Intestinal Epithelial Cell Intrinsic Zinc Homeostasis is Critical for Host-Microbiome Symbiosis

A robust intestinal barrier is essential for maintaining host-microbiome symbiosis. Defects in the intestinal barrier are associated with a broad range of inflammatory and metabolic diseases. Pharmacological doses of Zinc (Zn) are widely used to improve intestinal barrier function; however, the precise cellular role of Zn in regulating the intestinal barrier during health and disease is not known. A better understanding of how Zn regulates the gut barrier and intestinal epithelial cells (IEC) could enable the development of targeted Zn-based therapeutic approaches. To understand the impact of Zn homeostasis we developed a mouse model with the transcription factor MTF-1 specifically deleted in IECs (MTF ΔIEC). MTF-1 controls the expression of many different zinc importers and exporters. We find that MTF ΔIECmice had reduced expression of Zn homeostasis machinery, demonstrated a leaky barrier, and showed heightened neutrophil activation in the periphery. Additionally, MTF ΔIECmice had a higher bacterial load at the mucosa and were more susceptible to infection by Crohn’s disease associated adherent invasive E.coli. MTF ΔIECmice showed a striking loss of Paneth cells (PCs) from the small intestinal crypts. PCs are specialized antimicrobial-secreting cells with a unique requirement for Zn, but the exact role of Zn in PCs is not known. Based on our findings we conclude that Zn homeostasis is needed for regulating host-microbiome interaction via modulation of intestinal barrier permeability and maintenance of Paneth cells.Our work demonstrating the impact of zinc homeostasis on host-microbe interactions lays the groundwork for understanding zinc in the context of inflammatory bowel disease and dysbiosis in the mucosal microbiome. This work was supported by the NIH [R01DK113265] to Shipra Vaishnava