So there's this:
https://chronicillnessrecovery.org/i...article&id=223

I'm wondering what people think of it, and whether anyone knows about this concern. This is the actual study I want to read, but can't find it online: http://www.ncbi.nlm.nih.gov/pubmed/19758226. If anyone has it, I'd appreciate a copy.

Okay, so I have a copy of the article now. It's interesting. And behind it all is this protocol: https://web.archive.org/web/20130622...kb.org/home/mp.

The Marshall Protocol was developed by an Australian engineer with no apparent knowledge of Vitamin D or the VDR. Dr Mercola (whose views I am not always in support of) has discussed it here; http://articles.mercola.com/sites/ar...-protocol.aspx.

The protocol (from https://web.archive.org/web/20130622...kb.org/home/mp) looks very detailed to me - if this was evidence-based science I would have expected to see PubMed accounts of its development and clinical cases notes describing its success. There aren't any.

This link may amuse NT readers but I think that it makes a good point; http://phylogenomics.blogspot.com.au...-marshall.html.

Yes just because there is a paper suggesting they have found all the answers doesn't mean they actually have, especially when it is in a journal with a impact factor of 4. It sounds like a bold claim, I am suspicious of bold claims, if it really were true why has the paper only been cited 30ish times since 2009? There is a paper in some journal on everyone's favourite crackpot theory, but only a extremely small fraction of these will stand the test of time.

The gut microbiome is a hot topic at the moment, but like the author says we have no idea how to safely harness this as a therapy in a clinical environment. There are a lot of theories. The internet is full of snake charmers of people suffering from ill health, I have been victim of a few myself, this is why we have to enquire very deeply into everything, and ask ourselves is this really sensible or am I being misled?

Thanks Kiwi... you beat me to it today.

The MP is still controversial and given all the time that has
elapsed, there are still no real research papers to endorse it.

Dr. Mercola, has in this instance provided a good rebuttal.

I actually went through and I read all the articles and talks they've published and the details of the protocol. Yes, not all journals and articles and studies, etc. are created equal, but I like to know a position before accepting or rejecting it. I'm not really interested in ad hominems or anything dismissive along those lines, though I won't lie, I did have a laugh or two when reading the blog post...

Last night I also came across Mercola's piece, which though it makes some useful points, doesn't address the science behind the model Marshall advances. That's fine, he's not writing in a specialist journal.

A few thoughts:

1. Jumping from computer models to a clinical protocol is problematic in all sorts of obvious ways.

2. There are all sorts of other problems too, e.g., taking antibiotics long term is not prudent for a number of reasons that are apparent to anyone who knows about their side effects.

3. But I'm not really interested in the protocol, but the main claim underlying it all. The meat of the position/model is twofold: (a) vitamin D is an immunosuppressive akin to steroids, and (b) it works by suppressing VDR from functioning.

Firstly, underlying this model is the position that vitamin D deficiency is caused by disease not the other way around. Well, we know that this hasn't been settled. I could say much more here, but it just hasn't been settled either way by studies, so Marshall can't have this one. But for various reasons, my suspicion is that it is (perhaps at least sometimes) caused by disease but that's not based on hard science.

The reason this is important is that it allows Marshall to claim that autoimmunity causes VDR dysfunction and so immune system dysfunction (and it's this that leads to low D levels). Is there evidence for this? If anyone has read his work and his evidence for it, then I'd be curious to know what you think. If I'm not mistaken, the only evidence he has is computer simulation and then just some claims loosely based on some clinical examples, not actual studies, certainly not quality ones. But perhaps I'm wrong. Again, I'm not an expert on this stuff.

Now, let's take (a). This seems to be true and is supportive by all sorts of studies. Here are just two links:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166406/
http://www.readcube.com/articles/10.12659%2FAJCR.894849

What does this all mean though? It's rather complex. What exactly is being suppressed? I'm not an expert so input is appreciated. I don't see enough evidence via Marshall's computer models of (b), namely, that VDR is being suppressed, and that's what's going on, but again perhaps I'm wrong. Kiwi, perhaps you have some thoughts here? It doesn't seem like we can know this.

So, is D suppressing the adaptive immune system in the sense that it's reducing inflammation (by working on the T and B cells), which a number of studies an articles claim, or that it's also reducing the immune systems ability to fight pathogens and to do its work basically? Or do we just not know enough about what or all that it's going? Obviously, key to all this is that it functions like a cortocosteroid. So what exactly does a steroid do to the immune system/mechanism of action, etc.?

I say this because there's also a personal dimension to all this, or personal experience. My levels were low. Then even a 1000 IU a day reduced my symptoms immensely. It very obviously reduced inflammation in my body. But is it also hindering my immune system from fighting off infections and doing whatever else it needs to do? Well, I don't have a baseline, but a few days ago I received my IgG numbers and they're low, not too low, but below normal range, so in the 600s. The rest of the immunoglobulins are fine, it seems. I don't have the IgG subclasses, but soon. I also have mild neutropenia, so I'm just below the normal range. Again, these are the only set of numbers that I have, but they're low. Is the D suppressing production of neutrophils and IgGs? Is this even possible? I just don't know enough about how it all works to say anything here.

Do I think that taking vitamin D or hormone D is suppressing my VDR function? I don't know. Theoretically it's possible, but I don't see the evidence or I don't find it convincing based on what I've read from Marshall and those who argue along the same lines. My guess is no, though it's not impossible, perhaps not even implausible. We know that supplementing hormones can have short term benefits, which I clearly have from D, but that long term is can lead to problems with respect to the body's own natural function.

But at this point I'm more interested in the more supported point, namely, that D is functioning as a corticosteroid. This is a common point, but the studies seem to stop at saying with certainty exactly what's going on. I could say and write more, but I'll leave it at that. I'm not sure if others are as interested in this as I am, but it's clearly a very important issue.

DavidHC, I think that is a great summary of what we know and don't know about the jobs of the VDR - I always find your posts stimulating because they encourage me to try to learn new things. What I have come up with so far is:

A genome-wide screen for genes which may be regulated by the VDR found 229 strong candidates. Of particular interest to the NT community include genes which seem to be involved in Type 1 diabetes, multiple sclerosis, SLE, rheumatoid arthritis. Crohn's disease and a number of cancers. Here is the fairly technical link; http://genome.cshlp.org/content/20/10/1352.long.

Apart from that VDR knockout mice have been made (a knockout mouse is one in which the gene in question has been permanently inactivated). So far it seems that the mice show abnormalities of Ca metabolism (no surprise) - as far as I can see nobody has yet used them to look at other things (autoimmunity, inflammation, etc); http://www.ncbi.nlm.nih.gov/pubmed/22903507.

I will keep digging and report back if I find anything of interest.

Well vitamin d is definitely not as strong as steroids. It's interesting you notice a lot of relief from it. I wouldn't worry about it suppressing your immune system that much personally otherwise there would already be a black box around buying it. There is a question of how much to take, I started taking 5000IU a day after I started getting neuropathic & inflammatory problems, and haven't seen much improvement. However, we don't know how much is valuable for people suffering from potential autoimmune diseases to take.

Some of the benefits of the antibiotics for autoimmune problems probably come from antibiotics natural ability to fight inflammation not through killing microbes. There are a lot of articles about this I'm on my tablet now so can't link easily, but minocycline is used as a disease modifying drug in rheumatoid arthritis. Some fringe doctors will also try deoxycyline to treat a whole range of autoimmune diseases. Some of them thinks it works because they kill microbes that cause inflammation, but it is more likely I think to be direct anti inflammatory actions on certain biochemical pathways. Certainly relating every autoimmune disease back to dysregulation of the VDR pathway is likely to be a over simplification as there will be a wide range of mechanisms. That said maybe all these people that develop gut problems before autoimmune diseases have some steps in common like certain microbes changing in number or permeability of the intestinal walls increasing. I don't think we know this yet.

Sorry to get on your back about paper quality, because in some sense, we don't know what the future will hold. However, I try and quality check journals I read when searching by looking at things like impact factor, citations, and the number of people in the study. Not necessarily to dismiss peoples work or theories, but put it in context.

Kiwi,

Thank you for the kind words. I'm glad...I can't imagine a life without intellectual stimulation. For my part, I appreciate the responses and engagement form you. Honestly, I'm simply trying to clear some ground in an area in which I'm not a specialist, and to understand how best to proceed with my health.

I appreciate the resources. It seems the VDR is as complex as it gets. I read the technical article and will need to look at it a few more times. So impressive!

I also read through the study to which you linked, with the VDR ablated mice: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511627/. It's interesting. Did you notice this bit?

"The effect of VDR ablation on immune function has been extensively investigated. Although defects in T cell and macrophage function were observed, these were reversed by maintaining normocalcemia in the VDR null mice, suggesting that these abnormalities were secondary to impaired mineral ion homeostasis[28]. However, normocalcemic VDR null mice have decreased IFN production by T helper cells, thought to be secondary to impaired macrophage production of IL-18[29]. VDR null mice exhibit enhanced sensitivity to induction of inflammatory bowel disease[30], but are less susceptible to experimental autoimmune encephalomyelitis[31] and airway inflammation[32], suggesting that the VDR does modulate immune function, but its effects vary depending on the model and perhaps the underlying genetic background of the mice being studied."

It doesn't seem to settle the issue either way, almost a technical way of saying we just don't know what's going on, but there's stuff happening. It is interesting that by establishing mineral homeostasis they seemed to correct some of the issues. The study was clearly not focused on the issue, so perhaps a study focusing on immune system function is needed. You also wonder what would happen long term, or longer term so to speak.

I also read through this: https://www.google.ca/url?sa=t&rct=j...,d.dmo&cad=rja. Note this, especially at the very end:

"Figure 3. The immunomodulatory actions of 1,25(OH)2D. 1,25(OH)2D has diverse and extensive effects on the immune compartment. The innate immune response is affected, with monocytes producing more LL-37 and β-defensin, with increased NOD2 expression and autophagy, while also producing diminished amounts of inflammatory cytokines, with decreased expression of TLR2 and TLR4. Differentiation into macrophages is increased, with macrophages having an increased capacity for phagocytosis and chemotaxis. However, their APC and T-cell stimulatory capacity is decreased. Monocyte and macrophage production of ROS and iNOS is able to both be induced and inhibited, thus regulating their balance. Differentiation into DCs is inhibited, with DCs expressing decreased levels of maturation surface markers. DC production of IL-12 and IL-23 is decreased, while mannose receptor expression and production of IL-10 and CCL22 are increased. When these tolerogenic DCs interact with T-cells, development of Tregs and Th2 cells is increased, with increased production of IL-10, TGF-β, IL-4 and IL-5. The development of Th1 and Th17 cells is inhibited, with decreased production of IL-2, IFN-γ and TNF-α, and attenuation of macrophage activation. B-cells are also affected by 1,25(OH)2D, demonstrating decreased immunoglobulin production, proliferation and differentiation, but increased apoptosis."

I'm still not as well versed in the language to know exactly what's going on, but I can understand "decreased immunoglobulin production, proliferation and differentiation, but increased apoptosis." This can't be good. Though increasing differentiation and inhibition at the same time can explain it's use in cancer treatment, it may not be the best for increasing immunity. This seems to match up with Marshall's claim that D reduces production of antimicrobial peptides (and he refers to the knockout mice study too btw as showing that while 25 is low, biological active and available 1,25 is high). As I mentioned, I had low neutrophils and IgG. This may nothing to do with the D, as there are many other causes, but it might be worth mentioning.

Some further thoughts (even though this is getting too long):

1. I still see no evidence of Marshall's claim that D supplementation blocks VDR function. Computer simulation is not enough.

2. There is plenty of evidence that D works in complex ways and that includes suppressing the innate immune system and its ability for at least B cell proliferation, leading to reduced immunoglobulins and peptides, which may be problematic when trying to fight off a powerful infection. Am I understanding this correctly? There is also this, an older one: http://www.ncbi.nlm.nih.gov/m/pubmed/17641030/. Perhaps I'm misunderstanding this, since this study seems to take it for granted that inhibiting the ongoing proliferation of activated B cells and inducing their apoptosis is beneficial. I'm unclear about this. Is it that they're thinking along the lines of cancer rather than immune issues? This and the study I quote above come to the same conclusion, it seems. I'll think more about this, track it down and read the whole thing.

3. I am willing to believe the hypothesis that microbes can lead to VDR function reduction or dysfunction, given that it's a strategic way to shut off the body's immune system.

4. Despite 3, there's no evidence that the protocol he uses works, in particular there's no study showing that the so called "VDR agonist" olmesartan reactivated VDR function. There is just some computer model, and that's entirely insufficient as evidence for clinical practice. The physician he's working with doesn't even have the best data from his own patients. It seems they really don't know what's going on there, and I'm willing to bet the antibiotics have some benefit and that's what they're often recording.

I'd like to hear more about all this, and to discuss it going forward. Not to mention that I plan to keep reading, including whatever on here that I've yet to read: http://ortho.ucla.edu/body.cfm?id=206. But going forward practically, I'm thinking of just keeping my dose of D low or relatively low, keeping an eye on my IgG and neutrophils, which I should mention have slightly gone down in the last few months - I have two blood samples over 3 months on that - and the reading was already on the lowest end of the acceptable range. I'm also going to go ahead with the natural antibiotics, antifungals, etc., which has been the plan for months now. Basically, I don't agree with the Marshall protocol that you have to starve your body of D. That just can't be right, given what we know about human evolution and the importance of sunlight. But even if it is suppressing my immune system, I'll keep an eye on the markers, and will soon be seeing an immunologist anyway. I'll keep an eye on them, getting tested again in a few months, and then also beginning with the herbals to see how that goes. However suppressed my immune system is, the herbals will still do their job. Plus, the numbers show that my immune system is still in decent shape; that is, it's not failing/my numbers aren't dangerously low. And considering the symptom relief I get from such low dose D, and that I don't take a single pharma med, I can give myself at least that little bit.

If anyone is interested, Marshall's explanation of why D levels are low in the chronically ill is as follows: "As the hormone/secosteroid rises above a normal
range, it down-regulates, via the PXR Nuclear Receptor, the amount
of vitamin D converted into 25-D [19]." (Here's the paper: http://mpkb.org/home/publications/al...y_reviews_2009). And the reference is to this piece: http://mpkb.org/home/publications/ma...bioessays_2008.

Some of what he says is right, some of the plausible, and some of it a stretch with at best computer simulations to back it. I usually say beware of complete theories and protocols (or systems) that claim to have figured everything out, but there are interesting and potentially challenging parts to it, even if it doesn't completely stand (and it doesn't as a whole).

A bit more digging:

This long review might be worth a read; http://www.ncbi.nlm.nih.gov/pmc/arti...MC4078458/#B50.

Nothing crystal-clear has emerged but it seems that:

(1) There is evidence that Vitamin D (and by inference, genes which are under the control of the VDR) may be protective against multiple sclerosis.

(2) There is similar evidence which is suggestive of protective effects in rheumatoid arthritis and Inflammatory Bowel Disease.

(3) Low levels of Vitamin D in childhood may be a risk factor for Type 1 diabetes.

(4) There is complex evidence that Vitamin D can down-regulate the production of pro-inflammatory proteins.

(5) There is conflicting evidence about the effects of Vitamin D on asthma.