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 beta-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.

Automated summary

Some members of the human gut microbiota have significant impact on the host's physiology, health, and therapeutic responses, but the specific molecules and mechanisms responsible are not well understood. As part of a research project, the metabolome of Collinsella aerofaciens, a commonly studied actinobacterium, was analyzed to identify immune-regulating compounds produced by gut microbes. The active compound, CaLGL-1, a lysoglycoglycerolipid, was identified and its production was found to be dependent on TLR2 signaling.