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How does zinc deficiency impact epithelium?
Executive Summary
Zinc deficiency disrupts epithelial structure and function across multiple organs, producing clinical and experimental consequences that include impaired wound healing, altered keratinocyte proliferation and differentiation, weakened mucosal barrier integrity, and slowed regeneration of sensory epithelia such as the olfactory mucosa. Experimental and clinical literature converge on the view that physiological zinc supports epithelial restitution, tight junction maintenance, and anti‑inflammatory homeostasis, while both deficiency and, at high doses, excess zinc alter signaling pathways and tissue repair [1] [2] [3]. The body of work spans skin, oral and intestinal epithelia, and specialized sensory epithelia in animal models, showing consistent mechanistic themes—changes in proliferative capacity, extracellular matrix gene expression, inflammatory gene upregulation, and modulation of pathways such as PI3K/AKT/mTOR and ZnR-mediated Ca2+ signaling [4] [5] [3].
1. How epithelial repair falls apart without zinc — the wound‑healing story that unifies tissues
Zinc deficiency impairs the earliest steps of epithelial wound healing by reducing cell migration and proliferation that drive re‑epithelialization; physiological zinc accelerates epithelial restitution while supraphysiological zinc can injure tissue, indicating a dose‑dependent effect on repair [1]. Mechanistic studies identify extracellular zinc acting through a Zn2+‑sensing receptor (ZnR) to evoke a metabotropic Ca2+ response that triggers downstream signaling important for keratinocyte migration and proliferation, linking zinc availability directly to the signaling events that close epithelial gaps [2]. These findings are reported in controlled in vitro and animal experiments and are complemented by clinical observations that zinc supplementation can improve healing in zinc‑deficient contexts, whereas excessive supplementation carries potential for impaired healing and tissue injury [1] [2].
2. Skin and oral epithelium: clinical presentations and cellular disruption when zinc is low
Zinc deficiency produces characteristic cutaneous and mucosal lesions and histologic changes in stratified epithelia, with acrodermatitis enteropathica, parakeratosis, hyperplasia, and altered keratinocyte differentiation described across studies and animal models [4] [6]. A classic animal study showed stunted growth, weight loss, and marked epidermal changes in the oral mucosa of zinc‑deficient rabbits, demonstrating that structural epithelial alterations accompany systemic deficiency [6]. Contemporary reviews and experimental data link these morphological changes to disrupted keratinocyte proliferation and differentiation programs and to increased local inflammatory responses, providing a molecular rationale for the clinical skin and mucosal manifestations seen with deficient zinc status [4].
3. Intestinal epithelium: barrier breakdown, signaling loss, and disease relevance
Zinc is essential for intestinal epithelial barrier integrity; deficiency increases permeability and undermines tight junction protein expression, while zinc repletion enhances barrier function via signaling pathways including PI3K/AKT/mTOR [3] [7]. Experimental models show zinc transporters regulate mucosal homeostasis and that zinc supplementation can ameliorate mucosal barrier dysfunction, with implications for inflammatory bowel disease pathogenesis and symptom management [8] [9]. The convergence of transporter biology, barrier protein expression, and intracellular growth and differentiation signals offers a coherent mechanism for how zinc status alters intestinal epithelial resilience to injury and infection, linking cellular signaling perturbations to clinically observable increases in mucosal permeability and inflammation [3] [8].
4. Sensory epithelial regeneration: olfactory mucosa as a window into renewal deficits
In mouse models, zinc deficiency slows regeneration of the olfactory epithelium after injury, producing reduced epithelial thickness and fewer proliferating, immature, and mature olfactory neurons, with RNA sequencing revealing downregulation of extracellular matrix genes and upregulation of inflammatory pathways [5]. These changes map onto impaired regenerative capacity, suggesting zinc supports not only barrier and surface epithelia but also specialized, neuroepithelial renewal processes. The olfactory findings extend the general pattern seen in skin and gut: zinc scarcity depresses proliferative and differentiation programs while promoting inflammatory responses that collectively blunt tissue recovery after damage [5].
5. What the evidence leaves open and practical implications for clinicians and researchers
The literature consistently shows zinc’s central role in epithelial health but highlights context‑dependence: tissue type, deficiency severity, and zinc dose all shape outcomes, and excessive zinc can be harmful [1] [2]. Mechanistic gaps remain in translating signaling observations into optimized supplementation regimens across clinical scenarios, and transporter‑specific roles warrant further study. Across reviews and experiments, the evidence supports targeted correction of zinc deficiency to restore epithelial integrity and repair capacity while cautioning against indiscriminate high‑dose zinc use, because both deficiency and excess disturb epithelial homeostasis [4] [1] [9].