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Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions, both within and outside the gastrointestinal tract. Intestinal Paneth cells are considered to be guardians of the gut microbiota, but the events linking Paneth cell dysfunction with dysbiosis remain unclear. We report a three-step mechanism for dysbiosis initiation. Initial alterations in Paneth cells, as frequently observed in obese and inflammatorybowel diseases patients, cause a mild remodeling of microbiota, with amplification of succinate-producing species. SucnR1 -dependent activation of epithelial tuft cells triggers a type 2 immune response that, in turn, aggravates the Paneth cell defaults, promoting dysbiosis and chronic inflammation. We thus reveal a function of tuft cells in promoting dysbiosis following Paneth cell deficiency and an unappreciated essential role of Paneth cells in maintaining a balanced microbiota to prevent inappropriate activation of tuft cells and deleterious dysbiosis. This succinate--tuft cell inflammation circuit may also contribute to the chronic dysbiosis observed in patients. [ABSTRACT FROM AUTHOR]

Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function. [Display omitted] • Tuft cells play both sentinel and effector roles in type 2 immune responses • Tuft cell acetylcholine production increases during helminth infections • Tuft cells release acetylcholine into the gut lumen during type 2 immune responses • Acetylcloline inhibits helminth fecundity through worm muscarinic receptors Intestinal tuft cells are known as sentinels capable of initiating type 2 immune responses upon parasite infections. Ndjim et al. now report a direct effector function for intestinal tuft cells during such immune responses by increasing their acetylcholine biosynthesis and releasing it into the gut lumen. Helminth fecundity is directly inhibited by acetylcholine, acting through worm muscarinic receptors. [ABSTRACT FROM AUTHOR]