Epithelium intrinsic zinc sensor controls immune homeostasis with gut microbes via regulation of Tuft cell lineage.

Zinc is an essential micronutrient crucial for cell proliferation, differentiation, and apoptosis, yet its precise role in the constantly renewing intestinal epithelium remains unclear. We generated mice lacking the Zn-dependent transcription factor Metal-responsive Transcription Factor 1(MTF1(ΔIEC)) in intestinal epithelial cells. MTF1(ΔIEC) mice exhibited altered metal homeostasis and acute susceptibility to Zn supplementation. Transcriptional and cellular analyses revealed increased inflammatory immune responses to microbes in MTF1(ΔIEC) mice. Mechanistically MTF1 deletion resulted in the loss of Tuft cell lineages compromising barrier function against commensal microbes and pathogens. Ex vivo experiments demonstrated that at a cellular level, Zn treatment skewed the cellular composition from proliferating to differentiated cells. Specifically, we show that Zn sensing via MTF1 is required for IL-13 dependent induction of Tuft cells. Our findings underscore critical role of Zn in maintaining intestinal immune homeostasis through differentiation of specialized cell lineages, highlighting importance nutrient sensing in the constantly remodeling epithelial barrier.