Abstract
Approximately 1 billion people worldwide suffer from zinc deficiency, with severe consequences for their well-being, such as critically impaired intestinal health. In addition to an extreme degeneration of the intestinal epithelium, the intestinal mucus is seriously disturbed in zinc-deficient (ZD) animals. The underlying cellular processes as well as the relevance of zinc for the mucin-producing goblet cells, however, remain unknown. To this end, this study examines the impact of zinc deficiency on the synthesis, production, and secretion of intestinal mucins as well as on the zinc homeostasis of goblet cells using the in vitro goblet cell model HT-29-MTX. Zinc deprivation reduced their cellular zinc content, changed expression of the intestinal zinc transporters ZIP-4, ZIP-5, and ZnT1 and increased their zinc absorption ability, outlining the regulatory mechanisms of zinc homeostasis in goblet cells. Synthesis and secretion of mucins were severely disturbed during zinc deficiency, affecting both MUC2 and MUC5AC mRNA expression with ongoing cell differentiation. A lack of zinc perturbed mucin synthesis predominantly on the post-translational level, as ZD cells produced shorter O-glycans and the main O-glycan pattern was shifted in favor of core-3-based mucins. The expression of glycosyltransferases that determine the formation of core 1-4 O-glycans was altered in zinc deficiency. In particular, B3GNT6 mRNA catalyzing core 3 formation was elevated and C2GNT1 and C2GNT3 elongating core 1 were downregulated in ZD cells. These novel insights into the molecular mechanisms impairing intestinal mucus stability during zinc deficiency demonstrate the essentiality of zinc for the formation and maintenance of this physical barrier.
Highlights
The essential micronutrient zinc is required for catalytic, structural, and regulatory functions of various zinc-metalloproteins in the human body [1]
This study aims to illuminate the impact of zinc deficiency on zinc homeostasis, synthesis, and O-glycosylation of MUC apo-proteins, as well as on the secretion of intestinal mucins by goblet cells using the HT-29-MTX in vitro model for intestinal mucus-producing goblet cells
This study demonstrates the essentiality of nutritional zinc for cell differentiation and mucus production of intestinal goblet cells
Summary
The essential micronutrient zinc is required for catalytic, structural, and regulatory functions of various zinc-metalloproteins in the human body [1]. Prolonged deficiency enhances the risk of infection, often connected with diarrhea and impaired wound healing, resulting in high morbidity [3] This micronutrient deficiency affects about 16% of the world’s population [4] and is directly connected with inadequate zinc absorption in the intestinal tract, as zinc has to be replenished in order to counterbalance daily zinc losses [5]. As tissues with high turnover rates are impaired by zinc deficiency [6], the intestinal tract is severely affected; this is mainly manifested by morphological changes [7,8] and severe degeneration [9] of the intestinal epithelium The disruption of this barrier in zinc deficiency is further enhanced by a reduction in its integrity, resulting in increased membrane permeability [10]. The underlying molecular mechanism and cellular processes causing this deterioration remain to be investigated
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