Akkermansia muciniphila phospholipid induces homeostatic immune responses

Munhyung Bae, Chelsi D. Cassilly, Xiaoxi Liu, Sung-Moo Park, Betsabeh Khoramian Tusi, Xiangjun Chen, Jaeyoung Kwon, Pavel Filipčík, Andrew S. Bolze, Zehua Liu, Hera Vlamakis, Daniel B. Graham, Sara J. Buhrlage, Ramnik J. Xavier () and Jon Clardy ()
Additional contact information
Munhyung Bae: Harvard Medical School, Blavatnik Institute
Chelsi D. Cassilly: Harvard Medical School, Blavatnik Institute
Xiaoxi Liu: Harvard Medical School, Blavatnik Institute
Sung-Moo Park: Broad Institute of MIT and Harvard
Betsabeh Khoramian Tusi: Broad Institute of MIT and Harvard
Xiangjun Chen: Broad Institute of MIT and Harvard
Jaeyoung Kwon: Harvard Medical School, Blavatnik Institute
Pavel Filipčík: University of Otago
Andrew S. Bolze: Broad Institute of MIT and Harvard
Zehua Liu: Broad Institute of MIT and Harvard
Hera Vlamakis: Broad Institute of MIT and Harvard
Daniel B. Graham: Broad Institute of MIT and Harvard
Sara J. Buhrlage: Harvard Medical School, Blavatnik Institute
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Jon Clardy: Harvard Medical School, Blavatnik Institute

Nature, 2022, vol. 608, issue 7921, 168-173

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04985-7

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