Vitamin D in chronic inflammatory and autoimmune diseases. Reconciling contraditory literature

[frozenborderline]

Someone on the ray peat forum with a biochem background was pointing out that, contra to ray's claims, Vitamin D actually seems to lower metabolism, I think when measured by thermogenesis or something?

there are definitely some studies that show low vitamin D as a common factor in fatigue and pain but it's probably complicated.

Vitamins are rarely drug like in terms of having a very straightforward, linear action, they could have very different actions depending on other pathways, other cofactors, or whether or not they are lacked.

It seems unlikely to me that sunlight would broadly be bad for people. But sunlight at certain times of the day also has red light, which can stimulate cytochrome c oxidase and have a variety of protective effects. It seems like the red light and the UV light could work in conjunction

It's possible that vitamin D serves as some kind of necessary rate limiter on metabolism increase--to keep people from overheating in the sun. The difference between some kind of rate limiting might be why mitochondrial uncouplers like caffeine, aspirin, and thyroid (at the right dose) are not very dangerous, whereas DNP, which is also a mitochondrial uncoupler, is very dangerous

 

[pamojja]

By the way, this theory is not totally unproven. It is actually supported by direct interventional studies (with a VDR agonist) , as well as by indirect studies, which demonstrate parts of the puzzle conforming this theory.

Thanks. Could you directly point us to the interventional study, so we could take a look at it?

With indirect studies you probably meant in-vitro?

 

[uglevod]

@pamojja there is some data from the latest prof. Trevor Marshall presentation:

Abstract:
VITAMIN D - WHY DOES IT 'WORK' SO WELL?
A decade ago I wrote that the various forms of Vitamin D were not 'vitamins', but a secosteroid hormone and its precursors. I showed how every human cell makes the 'Vitamin D' it needs to transcribe genes without any of the precursors being present in the diet. Nobody has refuted my analysis, yet Medicine seems to have paid little attention.

There is still active debate over whether I was correct in warning about long-term deleterious actions of 'Vitamin D' in the human body. The consensus in the short-term is quite clear - most people find that taking high-dose 'Vitamin D' (the steroid precursor) makes them feel better.

I do not disagree, indeed, there is a good reason why 'Vitamin D' 'works' so well in the short-term, 1-10 years, timeframe. That reason is embodied in the statistic that 60% of US adults are taking a drug for at least one diagnosed chronic disease, and that 12.5% have 5 or more diagnoses. Any drug which modulates the symptoms of chronic disease is therefore going to affect a very large proportion of the population, and the Vitamin D precursors do just that. Supplementing with a precursor suppresses the patient's innate immune response - just as cortisone or prednisone would do, but less aggressively, with fewer short-term side-effects.

For nearly 16 years I have been observing a cohort of hundreds of elderly folk with chronic immune diseases who have chosen to avoid dietary sources of 'vitamin-D.' Their measured blood 25-D levels are routinely below 12ng/ml, below the level usually considered 'severely deficient'. Why hasn't this made their bones weak, and their chronic condition worse?

Is it perhaps because every human cell makes all the active Vitamin D it needs to transcribe DNA without any of the precursors being present in the diet, just as we have described?

We will revisit how the vitamins-D affect the human body, and discuss some of the options available to help mitigate chronic symptom surges

Co-authors
T. Marshall (Autoimmunity Research Foundation, Predictive and Preventative Medicine, Thousand Oaks, USA)

 

[pamojja]

For nearly 16 years I have been observing a cohort of hundreds of elderly folk with chronic immune diseases who have chosen to avoid dietary sources of 'vitamin-D.' Their measured blood 25-D levels are routinely below 12ng/ml, below the level usually considered 'severely deficient'.

Observational data 'of hundreds of elderly folk' isn't even an interventional study. Not to talk about a randomized one. Completely useless to support the hypothesis.

Co-authors
T. Marshall

Countless personal experiences, good and bad, in the endless comments of this blog-post:

http://www.cureality.com/blog/post/2008/03/31/the-marshall-protocol-and-other-fairy-tales.html

 

[uglevod]

@serg1942, thank you for putting the paper.

Maybe you'd be interested in updating your data with the additional info on EBV:

https://www.ncbi.nlm.nih.gov/pubmed/28731372
High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.

https://www.ncbi.nlm.nih.gov/pubmed/27325604
The mean 25(OH)D level more than doubled in the vitamin D group and was significantly higher than in the placebo group at study conclusion (123.2 versus 61.8 nmol/L, p < 0.001). Compared to the placebo group, both anti-EBNA1 protein and fragment antibody levels decreased in the vitamin D group from baseline to week 48 ( p = 0.038 and p = 0.004, respectively), but not from baseline to week 96. Vitamin D3 supplementation did not affect antibodies against VCA, CMV or VZV.
CONCLUSION:
The results indicate that high-dose oral vitamin D3 supplementation can affect humoral immune responses against the latent EBV antigen EBNA1 in RRMS.

Is vitamin D immuno suppressive or immune modulatory? I've always wondered this because sometimes vitamin D supplementation objectively increases my immune activity while at other times it seems to lower it.

Hard to say really. I personally believe that very low doses of D3 can be immune stimulative, especially if your base level of D25 is low enough(<20ng/ml). Whether it ultimately helps to reverse chronic condition like CFS on not is an open question.

High dosages seem to be immunosuppressive though(Figure 3), at least when it comes to stimulation of TLR receptors with bacterial products(like endotoxin aka LPS):
https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-176
We have also demonstrated a marked reduction in the induced cytokine profile, specifically IL6, TNF and IFN alpha associated with higher vitamin D levels and the reversibility of the innate immune profile with decreasing levels. There are multiple implications for this, including the potential role for vitamin D to dampen down the innate immune system in autoimmune conditions. In addition, there may be a role for vitamin D as a modulator of immune response to vaccines.

 

[uglevod]

I think about how sunlight is inhibitory to things like skin conditions. A lot of people experience improvements in psoriasis and eczema from UV exposure.

Yeah, another very interesting topic!

Here is what I've found:

An action spectrum for ultraviolet radiation-induced immunosuppression in humans:
https://www.ncbi.nlm.nih.gov/pubmed/21375518

Exposure to UV Wavelengths in Sunlight Suppresses Immunity. To What Extent is UV-induced Vitamin D3 the Mediator Responsible?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626364/

 

[pamojja]

A lot of people experience improvements in psoriasis and eczema from UV exposure.

Yeah, another very interesting topic!

Personally got rid of infrequent psoriasis outbreaks (for 20 years) after recently reaching above 20.000 IU vitamin A after years of slowly titrating it up.

PS: which also coincided with sun-shine starting to substantially contributing to my 25(OH)D levels.

 

[Stretched]

See my post above re dosage... . I also got rid of a lifetime of psoriasis on my knees and elbows.

 

[serg1942]

Thanks. Could you directly point us to the interventional study, so we could take a look at it?

With indirect studies you probably meant in-vitro?

Hi pamojja, there are just "case-reports and series" studies, which is equivalent to level of evidence "C", I suppose (i.e., expert's opinions).:
https://www.chronicillnessrecovery.org/images/stories/Book_Chapter_on_vitmain_D.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076734/#!po=32.1705

As for the indirect evidence, there's plenty of it, part of which you can find in my article; and no, most evidence I mean is in vivo. For example, there are studies showing low cathelicidin levels in some autoimmune conditions.Obviously, if you take vitamin D is because you want to form the anti-microbial peptides (cathelicidins, beta-defensins, etc.). If they are low, then the theory must be correct in that the VDR is not been stimulated by taking vitamin D, or by having high 1,25-dihydroxycholecalciferol levels, as usually occurs in chronic inflammatory diseases (this has been shown in several studies as well).

You can also find lots of studies showing low levels of 25-hydroxyvitamin D, and some studies showing high 1,25-dihydroxycholecalciferol, what also validates the theory.

Finally, you can find that many pathogens down-regulates the VDR in order to survive (including EBV or Borrelia B.), what further validates the theory.

Let me make clear that I am not defending the Marshall's treatment approach, based on this theory. On the other hand, I just said that this theory was not unproven , but "partially proven". So, of course, there are not randomized controlled clinical trials validating this theory. If this was the case, it wouldn't be a theory anymore, and I would not have done the compilation of evidence I carried out. The only thing I wanted to do is to form my own opinion on whether vitamin D supplementation could be dangerous for ME/CFS or for chronic Lyme disease.

I hope this helps,
Sergio

 

[serg1942]

Hard to say really. I personally believe that very low doses of D3 can be immune stimulative, especially if your base level of D25 is low enough(<20ng/ml).

Hi @uglevod , thanks for your input! Well, Actually, I had already cited in my article some studies showing that vitamin D supplementation lowers antibodies and auto-antibodies production. So, it is not surprising that anti-EBV antibodies production are decreased by vitamin D.

The first study you post, however, also states:

"Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism."
(https://www.ncbi.nlm.nih.gov/pubmed/28731372)

What might implicate that you are just down-regulating the immune system, but you are not forming a proper immune response against persistent pathogens. In other words, this would be similar to take a corticosteroid, which also lowers autoantibody levels.

It is interesting that, as I show in my article, a paper found that the EBV was reactivated only when levels of 25-hydroxivitamin D was higher than 75 nm/L, and that these higher levels of 25-hydroxivitamin D were associated with a 2 to 4-fold increased risk of pregnancy-associated breast cancer:
(https://www.ncbi.nlm.nih.gov/pubmed/20691583)

Thing is that, as we know, the physiological role of vitamin D is to boost the innate system, mainly by forming anti-microbial peptides through VDR activation. Well, it seems that this mechanism is haltered in chronic inflammatory conditions, and that vitamin D supplementation seems to make it worse, meaning that it does not promote the formation of this peptides, but instead, it further impedes their formation… (this is at least my layman’s opinion after making a comprehensive review on the subject, which coincides with the opinion of some authors defending the so called "alternate theory").

As for what happens when we have very low levels of 25-hydroxivitamin D, well, thing is that this seems to be a consequence of inflammation, and normally these low levels of the inactive form of the hormone are found together with high levels of 1,25 dihydroxyvitamin D…So if you take vitamin D3, you won’t be activating the VDR. Actually, it seems that you might be displacing the ligands from the thyroid-α1 receptor, the adrenal receptor, and the glucocorticoid receptor with vitamin D3 supplementation, and these receptors are (aside from their usual role) also necessary to express anti-microbial peptides. (Of course you could be causing adrenal insufficiency and hypothyroidism as well).

Thanks again for your inputs!
Sergio

 

[pamojja]

Hi pamojja, there are just "case-reports and series" studies, which is equivalent to level of evidence "C", I suppose (i.e., expert's opinions).:
https://www.chronicillnessrecovery.org/images/stories/Book_Chapter_on_vitmain_D.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076734/#!po=32.1705

Thanks. Sadly all confirms they looked at vitamin D within the pharmacological model, and seem completely unaware that nutrients in general need co-dependent other nutrients to function properly.

As for what happens when we have very low levels of 25-hydroxivitamin D, well, thing is that this seems to be a consequence of inflammation, and normally these low levels of the inactive form of the hormone are found together with high levels of 1,25 dihydroxyvitamin D…So if you take vitamin D3, you won’t be activating the VDR.

I would want to remind you of your other thread, where you asked for experiences with high 1,25 and supplementation. And where we found just one case where increased vitamin D intake plus co-factor nutrients brought 1,25 down.

 

[uglevod]

Hi @uglevod , thanks for your input! Well, Actually, I had already cited in my article some studies showing that vitamin D supplementation lowers antibodies and auto-antibodies production. So, it is not surprising that anti-EBV antibodies production are decreased by vitamin D.

Can it be something to do with antigen presentation via Dendritic Cells?

Levels of D25 are known to prevent their maturation:

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009193
Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586578/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913286/
https://www.ncbi.nlm.nih.gov/pubmed/26402698

Effect of vitamin D3 on maturation and antigen-presenting function of dendritic cells treated with Mycobacterium tuberculosis
https://www.sciencedirect.com/science/article/pii/S1995764515002321
To investigate the phenotypic characteristics and functional capability differences of mouse bone marrow-
derived dendritic cells after stimulation with Mycobacterium tuberculosis in the presence or absence of vitamin D3.
...
These findings suggest that 25(OH)D3 modulates the immune response by affecting the maturation and function of DCs in Mycobacterium tuberculosis period.
...
Inhibited antigen presenting function of DCs by 25(OH)D3
...
Compared with group 25(OH)D3, the DCs of the control group significantly improved the multiplication level of CD4+ T cells
...
The data of the study showed that 25(OH)D3 deceased the expressions of MHC-II and CD86. There were researches showing that the decreases of MHC-II and CD86 were common features of functional damages of DCs in all kinds of 25(OH)D3 models [24]. This study data also manifested that 25(OH)D3 could not only inhibit DCs from maturity, but also weaken its antigen-presenting capacity.
...
In conclusion, it is found in this study that 100 nmol/L of 25(OH)D3 decreases the expressions of DCs’ superficial co-stimulatory molecules MHC-II and CD86 so as to weaken the antigen-presenting capacity of DCs and inhibit the T cells from proliferation.

Dendritic cells for the induction of EBV immunity:
https://www.ncbi.nlm.nih.gov/pubmed/11785842

Oral vitamin D3 supplementation reduces monocyte-derived dendritic cell maturation and cytokine production in Crohn’s disease patients
https://www.researchgate.net/public...tokine_production_in_Crohn's_disease_patients

 

[pibee]

Just stay away from high doses like Coimbra protocol. It damaged me severely. First helped a lot and I felt in many ways best in long time, probably works like steroids, so I ignored small worsenings at the beginning. Later it got severe (mostly intellectual decline because of lowered energy in brain ) and first time I got classical ME symptoms. Got autistic feel in head

Thankfully I managed to reverse it but not fully at all (yet!!!)

 

[Chiron]

Personally got rid of infrequent psoriasis outbreaks (for 20 years) after recently reaching above 20.000 IU vitamin A after years of slowly titrating it up.

PS: which also coincided with sun-shine starting to substantially contributing to my 25(OH)D levels.

Can you tell me what you're using to achieve a dose of 20,000IU vitamin A? I've always wanted to try vitamin A at higher levels but I'm not really into eating liver, and the amount of cod liver oil you'd have to consume to reach those levels is pretty ridiculous. I'm particularly interested in retinol, which comes from animal sources.

 

[pamojja]

Can you tell me what you're using to achieve a dose of 20,000IU vitamin A? I've always wanted to try vitamin A at higher levels but I'm not really into eating liver, and the amount of cod liver oil you'd have to consume to reach those levels is pretty ridiculous. I'm particularly interested in retinol, which comes from animal sources.

In Europe there is very limited availability of high dose vitamin A products. Swanson Europe does however carry 10.000 IU softgels, and these are what I've been using. Before I used occasional cod liver in cans, which contain about 50.000 IU per 100 g can. But since I've found swanson's I lost my taste for cod liver.

 

[uglevod]

Here they found a direct anti inflammatory effect of even a small dosing of Vitamin D(1000 units/day):

Effects of isolated vitamin D supplementation on the immune-inflammatory biomarkers in younger postmenopausal women: a randomized, double-blind, placebo-controlled trial
https://www.ncbi.nlm.nih.gov/pubmed/29738417
...After 9 months, there was a significant increase in the 25(OH)D levels from 15.0±7.5 to 27.5±10.4 ng/ml in the VD group and decreased from 16.9±6.7 to 13.8±6.0 ng/ml in the placebo group(p<.001). The VD group showed significant decrease in IL-5, IL-12 p70, IL-17 alpha, TNF-alpha and IFN-gamma values (p<0.05). The levels of IL-5 and IL-6 in the VD group were significantly lower compared to the placebo group (p<0.05). There were no significant intervention effects on serum levels of IL-1? and IL-10 in both groups (p>0.05).
Conclusions: In younger postmenopausal women, isolated supplementation with 1,000IU of vitamin D3 for 9 months was associated with a reduction in pro-inflammatory biomarkers.

....

Enter any chronic infection name into google(lyme, toxoplasma, Cpn, etc) together with TNF-alpha(pro inflammatory cytokine) and it will be written that TNF-alpha is always raised as a consequence(IFN-gamma too).