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Host immunomodulatory lipids created by symbionts from dietary amino acids

Author

Listed:
  • Sungwhan F. Oh

    (Blavatnik Institute of Harvard Medical School
    Brigham and Women’s Hospital)

  • T. Praveena

    (Monash University)

  • Heebum Song

    (Seoul National University)

  • Ji-Sun Yoo

    (Brigham and Women’s Hospital)

  • Da-Jung Jung

    (Brigham and Women’s Hospital)

  • Deniz Erturk-Hasdemir

    (Blavatnik Institute of Harvard Medical School)

  • Yoon Soo Hwang

    (Seoul National University)

  • ChangWon C. Lee

    (Blavatnik Institute of Harvard Medical School)

  • Jérôme Nours

    (Monash University)

  • Hyunsoo Kim

    (Seoul National University)

  • Jesang Lee

    (Seoul National University)

  • Richard S. Blumberg

    (Brigham and Women’s Hospital)

  • Jamie Rossjohn

    (Monash University
    Monash University
    Cardiff University School of Medicine)

  • Seung Bum Park

    (Seoul National University)

  • Dennis L. Kasper

    (Blavatnik Institute of Harvard Medical School)

Abstract

Small molecules derived from symbiotic microbiota critically contribute to intestinal immune maturation and regulation1. However, little is known about the molecular mechanisms that control immune development in the host–microbiota environment. Here, using a targeted lipidomic analysis and synthetic approach, we carried out a multifaceted investigation of immunomodulatory α-galactosylceramides from the human symbiont Bacteroides fragilis (BfaGCs). The characteristic terminal branching of BfaGCs is the result of incorporation of branched-chain amino acids taken up in the host gut by B. fragilis. A B. fragilis knockout strain that cannot metabolize branched-chain amino acids showed reduced branching in BfaGCs, and mice monocolonized with this mutant strain had impaired colonic natural killer T (NKT) cell regulation, implying structure-specific immunomodulatory activity. The sphinganine chain branching of BfaGCs is a critical determinant of NKT cell activation, which induces specific immunomodulatory gene expression signatures and effector functions. Co-crystal structure and affinity analyses of CD1d–BfaGC–NKT cell receptor complexes confirmed the interaction of BfaGCs as CD1d-restricted ligands. We present a structural and molecular-level paradigm of immunomodulatory control by interactions of endobiotic metabolites with diet, microbiota and the immune system.

Suggested Citation

  • Sungwhan F. Oh & T. Praveena & Heebum Song & Ji-Sun Yoo & Da-Jung Jung & Deniz Erturk-Hasdemir & Yoon Soo Hwang & ChangWon C. Lee & Jérôme Nours & Hyunsoo Kim & Jesang Lee & Richard S. Blumberg & Jami, 2021. "Host immunomodulatory lipids created by symbionts from dietary amino acids," Nature, Nature, vol. 600(7888), pages 302-307, December.
  • Handle: RePEc:nat:nature:v:600:y:2021:i:7888:d:10.1038_s41586-021-04083-0
    DOI: 10.1038/s41586-021-04083-0
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    Cited by:

    1. Yolanda Y. Huang & Morgan N. Price & Allison Hung & Omree Gal-Oz & Surya Tripathi & Christopher W. Smith & Davian Ho & Héloïse Carion & Adam M. Deutschbauer & Adam P. Arkin, 2024. "Barcoded overexpression screens in gut Bacteroidales identify genes with roles in carbon utilization and stress resistance," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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