Metal Transporter SLC39A14/ZIP14-Mediated Zinc Transport Modulates the Gut Microbiome and Host Metabolism

OBJECTIVES: Intestinal permeability, gut dysbiosis, and Zn dyshomeostasis are emerging signatures of inflammatory bowel diseases and metabolic disorders such as type-2-diabetes and obesity. Zn deficiency is a common clinical finding among these diseases. Zinc (Zn) plays a critical role in maintaining intestinal homeostasis by regulating intestinal epithelial cells, host immune cells, and gut microbiome community composition. Zn transporters maintain Zn homeostasis by facilitating the cellular and subcellular distribution of Zn to and within tissues. Our previous studies revealed that deletion of metal transporter Slc39a14/Zip14 caused spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose, suggesting a role for ZIP14-mediated intestinal metal transport in regulating both intestinal homeostasis and systemic metabolism. Here we present our novel findings on the function of ZIP14-mediated Zn transport in intestinal tissue, microbial profile, and how ZIP14-linked changes in gut microbiome and metabolites modulate host metabolism. METHODS: Tissue metal concentrations were measured by microwave plasma atomic emission spectrometers. Gut microbiome community composition Saccharomyces cerevisiae levels were determined using 16S rRNA gene sequencing and < qPCR, respectively. To identify the host and microbial-originated metabolites in WT and KO mice serum, we conducted untargeted metabolomics using Gas chromatography coupled to time-of-flight mass spectrometry. Lastly, we conducted metabolic phenotyping by using a Comprehensive Laboratory Animal Monitoring System. RESULTS: Deletion of Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract; reduced bacterial diversity and Saccharomyces cerevisiae (S. cerevisiae) overgrowth; altered host metabolome; and shifted host energy metabolism toward glucose utilization. CONCLUSIONS: This work provided evidence for the regulation of gut microbiome composition, host metabolome, and energy metabolism by metal transporter ZIP14. FUNDING SOURCES: Cornell University Division of Nutritional Sciences Funds.