Vitamin D as a Master Regulator of Biological Barrier Integrity: A Systems Framework Linking Vitamin D Deficiency to Systemic Leaky Barrier Syndrome

Vitamin D is traditionally recognized for its role in calcium homeostasis and skeletal health; however, growing molecular and clinical evidence indicates that vitamin D signaling is a central regulator of biological barrier integrity across multiple organ systems. Epithelial and endothelial barriers—including the intestinal mucosa, vascular endothelium, blood–brain barrier, pulmonary epithelium, renal filtration barrier, and cutaneous barrier—depend on intact tight junctions, adherens junctions, and immune–redox homeostasis to maintain systemic health.We propose that vitamin D deficiency may contribute to a unifying pathophysiological state characterized by multi-barrier dysfunction, recently conceptualized as Systemic Leaky Barrier Syndrome (SLBS). Through regulation of junctional proteins (e.g., claudins, occludin, ZO-1), modulation of innate and adaptive immunity, suppression of chronic inflammation, and maintenance of redox balance, vitamin D plays a pivotal role in preserving barrier resilience. Failure of these protective mechanisms promotes translocation of microbial products, inflammatory mediators, and metabolic toxins, driving chronic diseases including cardiovascular disease, neurodegeneration, autoimmune disorders, cancer progression, and metabolic dysfunction.This review synthesizes mechanistic, translational, and clinical evidence supporting vitamin D as a barrier-protective hormone and positions SLBS as a systems-level framework for understanding the broad disease consequences of vitamin D insufficiency.