5 of the body's barriers (gut, skin, blood-brain, lung, vascular) are improved by Vitamin D

Systemic Leaky Barrier Syndrome and Low Vitamin D Perplexity AI Feb 2026

What Is Systemic Leaky Barrier Syndrome (SLBS)?

Systemic Leaky Barrier Syndrome (SLBS) is a recently proposed systems-level framework — not a formal medical diagnosis — introduced by Richard Z. Cheng, MD, PhD, Editor-in-Chief of the Orthomolecular Medicine News Service. In a 2026 preprint and companion articles, Cheng defines SLBS as a state of multi-barrier dysfunction in which epithelial, endothelial, and immune interfaces across multiple organ systems simultaneously lose integrity.[1][2]

SLBS posits that chronic diseases commonly treated as separate entities — cardiovascular disease, neurodegeneration, autoimmunity, metabolic syndrome, and even cancer — share a common upstream pathway: progressive failure of biological barriers in the gut, vasculature, blood-brain barrier, lungs, kidneys, and skin. When foundational requirements such as intact structural proteins, adequate cellular energy, balanced redox signaling, and ongoing micronutrient availability are chronically compromised, barriers lose the ability to fully repair.[1]

Vitamin D as a "Master Regulator" of Barrier Integrity

Cheng's invited review article submitted to the International Journal of Molecular Sciences (IJMS), titled "Vitamin D as a Master Regulator of Biological Barrier Integrity," explicitly positions vitamin D deficiency as a central driver of SLBS. The paper argues that vitamin D is not merely a nutrient but a regulatory node governing barrier gene expression and immune tone across multiple tissue systems.[3][2]

This framing builds on a substantial body of peer-reviewed research demonstrating that vitamin D and the vitamin D receptor (VDR) regulate barrier function in diverse tissues, including the skin, intestine, lung, kidney, and other organs.[4]

Mechanistic Evidence: Vitamin D and Barrier Function

Intestinal Barrier (Leaky Gut)

The most extensively studied connection is between vitamin D and the intestinal epithelial barrier. Vitamin D/VDR signaling maintains tight junction integrity by modulating key tight junction proteins including claudin-1, claudin-2, claudin-3, occludin, and zonula occludin-1 (ZO-1). An optimal vitamin D level promotes the stability of tight junctions — the cell-to-cell connections that prevent harmful substances from crossing the intestinal wall into the bloodstream.[5][6][7][8]

In experimental models, vitamin D-deficient mice challenged with intestinal infection showed significantly increased colonic permeability and epithelial barrier dysfunction compared to vitamin D-sufficient animals. Additionally, vitamin D deficiency resulted in altered gut microbiome composition, further compounding barrier dysfunction. Vitamin D supplementation has been shown to attenuate bacterial translocation and reduce intestinal permeability in animal models of liver cirrhosis.[9][10]

Blood-Brain Barrier

Vitamin D has a direct, VDR-mediated protective effect against blood-brain barrier (BBB) dysfunction. In a mouse brain endothelial cell model, 1,25(OH)₂D₃ treatment prevented the decrease in barrier function after hypoxic injury, preserved expression of tight junction proteins (ZO-1, claudin-5, occludin), blocked NF-κB activation, and reduced matrix metalloproteinase-9 expression. Studies confirm that vitamin D can prevent leaky brain by reducing inflammation and reducing BBB disruption.[11][12]

Skin Barrier

Vitamin D and VDR regulate the processing of long-chain glycosylceramides critical for skin barrier formation. Mice lacking VDR or the enzyme CYP27B1 show decreased lipid content of lamellar bodies, leading to a defective permeability barrier in the skin. Additionally, vitamin D promotes the expression of involucrin, transglutaminase, loricrin, and filaggrin — all essential proteins for proper epidermal differentiation and barrier integrity.[13]

Vascular Endothelial Barrier

The SLBS framework positions endothelial dysfunction as a vascular manifestation of systemic barrier failure. Vitamin D deficiency has long been associated with systemic autoimmune diseases, and emerging research highlights vitamin D's role in maintaining vascular endothelial integrity through its anti-inflammatory and immunomodulatory effects.[14][1]

Pulmonary and Renal Barriers

Zhang et al. (2013) in Tissue Barriers reviewed the potential therapeutic functions of vitamin D in treating defective tissue barriers involving the lungs, kidneys, and other organs, noting that VDR signaling and its associated intracellular junction proteins (β-catenin, claudins) are critical for barrier maintenance across these tissues.[4]

The SLBS–Vitamin D Connection:(table)

The relationship between SLBS and low vitamin D operates at multiple levels:

Barrier System	Vitamin D Role	Consequence of Deficiency
Intestinal	Maintains tight junctions (claudins, occludin, ZO-1); modulates microbiome	Increased permeability, bacterial translocation, immune activation [5][9]
Blood-Brain	Preserves BBB tight junction proteins; suppresses NF-κB and MMP-9	BBB disruption, neuroinflammation [11]
Skin	Regulates glycosylceramide processing, keratinocyte differentiation	Defective permeability barrier, impaired innate defense [13]
Vascular	Anti-inflammatory and immunomodulatory effects on endothelium	Endothelial dysfunction, atherosclerosis [14][1]
Pulmonary/Renal	VDR regulation of tissue junction complexes	Filtration and exchange failure [4]

Within the SLBS framework, vitamin D deficiency is viewed as a systemic destabilizer — when vitamin D levels are chronically low, barriers across multiple organ systems simultaneously become vulnerable to breakdown, driven by:

Loss of tight junction protein expression
Increased inflammatory signaling
Disrupted microbiome composition
Impaired tissue repair mechanisms
Reduced antimicrobial peptide production[6][15][5]

Current Status and Caveats

SLBS remains a theoretical framework, not an established medical diagnosis. The concept was first formally proposed in a 2026 preprint by Cheng, and the companion review article on vitamin D's role is currently under peer review at IJMS. While the individual components — vitamin D's regulation of intestinal, blood-brain, skin, and vascular barriers — are supported by a robust body of peer-reviewed literature, the unification of these findings under a single "syndrome" label is new and has not yet undergone broad scientific validation.[2][5][9][11][4]

That said, the underlying science is well-established: vitamin D deficiency is associated with autoimmune disease, increased intestinal permeability, blood-brain barrier disruption, and impaired skin barrier function. The SLBS framework essentially synthesizes these findings into a systems-level model, arguing that low vitamin D is one of the key upstream drivers of multi-organ barrier failure.[14][9][13][11]

References

SLBS as a Common Pathway to Chronic Disease - This question is central to Systemic Leaky Barrier Syndrome (SLBS), a systems-level framework that I...
Two Invited Papers. One Direction: Rebuilding Medicine Around ... - Systemic Leaky Barrier Syndrome (SLBS). A systems-level vulnerability state characterized by multi-b...
Vitamin D as a Master Regulator of Biological Barrier Integrity: A ... - Vitamin D as a Master Regulator of Biological Barrier Integrity: A Systems Framework Linking Vitamin...
Vitamin D, vitamin D receptor and tissue barriers - We also discuss the potential therapeutic functions of vitamin D in treating defective tissue barrie...
Mucosal vitamin D signaling in inflammatory bowel disease - Vitamin D signaling modulates the intestinal microbiome and immune functions. Intestinal barrier int...
Leaky Gut and vitamins - SIBO Academy - Learn here how vitamins such as vitamin D and A can strengthen the intestinal barrier and reduce inf...
Tight junction CLDN2 gene is a direct target of the vitamin D receptor - Recent evidence suggests that vitamin D and its receptor VDR may regulate intestinal barrier functio...
Vitamin D/vitamin D receptor protects intestinal barrier against colitis ... - Overexpression of vitamin D receptor in intestinal epithelia protects against colitis via upregulati...
Vitamin D Deficiency Promotes Epithelial Barrier Dysfunction and ... - The present study showed that an increase in intestinal paracellular permeability was further enhanc...
Vitamin D Receptor Influences Intestinal Barriers in Health and ... - Vitamin D3 treatment significantly attenuated bacterial translocation and reduced intestinal permeab...
Vitamin D Prevents Hypoxia/Reoxygenation-Induced Blood-Brain ... - Our findings show a direct, VDR-mediated, protective effect of 1,25(OH) ) 2 D 3 against ischemic inj...
Nutrients to help repair your blood-brain barrier - Vitamin D is a powerful tool in managing inflammation and autoimmunity. Every tissue in your body ha...
Vitamin D and the skin: Focus on a complex relationship - ... Vitamin D receptor and coactivators SRC 2 and 3 regulate epidermis-specific sphingolipid product...
Relationships Between Vitamin D, Gut Microbiome, and Systemic ... - Vitamin D deficiency has long been associated with systemic autoimmune disease and is suspected to p...
Vitamin D and intestinal homeostasis: Barrier, microbiota, ... - Vitamin D ensures an appropriate level of antimicrobial peptides in the mucus and maintains epitheli...

A Systems-Level Framework for Chronic Disease - Feb 2026

by Richard Z. Cheng, MD, PhD
Editor-in-Chief, Orthomolecular Medicine News Service (OMNS)

Over the past two decades, biomedical research has increasingly documented the loss of barrier integrity across multiple organ systems in chronic disease. Intestinal permeability ("leaky gut"), blood-brain barrier disruption, endothelial dysfunction, alveolar-capillary leakage, renal filtration injury, and skin barrier defects have typically been studied in isolation, within separate clinical and disciplinary silos.

In a recent preprint [1], Systemic Leaky Barrier Syndrome (SLBS): A Systems-Level Framework for Chronic Disease (Cheng, 2026), I proposed the term Systemic Leaky Barrier Syndrome (SLBS) as a unifying systems-level framework to integrate these observations across chronic disease.

SLBS describes a condition in which multiple biological barriers - intestinal, vascular, blood-brain, pulmonary, renal, hepatic, placental, and cutaneous - progressively lose structural and functional integrity due to shared upstream drivers. These include environmental toxins, chronic inflammation, oxidative and redox imbalance, micronutrient insufficiency, mitochondrial dysfunction, and impaired tissue repair capacity.

Across organ systems, barrier integrity depends on common structural and metabolic elements:

Tight junction proteins
Cytoskeletal support
Extracellular matrix stability
Endothelial and epithelial integrity
Adequate cellular energy supply
Redox-balanced repair systems

When these shared systems are stressed chronically, barrier resilience declines across multiple tissues simultaneously.

SLBS and Progressive Chronic Disease

This framework reframes chronic disease not as isolated organ failure, but as a systemic failure of barrier integrity and repair.

For example:

Chronic Kidney Disease

The kidney's filtration barrier depends on intact glomerular endothelium, basement membrane integrity, and podocyte structure. When redox imbalance, inflammation, and metabolic stress persist, filtration selectivity deteriorates. Albumin leakage and progressive nephron injury follow. What appears clinically as "renal failure" may reflect long-standing structural and oxidative compromise of the renal barrier system.

Hypertension

The vascular endothelium functions as a dynamic permeability and signaling barrier. Endothelial dysfunction - characterized by impaired nitric oxide signaling, increased permeability, oxidative stress, and inflammatory activation - precedes and drives sustained vascular stiffness and pressure dysregulation. High blood pressure, in this context, reflects loss of endothelial boundary regulation and structural vascular resilience.

Neuroinflammatory Disorders

Blood-brain barrier compromise permits peripheral inflammatory mediators and immune cells to enter neural tissue, amplifying oxidative stress and microglial activation.

Across these conditions, barrier breakdown functions both as an initiating factor and as a powerful amplifier of immune activation, inflammatory signaling, metabolic dysregulation, and iron-driven oxidative injury. Excess iron can cause ferroptosis and retinopathy leading to blindness [2]. A self-reinforcing cycle of tissue damage emerges.

The Cancer Connection

Barrier failure can be a critically important factor for cancer. Genetic mutations and cellular transformation are real and important, the tissue environment in which mutations accumulate is not biologically neutral.

Healthy tissues maintain strict structural and functional boundaries:

Epithelial layers maintain polarity and controlled proliferation
Endothelial barriers regulate nutrient and oxygen delivery
Extracellular matrix architecture constrains cell migration
Immune surveillance operates within defined compartments

When these boundary systems are chronically disrupted - through inflammation, oxidative stress, micronutrient depletion, and impaired repair - the tissue microenvironment becomes destabilized.

Loss of boundary control contributes to:

Persistent inflammatory signaling
Increased oxidative DNA stress
Impaired apoptosis and repair
Degradation of extracellular matrix structure
Increased vascular permeability
Reduced immune containment

In this destabilized environment, genetically abnormal cells are more likely to survive, expand, invade, and eventually metastasize.

From a systems perspective, cancer progression can therefore be viewed as occurring in the context of advanced barrier and regulatory failure - not merely as an isolated genetic event. Barrier breakdown does not "cause" cancer in a simplistic sense. Rather, it creates conditions that lower structural and metabolic constraints on malignant progression.

This interpretation aligns cancer with other progressive chronic diseases within a shared upstream terrain of redox imbalance, structural degradation, and impaired repair capacity.

Clinical Implications

Importantly, SLBS does not replace disease-specific diagnosis or treatment. It complements conventional approaches by shifting attention upstream - toward:

Barrier-centric biomarkers
Structural resilience
Redox balance
Micronutrient sufficiency
Mitochondrial energy support
Inflammation control

Rather than waiting for organ-specific failure, earlier intervention aimed at preserving barrier integrity may help prevent multi-system progression.

A Systems-Level Construct

As with other systems-level constructs in medicine, SLBS is offered as a conceptual framework intended to stimulate research, refine clinical thinking, and encourage preventive intervention. Further work will be needed to:

Delineate causal hierarchies
Develop barrier-focused diagnostics
Explore therapeutic strategies informed by this model

Orthomolecular medicine has long emphasized structural integrity, nutritional sufficiency, redox balance, and upstream causality. SLBS provides a modern systems framework that unifies these principles across biological barriers and chronic disease states.

References:

1. Cheng, R.Z. Systemic Leaky Barrier Syndrome (SLBS): A Systems-Level Framework for Chronic Disease. 2026. DOI: 10.20944/preprints202602.0069.v2; Available online: https://www.preprints.org/manuscript/202602.0069.

2. Li, L.; Dai, Y.; Ke, D.; et al. Ferroptosis: New Insight into the Mechanisms of Diabetic Nephropathy and Retinopathy. Front Endocrinol (Lausanne) 2023, 14, 1215292. DOI: 10.3389/fendo.2023.1215292.

Orthomolecular Medicine

Orthomolecular medicine uses safe, effective nutritional therapy to fight illness. For more information: http://www.orthomolecular.org

Vitamin D as a Master Regulator of Biological Barrier Integrity: A Systems Framework Linking Vitamin D Deficiency to Systemic Leaky Barrier Syndrome - Cheng Feb 2026

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From DINOMIT to Systemic Leaky Barrier Syndrome: Vitamin D as a Master Regulator of Biological Barrier Integrity

Richard Z. Cheng, MD, PhD

Honoring the legacy of Dr. Cedric Garland while advancing a systems view of vitamin D biology

For more than two decades, Dr. Cedric Garland and colleagues profoundly shaped our understanding of vitamin D as a central determinant of cancer risk and immune health. The DINOMIT model, originally proposed by Dr. Cedric Garland and colleagues, describes a constellation of biological processes associated with vitamin D deficiency, including Dysregulated cell differentiation, Impaired immune surveillance, Neoangiogenesis, Oxidative stress, Metastasis, Inflammation, and Tumor growth. DINOMIT provided an early integrative framework linking low vitamin D status to cancer development and progression, and remains highly influential in vitamin D research[1–3].

As vitamin D research has continued to evolve, a growing body of molecular, immunological, and clinical evidence suggests that DINOMIT captured not only downstream disease manifestations, but also a deeper upstream vulnerability: the loss of biological barrier integrity across multiple organ systems.

This article explores how recent discoveries allow us to extend and integrate DINOMIT into a broader systems framework—Systemic Leaky Barrier Syndrome (SLBS)—while fully honoring Dr. Garland’s foundational insights.

DINOMIT: a prescient model ahead of its time

DINOMIT was remarkably forward-looking. It recognized that vitamin D deficiency:

Weakens immune surveillance
Promotes chronic inflammation
Facilitates malignant progression rather than merely initiation
Influences angiogenesis and metastatic behavior

Epidemiologic and mechanistic studies from Garland and collaborators demonstrated inverse relationships between serum 25-hydroxyvitamin D levels and incidence or mortality of colorectal, breast, and other cancers [1–4].

What DINOMIT did not explicitly name—but implicitly pointed toward—was the structural failure of tissue barriers that normally separate the internal environment from external insults.

At the time DINOMIT was developed, the molecular biology of tight junctions, epithelial–endothelial crosstalk, and vitamin D receptor (VDR)–mediated barrier regulation was still emerging. Today, that landscape has changed dramatically.

Vitamin D and biological barriers: what we now know

Vitamin D signaling is now recognized as a key regulator of barrier integrity across multiple systems, including:

Intestinal epithelial barrier
Vascular endothelium
Blood–brain barrier
Pulmonary epithelium
Renal filtration barrier
Cutaneous barrier

At the molecular level, vitamin D—via the vitamin D receptor (VDR)—regulates tight junction proteins such as claudins, occludin, and ZO-1, while also modulating antimicrobial peptide expression, immune tolerance, and inflammatory signaling [5–8].

Experimental and clinical studies demonstrate that vitamin D deficiency increases intestinal permeability (“leaky gut”), endothelial dysfunction, and blood–brain barrier disruption, while vitamin D repletion improves junctional integrity and reduces inflammatory leakage [6–9].

When vitamin D signaling is inadequate, barriers do not fail in isolation. Instead, multiple barriers become subtly permeable over time, allowing microbial products, inflammatory mediators, and oxidative stress to enter systemic circulation.

This creates a chronic, low-grade inflammatory state that closely mirrors—and helps explain—the downstream processes described in DINOMIT.

Systemic Leaky Barrier Syndrome (SLBS): an integrative extension of DINOMIT

Systemic Leaky Barrier Syndrome (SLBS) is not a replacement for DINOMIT.
It is best understood as a structural and systems-level extension of it.

In this framework:

Vitamin D deficiency is an upstream driver
Barrier dysfunction is the central organizing pathology
DINOMIT phenomena emerge downstream as biological consequences of chronic barrier failure

DINOMIT Component	Barrier-Level Interpretation
Inflammation	Barrier permeability enables immune overactivation
Immune dysregulation	Loss of immune tolerance at barrier interfaces
Neoangiogenesis	Endothelial stress and hypoxia signaling
Metastasis	Compromised endothelial and extracellular matrix barriers
Tumor growth	Chronic inflammatory and oxidative microenvironment

Seen this way, DINOMIT describes what happens, while SLBS helps explain why it happens systemically.

Why this matters clinically

Understanding vitamin D through a barrier-centered lens has practical implications:

1. Cancer prevention

Vitamin D sufficiency may stabilize epithelial and endothelial barriers long before malignant transformation occurs, reducing inflammatory and angiogenic signaling that supports tumor development [1–4].

2. Autoimmune and inflammatory diseases

Autoimmune conditions frequently involve barrier dysfunction (gut, brain, skin). Vitamin D’s role in maintaining immune tolerance at barrier surfaces provides a unifying explanation for its association with multiple autoimmune diseases [7–10].

3. Aging and chronic disease

Barrier permeability increases with age, contributing to systemic inflammation (“inflammaging”). Vitamin D insufficiency accelerates this process, while repletion may slow barrier degradation [8–11].

4. Beyond single-organ thinking

SLBS explains why vitamin D deficiency is associated with multiple chronic diseases rather than one isolated condition.

Honoring Dr. Garland’s legacy

Dr. Garland’s work anticipated much of what systems biology is now confirming. DINOMIT remains a landmark conceptual model—one that correctly identified vitamin D deficiency as a root biological vulnerability, not a mere association.

The SLBS framework is offered in that same spirit: to refine, integrate, and extend his insights using today’s expanded molecular and systems knowledge.

Scientific progress is cumulative. DINOMIT laid the foundation; barrier biology helps complete the architecture.

Closing thoughts

Vitamin D is not simply a nutrient, a hormone, or a cancer risk modifier. It functions as a master regulator of biological boundaries—the interfaces that determine whether health or disease emerges.

By viewing DINOMIT and Systemic Leaky Barrier Syndrome together, we gain a more complete and clinically actionable understanding of vitamin D’s central role in human health.

Author note:

A peer-review-ready version of this framework has recently been submitted to the International Journal of Molecular Sciences.

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