(D)efense

Vitamin D is a well known nutrient, however, I think few people really understand the significance of this important vitamin.  To  begin with, vitamin D should hardly be classified as a vitamin at all, since it is really hormone that helps to signal our bodies calcium status (1).  However vitamin D (VD) has been implicated in a range of processes including obesity, renal disease, cardiovascular disease, male fertility and even sex hormone production (2,3).  With all these different actions of VD it is tough to know where to start, as there is so much research on how VD affects so much of our lives.  I do think these many actions are very interesting, and well deserving of a post in their own right, but I would like to focus this post on VD’s interactions with the immune system, as that is a topic consistently on my mind these days.  To do that we will first go over a quick look at VD metabolism, and then get into its effects on immunity, and finish up with some thoughts about our own VD status.

Vitamin D Metabolism

As humans there are two main ways we can get VD: through sun exposure and supplementation.  We will go over the optimal VD levels at the end of the post, but first lets see how sunlight affects our VD status.

As we have seen before cholesterol is a very important molecule for all mammals, and part of this is because it is the most basic precursor to VD.  Cholesterol in the skin is converted directly to 7-dehydrocholesterol.  This is the molecule that will absorb energy from UV B rays and turn into cholecalciferol.  Some of you may recognize cholecalciferol, as it is the form of VD that is used in most D3 supplements.  Cholecalciferol is then transported to the liver, where it is further converted to calcidiol, or 25(OH)D.  This calcidiol is then transported one more time, this time to the kidneys, where, with the help of parathyroid hormone, it is converted to calcitrol (1,25(OH)₂D), which is the “active form” of VD that is what is actually important.  This 1,25(OH)₂D is what will then travel through your body and can activate the VD receptor (VDR) that will activate the various processes VD is known to contribute to.

For those of you who might have gotten a little lost in all of that, here is a nice figure that shows VD metabolism in a visual form that is definitely helpful to understand all of this.

(3)

Vitamin D and Immunity

VD is known to interact with both the both innate and adaptive immune systems.  The innate immune system is the defenses that all mammals are born with, and have been programmed through thousands of years of evolution.  On the other hand, the adaptive immune system is the part that allows us to build defense to things we encounter during our life.  As an example, a flu shot is built around our adaptive immune system.  We force our selves to contact a pathogen so that we build up a defense to it.  However, something like inflammation is an example of innate immunity, this is a process that most animals have that allows them to properly fight off a variety of pathogens and other injuries. 

A group of important mediators for the innate immune system is the toll-like receptors (TLR’s), specifically TLR4.  Many of you may have heard of this specific receptor, as it is integral in our response to lipopolysaccharide (LPS), which is a component of bacteria cell walls, and is most one of the most important signals for gut health. However, it is also an integral part of our response to any bacterial pathogen.  While I mentioned above that most of our active VD (1,25(OH)₂D) is produced in the kidneys, several other tissues express the enzyme CYP27B1, which turns 25(OH)D into 1,25(OH)₂D, which means they can also produce active VD.  It turns out that certain immune cells will turn this pathway on when pathogen sensing receptors like TLR4 are activated, showing that VD is an important immunomodulator (4). 

Not only do immune cells create their own active VD in response to a pathogen, they also use the VD receptor (VDR) to regulate inflammatory signaling, and this is especially evident in the intestinal tract.  A study that engineered mice that had immune cells lacking VDR showed that IL-10 production, which has been shown to decrease inflammation in IBD patients, was greatly reduced by cells lacking VDR (5).  This table shows the percentage of cells that produced IL-10, and you can see the immense decrease in the VDR knock-out (KO) cells. 

Finally, a study in cows showed that immune cells stimulated by LPS produce more NO (Nitric Oxide) which is thought to be a part of the antimicrobial defenses in bovine animals (6). 

When we take all this data together I think we can see what an important role VD plays in our immune response, especially to pathogens.  We use VD to regulate our pro and anti-inflammatory agents, and also use it to stimulate production of defense molecules.  VD is such an important modulator of these processes that our immune cells express the enzymes required to create active VD when needed.

How to optimize Vitamin D status

If VD is so important to our bodies for a number of reasons, but especially in supporting immune function, how much of it do we actually need?  And what are the best ways to get it?  Well, obviously the best way to get VD would be through our natural creation pathways, and that would mean you need to make sure you get enough sunlight.  However, for many of us this simply isn’t a possibility, or may not be possible even (7).  Not only is VD hard to get during several months of the year for a wide range of latitudes, many people are incredibly deficient as it is.  This graph from a study of a Swiss population shows the serum levels of VD during different periods of the year (8).  I like this graph because it shows the VD levels in the two most common measurement styles, ng/mL and nmol/L.  Using this graph as a guide, we can make a crude estimate that 10 ng/mL is roughly equivalent to 25 nmol/L.

 So what can we do to get the required amount of VD?  Well as I mentioned before, cholecalciferol is a common form of vitamin D supplements, and is also a natural part of our own metabolic pathway.  But how much can supplementation help us?

This study of patients at a Chinese clinic helps us answer that exact question (9).  22 patients were given 800 IU of cholecalciferol, while 24 served as a control. They followed this protocol for 6 months, and found that the treated group had improved their serum VD levels by a significant amount.  The one thing this study doesn’t tell us is during what months of the year it was conducted.  I think this is an important factor for any study on VD status, especially as we have seen how hard it is to naturally produce VD during the winter months in many of the latitudes in China.  However, if we use the difference between treatment group and control as a baseline, we can hypothesize that 800 IU of VD is good for about a 7 ng/mL increase in serum VD.  Using our conversion from before, we can say this about a 17.5 nmol/L increase.

The final question we should ask is just what is an optimal level of VD?  Well, with many questions like this I think the best place to look for an answer would be traditional hunter-gatherer societies.  This is because these groups are living closest to our evolutionary roots, and you would expect them to have the closest levels to our ancestors, and thus be more in line with what our bodies are developed for.  A soon-to-be-published study on the VD levels of the Hadzabe and Maasai societies found the average VD levels to be around 115 nmol/L (using our estimation that’s ~46 ng/mL) (10).  I would say this is a good rough estimate for us to shoot for, however as I said before the time of year of the data collection would be an important variable in this study, although less so because it was done in Africa.  Unfortunately, at this time we can’t access the data, as this is pre-release abstract for the study. 

Let’s do some hypothetical math using a wide range of assumptions we have from the data above.  Using our Swiss population data from above we can say for a northern latitude our VD levels are about 29 ng/mL in the summer, 22 ng/mL in the spring/fall, and 17 ng/mL in the winter.  If we also hypothesize that an 800 IU cholecalciferol supplement is worth about 7 ng/mL, in order to reach the hunter-gatherer level of 46 ng/mL at all times during the year they would need to supplement with about 1943 IU in summer, 2742 IU during the spring/fall, and a whopping 3428 IU in the winter!

As we can see vitamin D is a very important nutrient for a wide variety of biological processes.  It is essential for calcium homeostasis, but is just as important for immune system regulation.  It can help prime our defenses when a pathogen is sensed, and helps to control the inflammation associated with many diseases caused by chronic low-grade inflammation. 

Vitamin D is also a nutrient that is tough to get in many parts of he world, especially during the winter months.  During these periods it is very important to optimize vitamin D levels through supplementation, and if use hunter-gather levels as a rough estimate of optimal levels of human vitamin D requirements, we can see how deficient many of us probably are.  I would not recommend everyone go out and start throwing back the vitamin D capsules like candy, but I think we can all benefit from some supplementation, especially during the cold, dark winters!