Collinsella aerofaciens Produces a pH-Responsive Lipid Immunogen.

Some members of the human gut microbiota profoundly influence their host's physiology, health, and therapeutic responses, but the responsible molecules and mechanisms are largely unknown. As part of a project to identify immunomodulators produced by gut microbes, we analyzed the metabolome of Collinsella aerofaciens, an actinomycete that figures prominently in numerous association studies. The associations are typically positive correlations of C. aerofaciens with pro-inflammatory responses and undesirable outcomes, but an association with favorable responses to PD-1/PD-L1 cancer immunotherapy is a notable exception. A phenotypic assay-guided screen using dendritic cells (mBMDCs) and cytokine readouts identified the active compound, which was structurally characterized as a lysoglycoglycerolipid with an acetal-bearing ß-galactofuranose head group (CaLGL-1, 1). The structural assignment was confirmed through total synthesis. Assays with tlr2-/-, tlr4-/-, and wt mBMDCs revealed TLR2-dependent signaling. CaLGL-1 is produced by a conversion of a bacterially biosynthesized plasmalogen (CaPlsM, 3) to CaLGL-1 (1) in a low-pH environment.

Akkermansia muciniphila phospholipid induces homeostatic immune responses.

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.