Here we show that both excretory–se

Here we show that both excretory–secretory products(E–S) and extract of T. spiralis can stimulate the release of thecytokine interleukin 25 (IL-25) from the mouse small intestinal villiand evoke calcium responses from tuft cells in the intestinal organoids,which can be blocked by a bitter-taste receptor inhibitor,allyl isothiocyanate. Heterologously expressed mouse Tas2r bittertastereceptors, the expression of which is augmented during tuftcellhyperplasia, can respond to the E–S and extract as well as tothe bitter compound salicin whereas salicin in turn can induce IL-25release from tuft cells. Furthermore, abolishment of the G-proteinγ13 subunit, application of the inhibitors for G-protein αo/i, Gβγsubunits, and phospholipase Cβ2 dramatically reduces the IL-25release. Finally, tuft cells are found to utilize the inositol triphosphatereceptor type 2 (Ip3r2) to regulate cytosolic calcium and thusTrpm5 activity, while potentiation of Trpm5 by a sweet-tastingcompound, stevioside, enhances tuft cell IL-25 release and hyperplasiain vivo. Taken together, T. spiralis infection activates a signalingpathway in intestinal tuft cells similar to that of taste-budcells, but with some key differences, to initiate type 2 immunity.