Dietary vitamin A restricts intestinal tuft cell differentiation

Despite evidence highlighting immunoregulatory roles of tuft cells, it is not known whether vitamin A or retinoic acid affects tuft cell homeostasis. Here, we find that epithelial-intrinsic retinoic acid receptor regulates tuft cell numbers in mice. However, loss of retinoic acid signaling in tuft cells does not replicate this effect, suggesting altered differentiation. Consistent with this, retinoic acid administration to stem cell-derived organoids reduces tuft cell numbers, and epithelial-intrinsic retinoic acid is sufficient to alter tuft cell responses. In addition, dietary vitamin A dynamically alters tuft cells in vivo and regulates anti-helminth immunity in a tuft cell-dependent manner. Mechanistically, epithelial retinoic acid signaling promotes expression of Sprouty2, a negative regulator of tuft cell differentiation. Furthermore, stem cell-specific Sprouty2 disruption abrogates vitamin A regulation of tuft cells. Collectively, these data indicate that retinoic acid restricts tuft cell differentiation and carries important implications for how vitamin A affects intestinal health and immunity.