Produces a Cryptic Pro-inflammatory Lipid.

is both one of the most studied and least understood members of the human gut microbiome. Most of the interest in this Gram-positive anaerobe originates from multiple robust associations of its population with a variety of autoimmune diseases, perhaps most notably inflammatory bowel disease (IBD). The links between bacteria and inflammation are only partially known. Inflammation is driven by Th17 cells and their inflammatory cytokine IL-17, and the population of these cells is promoted by a transcription factor, RORγt. Bacterial metabolites appear to activate RORγt in a cell- and antigen-independent fashion, but the metabolites and their activating mechanism are unknown. This report describes an assay-driven search for pro-inflammatory metabolites from that revealed a plasmalogen-triggered plasmalogen pair that forms a single molecule signal transduction device. Small electrophiles characteristic of inflammatory environments react with the plasmalogen's sensitive vinyl ether moiety to create a lipid signal, a lysoglycoglycerolipid that upregulates the inflammatory cytokines TNF-α and IL-6 through a TLR receptor. This provides a molecular mechanism that allows to upregulate inflammatory responses in a cell- and antigen-independent fashion. This molecular mechanism is similar to an endogenous signaling system that upregulates RORγt through a triggered mammalian plasmalogen signal, 1-18:0-lysophosphatidylethanolamine.