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

Abstract

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 Delta IEC) 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 Delta IEC 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 Delta IEC 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 Delta IEC 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.