Host immunomodulatory lipids created by symbionts from dietary amino acids

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, Jamie Rossjohn (), Seung Bum Park () and Dennis L. Kasper ()
Additional contact information
Sungwhan F. Oh: Blavatnik Institute of Harvard Medical School
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
Seung Bum Park: Seoul National University
Dennis L. Kasper: Blavatnik Institute of Harvard Medical School

Nature, 2021, vol. 600, issue 7888, 302-307

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-04083-0

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