2. Academic Validation
  3. Akkermansia muciniphila phospholipid induces homeostatic immune responses

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

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. xavier@molbio.mgh.harvard.edu.
  • 11 Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
  • 12 Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
  • 13 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA. jon_clardy@hms.harvard.edu.
  • # 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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