Mammalian sweet taste is primarily mediated by the type 1 taste receptor Tas1r2/Tas1r3, whereas Tas1r1/Tas1r3 act as the principal umami taste receptor. Bitter taste is mediated by a different group of G protein-coupled receptors, the Tas2rs, numbering 3 to ∼66, depending on the species. We showed previously that the behavioral indifference of cats toward sweet-tasting compounds can be explained by the pseudogenization of the Tas1r2 gene, which encodes the Tas1r2 receptor. To examine the generality of this finding, we sequenced the entire coding region of Tas1r2 from 12 species in the order Carnivora. Seven of these nonfeline species, all of which are exclusive meat eaters, also have independently pseudogenized Tas1r2 caused by ORF-disrupting mutations. Fittingly, the purifying selection pressure is markedly relaxed in these species with a pseudogenized Tas1r2 . In behavioral tests, the Asian otter (defective Tas1r2 ) showed no preference for sweet compounds, but the spectacled bear (intact Tas1r2 ) did. In addition to the inactivation of Tas1r2 , we found that sea lion Tas1r1 and Tas1r3 are also pseudogenized, consistent with their unique feeding behavior, which entails swallowing food whole without chewing. The extensive loss of Tas1r receptor function is not restricted to the sea lion: the bottlenose dolphin, which evolved independently from the sea lion but displays similar feeding behavior, also has all three Tas1r s inactivated, and may also lack functional bitter receptors. These data provide strong support for the view that loss of taste receptor function in mammals is widespread and directly related to feeding specializations.

The hallmark features of type 2 mucosal immunity include intestinal tuft and goblet cell expansion initiated by tuft cell activation. How infectious agents that induce type 2 mucosal immunity are detected by tuft cells is unknown. Published microarray analysis suggested that succinate receptor 1 (Sucnr1) is specifically expressed in tuft cells. Thus, we hypothesized that the succinate–Sucnr1 axis may be utilized by tuft cells to detect certain infectious agents. Here we confirmed that Sucnr1 is specifically expressed in intestinal tuft cells but not in other types of intestinal epithelial cells, and demonstrated that dietary succinate induces tuft and goblet cell hyperplasia via Sucnr1 and the tuft cell-expressed chemosensory signaling elements gustducin and Trpm5. Conventional mice with a genetic Sucnr1 deficiency (Sucnr1^−/−) showed diminished immune responses to treatment with polyethylene glycol and streptomycin, which are known to enhance microbiota-derived succinate, but responded normally to inoculation with the parasitic worm Nippostrongylus brasiliensis that also produces succinate. Thus, Sucnr1 is required for microbiota-induced but not for a generalized worm-induced type 2 immunity. Significance Tuft cells in the intestine are known to act as sentinels for infectious agents [e.g., helminths (worms) and bacterial microbiota] and express taste-signaling elements. In this work, the G protein-coupled receptor Sucnr1 was shown to be expressed specifically in tuft cells but not in other intestinal epithelial cells. Dietary succinate and perturbations in the microbiota activate tuft cells, and subsequently type 2 immunity, via tuft cell-expressed Sucnr1. Modulating this pathway using dietary succinate or specific Sucnr1 agonists may be a strategy for fighting bacterial and parasitic infections or other type 2 immune-related metabolic disorders such as obesity.

Significance: Taste tissue regenerates continuously throughout the life span in mammals. Here, using lineage tracing and a culture system, we show that leucine-rich repeat-containing G protein-coupled receptor 5-expressing and leucine-rich repeat-containing G protein-coupled receptor 6-expressing taste stem/progenitor cells generate mature taste cells in vivo and ex vivo. Importantly, our ex vivo studies show that single-progenitor cells can generate all mature taste cell types and that differentiated taste cells form in the absence of innervation. This ex vivo model mimics the development of taste bud cells in taste papillae, recapitulates the process of taste renewal from adult taste stem cells to mature taste cells, and provides a means to study the regulation of taste cell generation and to understand the origins and cell lineage relationships within taste buds.

Until recently, reliable markers for adult stem cells have been lacking for many regenerative mammalian tissues. Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5) has been identified as a marker for adult stem cells in intestine, stomach, and hair follicle; Lgr5-expressing cells give rise to all types of cells in these tissues. Taste epithelium also regenerates constantly, yet the identity of adult taste stem cells remains elusive. In this study, we found that Lgr5 is strongly expressed in cells at the bottom of trench areas at the base of circumvallate (CV) and foliate taste papillae and weakly expressed in the basal area of taste buds and that Lgr5-expressing cells in posterior tongue are a subset of K14-positive epithelial cells. Lineage-tracing experiments using an inducible Cre knockin allele in combination with Rosa26-LacZ and Rosa26-tdTomato reporter strains showed that Lgr5-expressing cells gave rise to taste cells, perigemmal cells, along with self-renewing cells at the bottom of trench areas at the base of CV and foliate papillae. Moreover, using subtype-specific taste markers, we found that Lgr5-expressing cell progeny include all three major types of adult taste cells. Our results indicate that Lgr5 may mark adult taste stem or progenitor cells in the posterior portion of the tongue.

Significance: Despite improved understanding of cellular and molecular events mediating type 2 immune responses in the gut, how these changes facilitate worm expulsion remains largely unknown. We identified pyroptosis-effector gasdermin C genes ( Gsdmc s) as type 2 cytokine-regulated target genes in intestinal epithelial cells. Furthermore, we showed that overexpression of Gsdmc2 triggered pyroptosis. Organoid cultures and in vivo mouse models were used to show that activating type 2 immunity leads to lytic cell death in gut epithelium and cleavage of Gsdmcs. We thus revealed a role of gasdermin-mediated lytic cell death in worm-induced type 2 immunity. Parasitic infection often leads to malnutrition and retarded growth; since this may involve villus atrophy, gasdermin activity may provide a pharmaceutical target for treatment.

Divalent and trivalent salts exhibit a complex taste profile. They are perceived as being astringent/drying, sour, bitter, and metallic. We hypothesized that human bitter-taste receptors may mediate some taste attributes of these salts. Using a cell-based functional assay, we found that TAS2R7 responds to a broad range of divalent and trivalent salts, including zinc, calcium, magnesium, copper, manganese, and aluminum, but not to potassium, suggesting TAS2R7 may act as a metal cation receptor mediating bitterness of divalent and trivalent salts. Molecular modeling and mutagenesis analysis identified 2 residues, H94^3.37 and E264^7.32, in TAS2R7 that appear to be responsible for the interaction of TAS2R7 with metallic ions. Taste receptors are found in both oral and extraoral tissues. The responsiveness of TAS2R7 to various mineral salts suggests it may act as a broad sensor, similar to the calcium-sensing receptor, for biologically relevant metal cations in both oral and extraoral tissues.