Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine

Tuft cells are a type of intestinal epithelial cells that exist in epithelial barriers and play a critical role in immunity against parasite infection. It remains insufficiently clear whether Tuft cells participate in bacterial eradication. Here, we identified Sh2d6 as a signature marker for CD45+ Tuft-2 cells. Depletion of Tuft-2 cells resulted in susceptibility to bacterial infection. Tuft-2 cells quickly expanded in response to bacterial infection and sensed the bacterial metabolite N-undecanoylglycine through vomeronasal receptor Vmn2r26. Mechanistically, Vmn2r26 engaged with N-undecanoylglycine activated G-protein-coupled receptor-phospholipase C gamma2 (GPCR-PLCγ2)-Ca2+ signaling axis, which initiated prostaglandin D2 (PGD2) production. PGD2 enhanced the mucus secretion of goblet cells and induced antibacterial immunity. Moreover, Vmn2r26 signaling also promoted SpiB transcription factor expression, which is responsible for Tuft-2 cell development and expansion in response to bacterial challenge. Our findings reveal an additional function of Tuft-2 cells in immunity against bacterial infection through Vmn2r26-mediated recognition of bacterial metabolites. [Display omitted] •Tuft-2 cells exert antibacterial function•Tuft-2 cells sense bacterial metabolites through Vmn2r26•PGD2 produced by Tuft-2 cells facilitates mucus secretion of goblet cells•SpiB is required for Tuft-2 cell expansion over bacterial infection Tuft cells play a critical role in immunity against parasite infection, but whether Tuft cells participate in bacterial eradication is presently unclear. Xiong et al. reveal that Tuft-2 cells mediate immunity against bacterial infection through Vmn2r26-mediated recognition of bacterial metabolites.