Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance

Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the “weep” response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells. [Display omitted] •Tuft cells promote secretion of Cl− from epithelial cells in the intestine and trachea•Tuft cell acetylcholine is required for Cl− secretion but not type 2 inflammation•Tuft cell-induced secretion is enhanced by tuft cell hyperplasia and neuron independent•Intestinal helminth clearance is delayed in mice lacking tuft cell acetylcholine Epithelial tuft cells serve as intestinal immune sentinels, but why they secrete acetylcholine remains unknown. Billipp et al. show that tuft cell chemosensing leads to acetylcholine release, which induces secretion of chloride and subsequently water from neighboring epithelial cells. Tuft cell hyperplasia enhances chloride secretion, and helminth clearance is delayed in mice lacking tuft cell acetylcholine.