Host immunomodulatory lipids created by symbionts from dietary amino acids

• Published in: Nature (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
• Language: English
• Published: London Nature Publishing Group UK 09.12.2021; Nature Publishing Group
• Subjects: 13/1; 13/21; 13/31; 38/39; 38/44; 38/77; 38/90; 38/91; 631/250/347; 631/326; 631/535/1266; 639/638/11/296; 639/638/549; 64/60; 82/16; 82/29; 82/58; 82/80; 82/83; Amino acids; Amino Acids, Branched-Chain - chemistry; Amino Acids, Branched-Chain - immunology; Amino Acids, Branched-Chain - metabolism; Animals; Antigens, CD1d - immunology; Bacteroides fragilis - genetics; Bacteroides fragilis - metabolism; Biosynthesis; Branching; CD1d antigen; Cell activation; Chain branching; Crystal structure; Diet; Fatty acids; Galactosylceramides - immunology; Galactosylceramides - metabolism; Gastrointestinal Microbiome - immunology; Gene expression; Genetic engineering; Humanities and Social Sciences; Humans; Immune system; Immunomodulation; Immunomodulators; Incorporation; Investigations; Ligands; Lipids; Metabolites; Mice; Microbiota; Microorganisms; Models, Animal; Models, Molecular; Molecular modelling; multidisciplinary; Natural killer cells; Natural Killer T-Cells - cytology; Natural Killer T-Cells - immunology; Receptors, Antigen, T-Cell - immunology; Science; Science (multidisciplinary); Signal Transduction - immunology; Sphinganine; Symbionts; Symbiosis - immunology
• DOI: 10.1038/s41586-021-04083-0
• ISSN: 0028-0836

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.