Non-Skeletal Roles of Vitamin D: Epithelial Barrier Function and Immune Regulation in Chronic Disease

Vitamin D is increasingly recognized as a key regulator of epithelial barrier integrity and mucosal immune homeostasis, with implications extending far beyond skeletal health. This review explores the multifactorial role of vitamin D in modulating inflammation and preserving tissue barriers, with particular emphasis on its effects on tight junction (TJ) regulation and disease states characterized by barrier dysfunction. Acting through the vitamin D receptor (VDR), vitamin D influences epithelial cohesion, innate immune re-sponses, and gene expression relevant to TJ. We critically examine current evidence linking vitamin D deficiency with chronic in-flammatory conditions in which epithelial barrier impairment is central—namely atopic dermatitis, psoriasis, inflammatory bowel disease (IBD), and celiac disease. In these set-tings, vitamin D/VDR signaling exerts protective actions by enhancing barrier structure, suppressing Th1/Th17-driven inflammation, modulating the gut and skin microbiome, and promoting epithelial repair. Animal studies and clinical data suggest that vitamin D supplementation can re-store TJ expression, reduce disease activity, and improve clinical outcomes in both intes-tinal and dermatologic diseases. In the cardiovascular system, its role remains complex: while vitamin D influences endothelial function, insulin sensitivity, and systemic inflammation, supplementation trials yield mixed results, indicating a need for individualized approaches. Overall, this review synthesizes mechanistic, translational, and clinical data sup-porting vitamin D as a crucial modulator of barrier integrity and inflammation. These findings highlight its therapeutic relevance in chronic diseases characterized by immune dysregulation and epithelial disruption.