Host immunomodulatory lipids created by symbionts from dietary amino acids

Small molecules derived from symbiotic microbiota critically contribute to intestinal immune maturation and regulation 1 . However, little is known about the molecular mechanisms that control immune development in the host–microbiota environment. Here, using a targeted lipidomic analysis and synthet...

Full description

Saved in:
Bibliographic Details
Published inNature (London) Vol. 600; no. 7888; pp. 302 - 307
Main Authors Oh, Sungwhan F., Praveena, T., Song, Heebum, Yoo, Ji-Sun, Jung, Da-Jung, Erturk-Hasdemir, Deniz, Hwang, Yoon Soo, Lee, ChangWon C., Le Nours, Jérôme, Kim, Hyunsoo, Lee, Jesang, Blumberg, Richard S., Rossjohn, Jamie, Park, Seung Bum, Kasper, Dennis L.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 09.12.2021
Nature Publishing Group
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary:Small molecules derived from symbiotic microbiota critically contribute to intestinal immune maturation and regulation 1 . 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. The symbiotic gut bacterium Bacteroides fragilis produces unique α-galactosylceramides from host dietary branched-chain amino acids, which are presented as CD1d ligands and immunomodulate natural killer T cells.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
S.F.O., H.S., and S.B.P. designed the structures of synthetic BfaGCs; H.S., Y.S.H., H.K., and J. L. synthesized BfaGC molecules.
S.F.O., J-S.Y., and C.C.L. designed and carried out all experiments with microbes.
S.F.O. and D-J.J. designed and carried out all animal experiments. J-S. Y. carried out transcriptomic analysis.
S.F.O., D-J.J., and D.E.H. executed in vitro/in vivo cytokine assays.
S.F.O., S.B.P., J.R. and D.L.K. wrote the manuscript, and all authors contributed to relevant discussion.
AUTHOR CONTRIBUTIONS
S.F.O., D.L.K., and R.S.B. conceived the idea and designed the outline of the research.
T.P., J.L.N. and J.R. generated crystals of 2C12 TCR–CD1d–BfaGCs and carried out X-ray crystallography analysis as well as affinity measurements by SPR.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-021-04083-0