Akkermansia muciniphila phospholipid induces homeostatic immune responses

  • Nature. 2022 Aug;608(7921):168-173. doi: 10.1038/s41586-022-04985-7.
Munhyung Bae  #  1  2 ,  Chelsi D Cassilly  #  1 ,  Xiaoxi Liu  1  3 ,  Sung-Moo Park  4  5  6 ,  Betsabeh Khoramian Tusi  4  5  6 ,  Xiangjun Chen  4  5  6 ,  Jaeyoung Kwon  1  7 ,  Pavel Filipčík  8  9 ,  Andrew S Bolze  4 ,  Zehua Liu  4 ,  Hera Vlamakis  4 ,  Daniel B Graham  4  5  6 ,  Sara J Buhrlage  1  3 ,  Ramnik J Xavier  10  11  12 ,  Jon Clardy  13
Affiliations
  • 1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.
  • 2. College of Pharmacy, Gachon University, Incheon, South Korea.
  • 3. Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 5. Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 7. Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Ganeung, South Korea.
  • 8. Biochemistry Department, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
  • 9. SBGrid Consortium, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.
  • 10. Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • 11. Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  • 12. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  • 13. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 35896748 DOI: 10.1038/s41586-022-04985-7
Abstract

Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1-3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in Cancer Immunotherapy and homeostatic immunity4-7. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected Toll-like Receptor TLR2-TLR1 heterodimer9,10. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.

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