Vitamin D Deficiency

I don't think that we talked about this. There seems to be a connection between vitamin D and glutathione:

Aims:

25-Hydroxyvitamin D [25(OH)VD] deficiency/inadequacy is a major public health issue affecting more than 1 billion people worldwide. A convincing association exists between low levels of circulating 25(OH)VD and the poor health outcomes associated with chronic diseases. However, high supraphysiological doses of VD are needed to achieve the required 25(OH)VD levels in the blood, because many subjects respond poorly to supplementation.

Results:

This study reports a link between 25(OH)VD deficiency and a reduction in glutathione (GSH) in obese adolescents. The improvement in GSH status that results from cosupplementation with VD and l-cysteine (LC; a GSH precursor) significantly reduced oxidative stress in a mouse model of 25(OH)VD deficiency. It also positively upregulated VD regulatory genes (VDBP/VD-25-hydroxylase/VDR) in the liver and glucose metabolism genes (PGC-1α/VDR/GLUT-4) in muscle, boosted 25(OH)VD, and reduced inflammation and insulin resistance (IR) levels in the blood compared with supplementation with VD alone. In vitro GSH deficiency caused increased oxidative stress and downregulation of VDBP/VD-25-hydroxylase/VDR and upregulation of CYP24a1 in hepatocytes and downregulation of PGC-1α/VDR/GLUT-4 in myotubes. This study demonstrates that improvement in the GSH status exerts beneficial effects on the blood levels of 25(OH)VD, as well as on the inflammation and IR in a VD-deficient mouse model. Thus, the VD supplements widely consumed by the public are unlikely to be successful unless the GSH status is also corrected.

Innovation:

These studies demonstrate a previously undiscovered mechanism by which GSH status positively upregulates the bioavailability of 25(OH)VD.

Conclusion:

Supplementation with a combination of VD and LC or GSH precursor, rather than supplementation with VD alone, is beneficial and helps achieve more successful VD supplementation.

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www.nature.com

Glutathione deficiency induces epigenetic alterations of vitamin D metabolism genes in the livers of high-fat diet-fed obese mice - Scientific Reports

Obesity has been correlating with low levels of glutathione (GSH) and 25-hydroxyvitamin D3 (25(OH)VD3). The liver is the principal site for the 25(OH)VD3 biosynthesis. This study investigated whether GSH deficiency induces epigenetic alterations that impair Vitamin D (VD) metabolism genes in the...
www.nature.com www.nature.com
pubmed.ncbi.nlm.nih.gov

Effects of vitamin D and L-cysteine cosupplementation on circulating bioavailable and total 25-hydroxy-vitamin D, the free/total testosterone ratio and inflammatory biomarkers in healthy vitamin D-deficient African Americans: a placebo-controlled dou

NCT04939792.
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
neonix said:
I heard that absorption of vitamin D3 is beter when we take it with fat (from high quality food).
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Yes, that's true, but there seems to be further problems after absorption because we still have to transform cholecalciferol into active form. And it seems that things that increase glutathione, hydrogen sulfide and nitric oxide can also increase the vitamin D levels. That could perhaps explain why certain foods are good at increasing vitamin D even though they do not contain much vitamin D in themselves. Yes, eggs also contain some calcifediol, which is more potent than cholecalciferol, but even that is not much. But eggs are also good at raising glutathione so perhaps that combination is what gives strong effect.

So instead of taking high doses of vitamin D, we could perhaps take moderate dose with some amino acids which help to metabolise vitamin D (cysteine, taurine, arginine...).
 
Persej said:
So instead of taking high doses of vitamin D, we could perhaps take moderate dose with some amino acids which help to metabolise vitamin D (cysteine, taurine, arginine...).
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Apparently 10,000 IU Vit D is equivalent to 30 min of sun bathing (around noon) for lighter skins - hard to get in the winter.
 
Persej said:
So instead of taking high doses of vitamin D, we could perhaps take moderate dose with some amino acids which help to metabolise vitamin D (cysteine, taurine, arginine...).
Click to expand...
And those substances are usually in animal based products.

I find out in Poland mineral water that contains <0,01 mg/l selenium (it's called Selenka Wieniec Zdroj). But it's probably very small.
 
neonix said:
And those substances are usually in animal based products.
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Yes, but it seems that some are better than others (whey and egg white proteins are good for increasing glutathione).

neonix said:
I find out in Poland mineral water that contains <0,01 mg/l selenium (it's called Selenka Wieniec Zdroj). But it's probably very small.
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That's 10 mcg/l. Not bad if you drink it every day, but not enough for supplementation.
 
After the COVID era, barrier permeability or systemic leaky barrier syndrome is quite the thing. People who were healthy, now know what it feels to have conjonctive tissue disorders. The following also clarifies why vitamin D is crucial for those with these disorders.

Vitamin D as a Master Regulator of Biological Barrier Integrity

For more than two decades, the work of Cedric Garland and colleagues-including Frank Garland, Edward Gorham, and collaborators-has profoundly shaped our understanding of vitamin D as a central determinant of cancer risk and immune health (Garland et al., 2009).

Among these contributions, the DINOMIT model stands as a landmark conceptual framework describing a sequence of biological processes associated with vitamin D deficiency: Disjunction, Initiation, Natural selection, Overgrowth, Metastasis, Involution, and Transition.

DINOMIT was not merely descriptive-it was prescient. It recognized early that disruption of intercellular adhesion and tissue integrity represents a foundational step in disease progression.

As vitamin D research has advanced, accumulating 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 proposes that DINOMIT can be further understood and extended within a broader systems framework: Systemic Leaky Barrier Syndrome (SLBS), a systems-level model describing the role of barrier dysfunction in chronic disease development (Cheng, 2026a).

DINOMIT: A Model Ahead of Its Time​

DINOMIT recognized that vitamin D deficiency contributes to:

  • Loss of intercellular adhesion
  • Selection of aggressive cellular phenotypes
  • Enhanced angiogenesis
  • Tissue invasion and metastasis
These insights were supported by epidemiologic observations linking low serum 25-hydroxyvitamin D levels with increased risk of multiple cancers (Garland et al., 1980; Garland et al., 1985; Garland et al., 1989), and by mechanistic studies on cellular differentiation and junctional biology (Pálmer et al., 2001; Farquhar and Palade, 1963).

At the time the model was proposed, the molecular understanding of epithelial barriers, tight junctions, and vitamin D receptor signaling was still emerging. Today, these mechanisms are far better characterized-and they strongly support the biological plausibility of DINOMIT.

Vitamin D and Biological Barrier Integrity​

Vitamin D is now recognized as a key regulator of barrier function across multiple systems, including intestinal epithelium, vascular endothelium, blood-brain barrier, pulmonary epithelium, renal filtration barrier, and skin.

Through vitamin D receptor-mediated signaling, vitamin D regulates tight junction proteins such as claudins, occludin, and ZO-1, while also modulating antimicrobial peptides, immune tolerance, and inflammatory pathways (Chun et al., 2014; Hewison, 2012; Cheng, 2026b).

Vitamin D deficiency has been associated with increased intestinal permeability ("leaky gut"), endothelial dysfunction, and disruption of the blood-brain barrier (Assa et al., 2014; Garcion et al., 2002; Talmor-Barkan et al., 2021). Conversely, vitamin D repletion has been shown to improve junctional integrity and reduce inflammatory leakage.

Importantly, barrier dysfunction does not occur in isolation. Multiple barriers may become progressively permeable, allowing microbial products, inflammatory mediators, and oxidative stress signals to enter systemic circulation, contributing to chronic low-grade inflammation.

Systemic Leaky Barrier Syndrome (SLBS): A Systems-Level Extension​

Systemic Leaky Barrier Syndrome (SLBS) is not a replacement for DINOMIT, but an extension of it, grounded in systems-level models of barrier dysfunction in chronic disease (Cheng, 2026a).

Within this framework:

  • Vitamin D deficiency acts as an upstream driver
  • Barrier dysfunction becomes the central organizing pathology
  • DINOMIT processes emerge downstream as biological consequences
In this sense, DINOMIT describes what happens, while SLBS helps explain why it happens systemically.

Broader Disease Implications​

The barrier-centered model provides a unifying framework across multiple conditions.

In cancer, vitamin D sufficiency may help stabilize epithelial and endothelial barriers, reducing inflammatory and angiogenic signaling that support tumor development.

In autoimmune and inflammatory diseases, barrier dysfunction is increasingly recognized as a common underlying feature. Vitamin D plays an important role in maintaining immune tolerance at barrier interfaces (Aranow, 2011).

In Type 1 diabetes, epidemiologic and mechanistic models suggest that vitamin D deficiency may contribute to disease risk through barrier dysfunction and immune dysregulation (Mohr et al., 2008).

In aging, increased barrier permeability contributes to chronic inflammation. Vitamin D insufficiency may accelerate this process.

Clinical and Research Implications​

A barrier-centered understanding of vitamin D suggests:

  • A shift from single-organ to systems-level thinking
  • Recognition of variability in clinical response to vitamin D
  • Greater emphasis on maintaining sufficient serum 25-hydroxyvitamin D levels
  • Consideration of nutrient interactions and overall metabolic context
Population-level evidence suggests that maintaining serum 25-hydroxyvitamin D concentrations at or above 50 ng/mL may be associated with reduced risks of cancer and chronic disease (Lappe et al., 2017; McDonnell et al., 2018).

Honoring a Scientific Legacy​

The contributions of Cedric Garland and colleagues laid the conceptual foundation for understanding vitamin D as a root determinant of disease, rather than a secondary association.

The SLBS framework is offered in that same spirit: to refine and extend these insights using contemporary systems biology.

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