Gone are the days when vitamin D meant bone health, full stop; vitamin D has a host of extra-skeletal effects, including some relevant to autoimmunity.
What is vitamin D and how can we get it?
Unlike most vitamins, vitamin D’s primary source is synthesis in our body, and not food. A precursor of cholesterol (7- dehydrocholesterol) turns into pre-vitamin D3 in the skin upon ultraviolet irradiation, then into vitamin D3. To reach the active form, vitamin D3 undergoes further chemical transformations. The first is in the liver (into 25-OH-vitamin D), then in kidneys (into 1,25-(OH)2-vitamin D).
A secondary source of vitamin D3 is diet (e.g., oily fish or cod liver oil, red meat, egg yolk).
There is also a vitamin D2. This comes from dietary sources, such as plants, yeast, or mushrooms exposed to ultraviolet light. D2 is also goes through the same steps of transformation into the active vitamin D.
Dietary sources do not contain much vitamin D. Furthermore, the UK’s latitude means we can’t produce vitamin D in the skin between October and April. Luckily, we also have the option to supplement with vitamin D.
How much vitamin D do we need?
There is not a one size fits all when it comes to vitamin D. A lot of factors need consideration, such as, but not exclusively:
- sun exposure
- genetic variants in the vitamin D receptor (VDR)
- variability in the expression of VDR which may be influenced by associated conditions, age, obesity and other diseases, medication, etc.
Furthermore, just like with other mediators, vitamin D levels themselves may influence the expression of VDR in tissues, thus its effect, irrespective of circulating levels of vitamin D.
Yes, you can easily find general guidance which specifies daily dosages for large population categories. However, this is not how we practise in Functional Medicine. Each patient is unique and should be treated as such. Plus, whenever possible, we test, and don’t guess. This is why we aim to first establish if the patient needs supplemental vitamin D. Then, if so, how much of it, to get to an optimal level.
What is a good level of vitamin D?
Usually, we measure 25-OH-vitamin D. There isn’t a universal consensus on the thresholds applicable to vitamin D levels. Nevertheless, according to the National Institute for Health and Care Excellence (NICE), here is a good indication of where your 25-OH-vitamin D level is:
- <25 nmol/L (<10 ng/mL) Deficient
- 25-50 nmol/L (10-20 ng/mL) Insufficient
- >50 nmol/L (>20 ng/mL) Sufficient
Furthermore, as some studies showed decreased risk for autoimmune diseases like multiple sclerosis as well as for some infections and fractures, and better physical performance, plus potentially better development of children from mothers with vitamin D >75 nmol/L (30 ng/mL) (1), some consider this as the optimal threshold.
However, as always, the individualised approaches are best. Upper-normal vitamin D levels might be associated with a greater risk for some diseases, at least in certain populations (1).
Furthermore, an interesting statistical model based on simplified immune interactions (2) revealed that the optimum vitamin D levels, from an autoimmunity prevention perspective, may be between 50-100 nmol/L (20-40 ng/mL). Above this value, there may become evident health risks associated with excessive immune tolerance.
Vitamin D toxicity is possible above 150 nmol/L (60 ng/mL).
Bear in mind that this is a fat-soluble vitamin, so we want to avoid excessive administration. More comprehensive laboratory tests are needed to monitor the progress of a vitamin D treatment and avoid imbalances in the body’s biochemistry.
How prevalent is vitamin D deficiency?
Obviously, it depends on reference values and the results of different studies may be more or less reliable. Vitamin D’s blood levels depend on
- geographical location,
- skin colour,
- dietary habits,
- other associated health conditions or treatments,
- genetic polymorphisms, and
- habits such as use of sunscreen and clothing.
However, some data suggest vitamin D deficiency in at least 70% of the USA population and 50% in the UK, going up to over 80% of the entire population in some Middle Eastern countries, where cultural habits limit exposure to otherwise adequate ultraviolet radiation (3).
Vitamin D and the immune function
VDR is present in a number of immune cells, thus allowing vitamin D to influence their function. Furthermore, immune cells were shown to activate vitamin D themselves, depending on its blood levels, thus influencing the inflammatory micro-environment (4).
VDR allows vitamin D to directly influence the expression of genes, thus the cell’s function. Interestingly, Vitamin D also exerts epigenetic changes (5). This means it alters the way genes are accessible to decoding so that information is materialised as protein synthesis. This is possible because vitamin D also influences the structure of proteins that package DNA molecules inside the cell’s nucleus.
Indeed, studies have found correlation between vitamin D levels and conditions where the immune response is essential, from infections to allergies and autoimmunity.
In multiple sclerosis for example, routine vitamin D measurement has become the norm in mainstream approaches. Moreover, the association with low vitamin D levels has been noted in other autoimmune conditions, such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, or dermatomyositis (6), as well as Hashimoto’s thyroiditis and Graves disease (7).
Vitamin D’s mechanisms in autoimmunity
We cannot affirm causality between vitamin D deficiency and extra-skeletal diseases. In most cases, we still need interventional studies to confirm that vitamin D administration influences disease outcomes.
However, it is clear that vitamin D promotes immune tolerance (8), which is what we want to achieve in autoimmunity. Vitamin D influences both innate and adaptive immunity. Innate immunity is our first line of defence and a coordinator of further immune responses, and vitamin D makes it more efficient. The adaptive immunity comprises of specific cellular and antibody responses, which are the basis of the autoimmune disease process.
Furthermore, there are indirect ways for vitamin D to influence the immune system. We are finally starting to gain evidence supporting what Hippocrates, the father of modern medicine, believed more than two millennia ago, that ‘All disease begins in the gut’. The gut lining is one of the most important interfaces with the external environment. Its altered function has been associated with inflammatory conditions, including autoimmunity. Vitamin D has been shown to promote intestinal barrier integrity, and a good microbial balance. This has significant effects on the immune function (4).
Moreover, there are other processes in autoimmune diseases that vitamin D may influence (e.g., tissue fibrosis, bone erosions etc.) (9).
‘All disease begins in the gut’ – the vitamin D-microbiota interactions
One putative mechanism by which vitamin D can influence the immune function is by contributing to changes in the gut microbial composition. Vitamin D intake was shown to have significant associations with microbiota composition, although this may only be the case with certain segments of the intestinal tract (10).
Some evidence points to a direct effect of vitamin D on certain bacterial species. However, it is not clear if some of the microbial composition changes are not, in fact, the result of changes in immune function determined by vitamin D.
Furthermore, excessive intake of vitamin D might actually exacerbate some autoimmune diseases, presumably by promoting a certain microbial pattern (10).
Interestingly, some bacteria have the capacity to activate vitamin D, thus potentially having a role in maintaining vitamin D levels (10).
Even more intriguingly, vitamin D appears to have effects on microbiota of autoimmune patients when no changes happened in the same study in the normal control group (disease-free). In certain cases, the effect of vitamin D on microbial composition appeared to be dependent on the treatment the patient was receiving for the autoimmune disease (10). Additional studies should explore these aspects further to create an evidence base for clinical applications.
The relationship between vitamin D and intestinal flora is a bidirectional one. Vitamin D can promote beneficial intestinal microbiota. Bacterial products, such as short-chain fatty acids resulted from the bacterial transformation of vegetal fibre, can increase the expression of intestinal VDR (5). Thus, the effects of vitamin D, including the anti-inflammatory one, are more pronounced, and this happens in the synergistic context of an overall healthier, plant-rich diet. Furthermore, as discussed, some bacteria have the necessary enzymes to activate vitamin D locally in the gut.
So, if low levels are problematic, then let’s supplement to the maximum, right?
No, not exactly. Many studies have shown benefit with supplementation in patients who were vitamin D-deficient at baseline. However, whether it is beneficial or it offers additional benefits to maintain blood levels of vitamin D in the upper-normal region, or even above, is still controversial.
Some studies used massive doses of vitamin D in multiple sclerosis (4). Still, we need further evidence to confirm the safety and efficacy of this strategy.
In fact, mechanistic evidence highlights the possibility that very high dose vitamin D supplementation may exacerbate central nervous system autoimmunity by raising calcium levels and consequently the activation of the immune cells (11).
Interestingly, it appears that the vitamin D blood level is not the only factor determining its effects on the body. By acting on the VDR, vitamin D alters the expression of genes, thus the cellular functions (12). Research shows that it is possible that genetic variations in VDR are responsible for individual responses to vitamin D, even if blood levels are the same in different patients. This also applies to variations in the protein that binds vitamin D and carries it through the bloodstream, which influences the vitamin’s availability for different tissues (4).
The show will go on…
Further questions need answers and will make research into the roles of vitamin D in autoimmune disease, very interesting indeed.
For example, it would be worth clarifying if there is an optimal vitamin D level for each target-tissue, if 25-OH-D3 administration is equivalent to other forms of supplementation, if vitamin D metabolites other that 25-OH-D and 1,25-(OH)2-D hold significant biological roles, and, very relevant to autoimmunity, if there is a detrimental effect of upper-normal vitamin D blood levels even below the toxicity threshold (13).
Does vitamin D deficiency cause autoimmunity? We currently don’t have evidence to support this. Vitamin D may be involved in the development of autoimmune disease (bearing in mind that the disease process usually begins years before autoimmune diseases are diagnosed, so it is difficult to have direct evidence of association, much less causation). If so, vitamin D deficiency would be just one of the factors involved in autoimmune disease development, and it would be difficult to extrapolate its individual contribution.
Vitamin D can also be a potential component of the treatment of autoimmune diseases, and may influence prognosis. Experimental studies support the potential role of vitamin D in modulating the immune response and influencing autoimmune diseases’ outcomes.
We know that vitamin D does influence the immune function and the possible mechanisms involved are:
- Direct action of vitamin D on immune cells’ function;
- Microbiota composition and balance (shown to have correlation with both vitamin D deficiency and supplementation);
- Alterations in intestinal barrier integrity, thus the immune system’s exposure to foreign structures.
Vitamin D is certainly essential for our health, and its effects, and the effects of its often-encountered deficiency, are complex. There is strong evidence supporting the avoidance of vitamin D deficiency as part of an autoimmune disease preventive strategy.
How to best approach vitamin D management for autoimmunity
No single marker will ever be enough when we aim for optimal health. And, unfortunately, we don’t have the simple, straightforward formula for optimal vitamin D in autoimmunity. As discussed, the optimal level may be different between patients and in different clinical contexts.
Furthermore, there are probably differences in vitamin D’s effect depending on its administration regimen (intermittent bolus doses vs. continuous administration) (8).
Worth keeping in mind is that, what we measure in the blood is 25-OH-vitamin D. The active form is 1,25-(OH)2-vitamin D, produced in the kidneys, and also by some immune cells. Thus, the blood levels routinely measured may not accurately reflect the activity of vitamin D on the immune system.
As shown in this article, it is not necessarily straightforward to predict vitamin D levels. So, testing in order to assess the need and level of supplementation would be the optimal course of action. Even better, nuanced and personalised recommendations in the overall context of health should yield optimal results in the long run.
At The Allergy-Immunology Doctor, we perform comprehensive assessments of patients and we design personalised interventions. Our main focus is optimising immune function.
You may want to book a free discovery call to find out how suitable is our approach for your current goals.
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