Akkermansia muciniphila phospholipid induces homeostatic immune responses

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, favorable 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 has9 a highly restricted structure-activity relationship, and its immune signaling requires an unexpected toll-like receptor 2/1 heterodimer9,10. Certain features of the phospholipid’s activity are noteworthy: it is significantly less potent than known natural and synthetic toll-like receptor 2 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 signaling. Identifying both the molecule and an equipotent synthetic analog, its non-canonical toll-like receptor 2/1 signaling pathway, its immunomodulatory selectivity, and its low dose immunoregulatory effects provides a molecular mechanism for a model for A. muciniphila’s ability to set immunological tone and its varied roles in health and disease.