Tuft cells in the gut limit cognitive disorders by regulating gut homeostasis

Cognitive deficits, such as Alzheimer's disease (AD), encompass not only abnormalities in the brain but also dysfunctions in the gut. However, the characterization and influence of colonic epithelial cells during AD development have remained elusive. In this study, we identified a reduced abundance of tuft cells and dysfunction of CD4+ T cell response in the colon of AD model mice (APP/PS1-21), which may result from the specific inhibition of tuft cell differentiation by Aß. The cognitive function was found to be further impaired when tuft cells were deficient in APP/PS1-21 mice. Remarkably, activation of tuft cells using succinic acid—a specific promoter—restored cognitive function and gut homeostasis in AD mice. In addition, tuft cell deficiency in normal mice (10-month-old) is sufficient to induce gut leakage, immune imbalance, and subsequent cognitive dysfunction. Thus, tuft cell is necessary for gut homeostasis during cognitive disorders. Overall design: We performed single-cell RNA sequencing analysis on the colonic epithelium of wild type (WT) and transgenic Alzheimer's disease (AD) model (APP/PS1-21) mice. We generated tuft cell-deficient AD mice and stimulated tuft cells using succinic acid to assess the impact on behavioral performance and CD4+ T cell responses in the colon. We utilized colonic organoids to directly evaluate the effect of ß-amyloid (Aß) on tuft cell differentiation. Furthermore, we compared behavioral performance and CD4+ T-cell responses between different ages of tuft cell-absent mice and age-matched wild-type littermates.