Gut Epithelial Inositol Polyphosphate Multikinase Alleviates Experimental Colitis via Governing Tuft Cell Homeostasis

BACKGROUND & AIMS: Inositol polyphosphate multikinase (IPMK), an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. Recent studies have identified single-nucleotide polymorphisms in the IPMK gene associated with inflammatory bowel disease predisposition. Therefore, we aimed to investigate the functional significance of IPMK in gut epithelium. METHODS: We generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMK(ΔIEC)) mice, and assessed their vulnerability against dextran sulfate sodium–induced experimental colitis. Both bulk and single-cell RNA sequencing were performed to analyze IPMK-deficient colonic epithelial cells and colonic tuft cells. RESULTS: Although IPMK(ΔIEC) mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium–induced colitis, with higher clinical colitis scores, and increased epithelial barrier permeability. Surprisingly, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other IECs. Single-cell RNA sequencing of mouse colonic tuft cells showed 3 distinct populations of tuft cells, and further showed that a transcriptionally inactive population was expanded markedly in IPMK(ΔIEC) mice, while neuronal-related cells were relatively decreased. CONCLUSIONS: Cholinergic output from tuft cells is known to be critical for the restoration of intestinal architecture upon damage, supporting that tuft cell–defective IPMK(ΔIEC) mice are more prone to colitis. Thus, intestinal epithelial IPMK is a critical regulator of colonic integrity and tissue regeneration by determining tuft cell homeostasis and affecting cholinergic output.