Acute tuft cell ablation in mice induces malabsorption and alterations in secretory and immune cell lineages in the small intestine

Intestinal tuft cells have recently been the focus of many studies due to their function in chemosensation and type 2 immunity in human gastrointestinal diseases. This study investigated the impact of acute tuft cell loss on intestinal physiological function. Tuft cell deletion was induced in DCLK1-IRES-GFP-CreERT2/+;Rosa-DTA (DCLK1-DTA) mice by a single tamoxifen injection, concomitant with littermate controls. Transient deletion of intestinal and biliary tuft cells was maximal on day 4 and recovered by day 7 post tamoxifen. DCLK1-DTA mice presented with significantly shortened small intestinal length and greater body weight loss by day 4. The activity of Na⁺-dependent glucose transporter 1 (SGLT1) and cystic fibrosis transmembrane regulator (CFTR) was reduced. Correlated with tuft cell reduction, the frequency of cholecystokinin (CCK)⁺ enteroendocrine and intermediate secretory cells, which co-express Paneth and goblet cell markers, was increased. In the lamina propria, fewer mast cells and leukocytes were found in the Day 4 DCLK1-DTA mice compared to controls. Ablation of tuft cells may induce nutrient malabsorption through alterations in epithelial cell proliferation and differentiation, along with changes in the mucosal defense response. These observations identify a new role for tuft cells in regulating intestinal absorption and mucosal regeneration.