Intestinal ZIP8 Regulates Tissue Manganese Distribution and Modifies Manganese Overload in ZIP14 Deficiency

ZIP8 (SLC39A8) is a metal transporter known to facilitate the uptake of manganese, zinc, and iron, but its role in the intestinal epithelium remains unclear. In this study, we investigated the function of intestinal ZIP8 using intestine-specific Zip8 knockout (Zip8-I-KO) mice and a manganese overload model by crossing Zip8-I-KO mice with Zip14^-/- mice to generate double knockout mice. We confirmed that ZIP8 is localized to the apical membrane of colonic Caco-2 cells, a widely used model for enterocytes. Deletion of intestinal ZIP8 did not affect blood manganese levels under basal conditions but led to significantly reduced manganese concentrations in the liver and bone, suggesting a role in tissue-level manganese distribution. In the ZIP14-deficient background, intestinal ZIP8 deletion resulted in a significant reduction of blood and brain manganese levels in female double knockout mice, while no changes were observed in males. Bone manganese remained elevated in all groups. These findings indicate that intestinal ZIP8 contributes to manganese absorption and distribution with its effects varying depending on sex and may serve as a modifier of manganese overload in ZIP14 deficiency.