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, Chang Won C. Lee, Jérôme Le Nours, Hyunsoo Kim, Jesang Lee, Richard S. Blumberg, Jamie Rossjohn, Seung Bum Park, Dennis L. Kasper

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)302-307+
Number of pages24
JournalNature
Volume600
Issue number7888
DOIs
Publication statusPublished - 9 Dec 2021

Cite this