Abstract
BACKGROUND & AIMS: Tuft cells, a type of epithelial cell in the gut, play a pivotal role in regulating type 2 immunity and maintaining the gut barrier. However, their role in cognitive impairments remains unclear. METHODS: We compared behavioral performance between male tuft cell-absent mice (Pou2f3(-/-)) and their wild-type (WT) littermates. We analyzed gut microbiota using fecal 16S rRNA, measured gut permeability via FITC-dextran assay, and detected CD4(+)-T cells and type 2 innate lymphoid cells by flow cytometry in both genotypes. Co-housing and fecal microbiota transplantation experiments were conducted to explore the role of gut microbiota in cognitive diseases. Single-cell RNA sequencing and fluorescence imaging were used to examine tuft cell changes in the colon of WT and Alzheimer's disease (AD) model mice. Colonic organoids were used to assess the effect of β-amyloid on tuft cell differentiation. Succinic acid, a promoter of tuft cells, was administered, and tuft cell-deficient AD mice were generated to evaluate its impact on behavior and gut homeostasis. RESULTS: Increased gut permeability, immune imbalance, neuroinflammation, and cognitive dysfunction occurred in 10-month-old mice lacking tuft cells. These alterations were mediated by gut microbiota, evidenced by shifts in microbiota composition and abundance, and supported by co-housing and fecal microbiota transplantation experiments. AD model mice had fewer tuft cells and impaired type 2 immunity in the gut, potentially because of β-amyloid inhibiting tuft cell differentiation. Succinic acid, a tuft cell activator, restored cognitive function and gut homeostasis in AD mice. CONCLUSIONS: Tuft cells may be necessary for maintaining gut homeostasis in cognitive disorders.