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 proposedsystems-level framework — not a formal medical diagnosis —introduced by Richard Z. Cheng, MD, PhD, Editor-in-Chief of theOrthomolecular Medicine News Service. In a 2026 preprint and companionarticles, Cheng defines SLBS as a state of multi-barrier dysfunctionin which epithelial, endothelial, and immune interfaces across multipleorgan systems simultaneously lose integrity.[1][2]
SLBS posits that chronic diseases commonly treated as separate entities— cardiovascular disease, neurodegeneration, autoimmunity, metabolicsyndrome, 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 foundationalrequirements such as intact structural proteins, adequate cellularenergy, balanced redox signaling, and ongoing micronutrient availabilityare chronically compromised, barriers lose the ability to fullyrepair.[1]
Vitamin D as a "Master Regulator" of Barrier Integrity
Cheng's invited review article submitted to the International Journalof Molecular Sciences (IJMS), titled "Vitamin D as a Master Regulatorof Biological Barrier Integrity," explicitly positions vitamin Ddeficiency as a central driver of SLBS. The paper argues that vitamin Dis not merely a nutrient but a regulatory node governing barriergene expression and immune tone across multiple tissuesystems.[3][2]
This framing builds on a substantial body of peer-reviewed researchdemonstrating that vitamin D and the vitamin D receptor (VDR) regulatebarrier 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 theintestinal epithelial barrier. Vitamin D/VDR signaling maintains tightjunction integrity by modulating key tight junction proteins includingclaudin-1, claudin-2, claudin-3, occludin, and zonula occludin-1(ZO-1). An optimal vitamin D level promotes the stability of tightjunctions — the cell-to-cell connections that prevent harmful substancesfrom crossing the intestinal wall into thebloodstream.[5][6][7][8]
In experimental models, vitamin D-deficient mice challenged withintestinal infection showed significantly increased colonicpermeability and epithelial barrier dysfunction compared to vitaminD-sufficient animals. Additionally, vitamin D deficiency resulted inaltered gut microbiome composition, further compounding barrierdysfunction. Vitamin D supplementation has been shown to attenuatebacterial translocation and reduce intestinal permeability in animalmodels of liver cirrhosis.[9][10]
Blood-Brain Barrier
Vitamin D has a direct, VDR-mediated protective effect againstblood-brain barrier (BBB) dysfunction. In a mouse brain endothelial cellmodel, 1,25(OH)₂D₃ treatment prevented the decrease in barrier functionafter hypoxic injury, preserved expression of tight junction proteins(ZO-1, claudin-5, occludin), blocked NF-κB activation, and reducedmatrix metalloproteinase-9 expression. Studies confirm that vitamin Dcan prevent leaky brain by reducing inflammation and reducing BBBdisruption.[11][12]
Skin Barrier
Vitamin D and VDR regulate the processing of long-chainglycosylceramides critical for skin barrier formation. Mice lacking VDRor 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 forproper epidermal differentiation and barrier integrity.[13]
Vascular Endothelial Barrier
The SLBS framework positions endothelial dysfunction as a vascularmanifestation of systemic barrier failure. Vitamin D deficiency has longbeen associated with systemic autoimmune diseases, and emerging researchhighlights vitamin D's role in maintaining vascular endothelialintegrity through its anti-inflammatory and immunomodulatoryeffects.[14][1]
Pulmonary and Renal Barriers
Zhang et al. (2013) in Tissue Barriers reviewed the potentialtherapeutic functions of vitamin D in treating defective tissue barriersinvolving the lungs, kidneys, and other organs, noting that VDRsignaling and its associated intracellular junction proteins (β-catenin,claudins) are critical for barrier maintenance across thesetissues.[4]
The SLBS–Vitamin D Connection:(table)
The relationship between SLBS and low vitamin D operates at multiplelevels:
| Barrier System | Vitamin D Role | Consequence of Deficiency |
| Intestinal | Maintains tight junctions (claudins, occludin, ZO-1); modulatesmicrobiome | Increased permeability, bacterial translocation, immune activation[5][9] |
| Blood-Brain | Preserves BBB tight junction proteins; suppresses NF-κB andMMP-9 | BBB disruption, neuroinflammation [11] |
| Skin | Regulates glycosylceramide processing, keratinocytedifferentiation | 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 asystemic destabilizer — when vitamin D levels are chronically low,barriers across multiple organ systems simultaneously become vulnerableto 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 medicaldiagnosis. The concept was first formally proposed in a 2026 preprint byCheng, and the companion review article on vitamin D's role is currentlyunder peer review at IJMS. While the individual components — vitamin D'sregulation of intestinal, blood-brain, skin, and vascular barriers — aresupported by a robust body of peer-reviewed literature, the unificationof these findings under a single "syndrome" label is new and has not yetundergone broad scientific validation.[2][5][9][11][4]
That said, the underlying science is well-established: vitamin Ddeficiency is associated with autoimmune disease, increased intestinalpermeability, blood-brain barrier disruption, and impaired skin barrierfunction. The SLBS framework essentially synthesizes these findings intoa systems-level model, arguing that low vitamin D is one of the keyupstream drivers of multi-organ barrier failure.[14][9][13][11]
References
SLBS as a Common Pathway to ChronicDisease -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-levelvulnerability 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: ASystems Framework Linking Vitamin...
Vitamin D, vitamin D receptor and tissuebarriers - Wealso discuss the potential therapeutic functions of vitamin D intreating defective tissue barrie...
Mucosal vitamin D signaling in inflammatory boweldisease -Vitamin D signaling modulates the intestinal microbiome and immunefunctions. Intestinal barrier int...
Leaky Gut and vitamins - SIBOAcademy -Learn here how vitamins such as vitamin D and A can strengthen theintestinal barrier and reduce inf...
Tight junction CLDN2 gene is a direct target of the vitamin Dreceptor - Recentevidence suggests that vitamin D and its receptor VDR may regulateintestinal barrier functio...
Vitamin D/vitamin D receptor protects intestinal barrier againstcolitis... -Overexpression of vitamin D receptor in intestinal epitheliaprotects against colitis via upregulati...
Vitamin D Deficiency Promotes Epithelial Barrier Dysfunction and... - Thepresent study showed that an increase in intestinal paracellularpermeability was further enhanc...
Vitamin D Receptor Influences Intestinal Barriers in Health and... - Vitamin D3treatment significantly attenuated bacterial translocation andreduced intestinal permeab...
Vitamin D Prevents Hypoxia/Reoxygenation-Induced Blood-Brain... -Our findings show a direct, VDR-mediated, protective effect of1,25(OH) ) 2 D 3 against ischemic inj...
Nutrients to help repair your blood-brainbarrier -Vitamin D is a powerful tool in managing inflammation andautoimmunity. Every tissue in your body ha...
Vitamin D and the skin: Focus on a complexrelationship -... Vitamin D receptor and coactivators SRC 2 and 3 regulateepidermis-specific sphingolipid product...
Relationships Between Vitamin D, Gut Microbiome, and Systemic... -Vitamin D deficiency has long been associated with systemicautoimmune disease and is suspected to p...
Vitamin D and intestinal homeostasis: Barrier, microbiota,... - Vitamin D ensuresan appropriate level of antimicrobial peptides in the mucus andmaintains epitheli...
A Systems-Level Framework for Chronic Disease - Feb 2026
by Richard Z. Cheng, MD, PhD
Editor-in-Chief, OrthomolecularMedicine News Service (OMNS)
Over the past two decades, biomedical research has increasinglydocumented the loss of barrier integrity across multiple organ systemsin chronic disease. Intestinal permeability ("leaky gut"), blood-brainbarrier disruption, endothelial dysfunction, alveolar-capillary leakage,renal filtration injury, and skin barrier defects have typically beenstudied in isolation, within separate clinical and disciplinarysilos.
In a recent preprint [1],Systemic Leaky Barrier Syndrome (SLBS): A Systems-Level Frameworkfor Chronic Disease (Cheng, 2026), I proposed the termSystemic Leaky Barrier Syndrome (SLBS) as a unifyingsystems-level framework to integrate these observations across chronicdisease.
SLBS describes a condition in which multiple biological barriers -intestinal, vascular, blood-brain, pulmonary, renal, hepatic, placental,and cutaneous - progressively lose structural and functional integritydue to shared upstream drivers. These include environmental toxins,chronic inflammation, oxidative and redox imbalance, micronutrientinsufficiency, mitochondrial dysfunction, and impaired tissue repaircapacity.
Across organ systems, barrier integrity depends on common structuraland 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, barrierresilience declines across multiple tissues simultaneously.
SLBS and ProgressiveChronic Disease
This framework reframes chronic disease not as isolated organfailure, but as a systemic failure of barrier integrity and repair.
For example:
Chronic Kidney Disease
The kidney's filtration barrier depends on intact glomerularendothelium, basement membrane integrity, and podocyte structure. Whenredox imbalance, inflammation, and metabolic stress persist, filtrationselectivity deteriorates. Albumin leakage and progressive nephron injuryfollow. What appears clinically as "renal failure" may reflectlong-standing structural and oxidative compromise of the renal barriersystem.
Hypertension
The vascular endothelium functions as a dynamic permeability andsignaling barrier. Endothelial dysfunction - characterized by impairednitric oxide signaling, increased permeability, oxidative stress, andinflammatory activation - precedes and drives sustained vascularstiffness and pressure dysregulation. High blood pressure, in thiscontext, reflects loss of endothelial boundary regulation and structuralvascular resilience.
Neuroinflammatory Disorders
Blood-brain barrier compromise permits peripheral inflammatorymediators and immune cells to enter neural tissue, amplifying oxidativestress and microglial activation.
Across these conditions, barrier breakdown functions both as aninitiating factor and as a powerful amplifier of immune activation,inflammatory signaling, metabolic dysregulation, and iron-drivenoxidative injury. Excess iron can cause ferroptosis and retinopathyleading to blindness [2]. Aself-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 biologicallyneutral.
Healthy tissues maintain strict structural and functionalboundaries:
- Epithelial layers maintain polarity and controlledproliferation
- 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 - throughinflammation, oxidative stress, micronutrient depletion, and impairedrepair - 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 morelikely to survive, expand, invade, and eventually metastasize.
From a systems perspective, cancer progression can therefore beviewed as occurring in the context of advanced barrier and regulatoryfailure - not merely as an isolated genetic event. Barrier breakdowndoes not "cause" cancer in a simplistic sense. Rather, it createsconditions that lower structural and metabolic constraints on malignantprogression.
This interpretation aligns cancer with other progressive chronicdiseases within a shared upstream terrain of redox imbalance, structuraldegradation, and impaired repair capacity.
Clinical Implications
Importantly, SLBS does not replace disease-specific diagnosis ortreatment. It complements conventional approaches by shifting attentionupstream - toward:
- Barrier-centric biomarkers
- Structural resilience
- Redox balance
- Micronutrient sufficiency
- Mitochondrial energy support
- Inflammation control
Rather than waiting for organ-specific failure, earlier interventionaimed at preserving barrier integrity may help prevent multi-systemprogression.
A Systems-Level Construct
As with other systems-level constructs in medicine, SLBS is offeredas a conceptual framework intended to stimulate research, refineclinical thinking, and encourage preventive intervention. Further workwill 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. SLBSprovides a modern systems framework that unifies these principles acrossbiological barriers and chronic disease states.
References:
1. Cheng, R.Z. Systemic Leaky Barrier Syndrome (SLBS): ASystems-Level Framework for Chronic Disease. 2026. DOI:
2. Li, L.; Dai, Y.; Ke, D.; et al. Ferroptosis: New Insight into theMechanisms of Diabetic Nephropathy and Retinopathy. Front Endocrinol(Lausanne) 2023, 14, 1215292. DOI:
Orthomolecular Medicine
Orthomolecular medicine uses safe, effective nutritional therapy tofight illness. For more information:
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
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 systemsview of vitamin D biology
For more than two decades, Dr. Cedric Garland and colleaguesprofoundly shaped our understanding of vitamin D as a centraldeterminant of cancer risk and immune health. The DINOMIT model,originally proposed by Dr. Cedric Garland and colleagues, describes aconstellation of biological processes associated with vitamin Ddeficiency, including Dysregulated cell differentiation,Impaired immune surveillance, Neoangiogenesis, Oxidativestress, Metastasis, Inflammation, and Tumor growth. DINOMITprovided an early integrative framework linking low vitamin D status tocancer development and progression, and remains highly influential invitamin D research[1–3].
As vitamin D research has continued to evolve, a growing body ofmolecular, immunological, and clinical evidence suggests that DINOMITcaptured not only downstream disease manifestations, but also a deeperupstream vulnerability: the loss of biological barrier integrityacross multiple organ systems.
This article explores how recent discoveries allow us to extend andintegrate DINOMIT into a broader systems framework—Systemic LeakyBarrier Syndrome (SLBS)—while fully honoring Dr. Garland’sfoundational insights.
DINOMIT: a prescient model ahead of its time
DINOMIT was remarkably forward-looking. It recognized that vitamin Ddeficiency:
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 collaboratorsdemonstrated inverse relationships between serum 25-hydroxyvitamin Dlevels and incidence or mortality of colorectal, breast, and othercancers [1–4].
What DINOMIT did not explicitly name—but implicitly pointed toward—wasthe structural failure of tissue barriers that normally separate theinternal environment from external insults.
At the time DINOMIT was developed, the molecular biology of tightjunctions, epithelial–endothelial crosstalk, and vitamin D receptor(VDR)–mediated barrier regulation was still emerging. Today, thatlandscape has changed dramatically.
Vitamin D and biological barriers: what we now know
Vitamin D signaling is now recognized as a key regulator of barrierintegrity 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 deficiencyincreases intestinal permeability (“leaky gut”), endothelialdysfunction, and blood–brain barrier disruption, while vitamin Drepletion improves junctional integrity and reduces inflammatory leakage[6–9].
When vitamin D signaling is inadequate, barriers do not fail inisolation. Instead, multiple barriers become subtly permeable overtime, allowing microbial products, inflammatory mediators, and oxidativestress to enter systemic circulation.
This creates a chronic, low-grade inflammatory state that closelymirrors—and helps explain—the downstream processes described in DINOMIT.
Systemic Leaky Barrier Syndrome (SLBS): an integrative extension ofDINOMIT
Systemic Leaky Barrier Syndrome (SLBS) is not a replacement forDINOMIT.
It is best understood as a structural and systems-level extension ofit.
In this framework:
Vitamin D deficiency is an upstream driver
Barrier dysfunction is the central organizing pathology
DINOMIT phenomena emerge downstream as biological consequences ofchronic 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 helpsexplain why it happens systemically.
Why this matters clinically
Understanding vitamin D through a barrier-centered lens haspractical implications:
1. Cancer prevention
Vitamin D sufficiency may stabilize epithelial and endothelial barrierslong before malignant transformation occurs, reducing inflammatory andangiogenic 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 atbarrier surfaces provides a unifying explanation for its associationwith multiple autoimmune diseases [7–10].
3. Aging and chronic disease
Barrier permeability increases with age, contributing to systemicinflammation (“inflammaging”). Vitamin D insufficiency accelerates thisprocess, while repletion may slow barrier degradation [8–11].
4. Beyond single-organ thinking
SLBS explains why vitamin D deficiency is associated with multiplechronic diseases rather than one isolated condition.
Honoring Dr. Garland’s legacy
Dr. Garland’s work anticipated much of what systems biology is nowconfirming. DINOMIT remains a landmark conceptual model—one thatcorrectly identified vitamin D deficiency as a root biologicalvulnerability, 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 systemsknowledge.
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 riskmodifier. It functions as a master regulator of biologicalboundaries—the interfaces that determine whether health or diseaseemerges.
By viewing DINOMIT and Systemic Leaky Barrier Syndrome together, we gaina more complete and clinically actionable understanding of vitamin D’scentral role in human health.
Author note:
A peer-review-ready version of this framework has recently beensubmitted to the International Journal of Molecular Sciences.
Key References (selected)
Garland CF, Garland FC.
Do sunlight and vitamin D reduce the likelihood of coloncancer?
Int J Epidemiol. 1980.
https://academic.oup.com/ije/article/9/3/227/695873Garland CF, Gorham ED, Mohr SB, Grant WB.
Vitamin D for cancer prevention: global perspective.
Ann Epidemiol. 2009.
https://www.sciencedirect.com/science/article/pii/S1047279709000559Gorham ED, Garland CF, Garland FC, et al.
Vitamin D and prevention of colorectal cancer.
J Steroid Biochem Mol Biol. 2005.
https://pubmed.ncbi.nlm.nih.gov/15985326/Grant WB, Garland CF.
The role of vitamin D3 in preventing infections and reducingcancer risk.
Nutrients. 2022.
https://www.mdpi.com/2072-6643/14/4/779Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M.
Impact of vitamin D on immune function.
Nutrients. 2014.
https://www.mdpi.com/2072-6643/6/2/250Assa A, et al.
Vitamin D deficiency promotes epithelial barrier dysfunction.
Gut. 2014.
https://gut.bmj.com/content/63/4/588Hewison M.
Vitamin D and immune function: autocrine, paracrine,endocrine.
J Endocrinol. 2012.
https://joe.bioscientifica.com/view/journals/joe/215/2/225.xmlTalmor-Barkan Y, et al.
Vitamin D and endothelial function.
J Steroid Biochem Mol Biol. 2021.
https://pubmed.ncbi.nlm.nih.gov/33647312/Garcion E, et al.
Vitamin D and blood–brain barrier integrity.
Trends Endocrinol Metab. 2002.
https://pubmed.ncbi.nlm.nih.gov/12128284/Aranow C.
Vitamin D and the immune system.
J Investig Med. 2011.
https://pubmed.ncbi.nlm.nih.gov/21527855/Cheng RZ.
Vitamin D as a Master Regulator of Biological BarrierIntegrity.
Preprints 2026.
https://doi.org/10.20944/preprints202602.0694.v1
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