Crosstalk between Paneth and tuft cells drives dysbiosis and inflammation in the gut mucosa

Gut microbiota imbalance (dysbiosis) is increasingly associated with pathological conditions within and outside of 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 IBD 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 novel 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 observed patients dysbiosis chronicity.