Epithelium intrinsic zinc sensing maintains host-microbiome symbiosis via modulation of Tuft and Paneth cell lineages [rna-seq_mtf_ko_si]

Zinc (Zn) is widely recognized as an essential diet-derived micronutrient for optimal growth due to its crucial role in cell proliferation, differentiation, and apoptosis[1-3]. Yet the precise role of Zn in barrier sites such as the intestinal epithelium that is constantly renewing and remodeling remains poorly defined. To address how Zn impacts epithelial lining and gut homeostasis, we generated mice defective in Zn sensing by deleting Metal-responsive Transcription Factor 1 (MTF1) specifically in the intestinal epithelial cells (IECs). MTF1 is a highly conserved Zn-dependent transcription factor that regulates cellular Zn homeostasis [4]. Mice deleted for MTF1 in intestinal epithelial cells (MTF1 ΔIEC) had altered Zn homeostasis that coincided with significant increase in inflammatory immune response to microbes, indicating a critical role of IEC intrinsic Zn sensing in regulating immune homeostasis in the gut. MTF1 deletion resulted in loss of specialized secretory cell lineages such as Paneth and Tuft cells, compromised barrier function against commensal bacteria, and altered susceptibility to helminth and viral infections. MTF1-dependent Zn sensing proved essential for differentiating specialized epithelial cell lineages from newly proliferated intestinal stem cells. Ex vivo experiments using small intestinal organoids (SIOs) demonstrated that Zn treatment promoted the differentiation of proliferating epithelial cells into specialized cell lineages in wild-type organoids, an effect which is absent in MTF1ΔIEC SIOs. This study provides compelling evidence for the fundamental role of Zn in promoting the differentiation of specialized intestinal epithelial cell lineages, which are key to interactions with diverse microbes and maintaining immune homeostasis in the gut.