federico Baltar & Manuel Martinez-Garcia, 2023. "Viruses under the Antarctic Ice Shelf are active and potentially involved in global nutrient cycles," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Dandan Wang & Lingfang Zhu & Xiangkai Zhen & Daoyan Yang & Changfu Li & Yating Chen & Huannan Wang & Yichen Qu & Xiaozhen Liu & Yanling Yin & Huawei Gu & Lei Xu & Chuanxing Wan & Yao Wang & Songying O, 2022. "A secreted effector with a dual role as a toxin and as a transcriptional factor," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Awatef Allouch & Laurent Voisin & Yanyan Zhang & Syed Qasim Raza & Yann Lecluse & Julien Calvo & Dorothée Selimoglu-Buet & Stéphane Botton & Fawzia Louache & Françoise Pflumio & Eric Solary & Jean-Luc, 2022. "CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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