Characterization of a role for inositol polyphosphate multikinase in the control of colonic epithelial homeostasis

Abstract

Inflammatory bowel disease (IBD), consisting mainly of Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract. Recent studies have identified single-nucleotide polymorphisms in the inositol polyphosphate multikinase (IPMK) gene associated with IBD predisposition. IPMK, an essential enzyme for inositol phosphate metabolism, has been known to mediate major biological events such as growth. To investigate the functional significance of IPMK in gut epithelium, I generated intestinal epithelial cell (IEC)-specific Ipmk knockout (IPMK$^{ΔIEC}$) mice. Whereas IPMK$^{ΔIEC}$ mice developed normally and showed no intestinal abnormalities during homeostasis, Ipmk deletion aggravated dextran sulfate sodium (DSS)-induced colitis with higher epithelial damage. Surprisingly, no apparent defects in epithelial growth signaling pathway and inflammation were found in DSS-challenged, IPMK-deficient colons. Rather, Ipmk deletion led to a significant decrease in the number of tuft cells without influencing other intestinal epithelial cells. Tuft cells are rare chemosensory cells in intestinal epithelium that not only mediate type 2 immune response but also support stem cell niche by paracrine signaling. Ipmk deletion in the gut epithelium was found to reduce choline acetyltransferase but not cytokines (e.g., IL-25), suggesting selective loss of cholinergic signaling. Single-cell RNA-sequencing of mouse colonic tuft cells and immunohistochemistry revealed the heterogeneity of tuft cells and further showed that, in IPMK$^{ΔIEC}$ mice, a transcriptionally inactive tuft club cell population was markedly expanded, and neuronal-related tuft cells were relatively decreased. Thus, IPMK acts as a physiological determinant of colonic tuft cell homeostasis, thereby mediating tissue regeneration upon injury.