Chronic Infections Suppress Vitamin D Receptor (VDR) Function

For many years now, Vitamin D has been the darling of the nutritional world. After all, Vitamin D does so many things: it regulates immune function, improves insulin sensitivity, and even helps to heal acne.

And yet, so many of us are testing chronically low, even if we’re healthy. In the case of healthy patients, the reason for this largely has to do with the length of time it takes to convert sunlight to the active form of Vitamin D and our modern bathing routines. Low Vitamin D (25OHVitD on labs, to be specific) isn’t necessarily concerning in and of itself.

But for those who are chronically ill, low 25OHVitD on labs might mask a more insidious process.

The Vitamin D Conversion Process

Vitamin D3 (cholecalciferol) either gets made in the skin via the sun, or ingested in food. This gets transported to the liver, where it’s turned into the commonly tested form, 25OHVitD. This is not the most metabolically active form, however; it’s the precursor for the most active form called 1,25(OH)2D (calcitriol), which is made in the kidneys with the help of parathyroid hormone (PTH).Calcitriol then travels into the cell nucleus, where it binds to the Vitamin D Receptor (VDR). This is where the magic happens.

Calcitriol is considered the most powerful steroid in the body, for reasons I’ll explain. But it’s not generally the form that’s tested, because its production from 25OHVitD is dependent upon other factors, like PTH levels, calcium, and phosphate levels. So if the question is, “are you deficient in vitamin D,” it’s understood that the question means, are you ingesting enough or getting enough sunlight exposure? Therefore, testing 25OHVitD makes more sense.

At least in theory.

Unfortunately, 25OHVitD levels and calcitriol levels don’t always agree. If calcitriol is too high while 25OHVitD levels are too low, this can mean chronic infection.

Calcitriol and the Immune System

Most immune cells have VDR receptors. When the VDR receptor gets stimulated, it responds by triggering the cell to produce peptides (tiny protein sequences) that attack microbes. Specifically, the peptides produced are called cathelicidin and beta-defensin.

The effect of this is to increase innate immunity (that first line of defense to attack an invader) and decrease specific immunity, since this is always a balancing act.

Unfortunately, this study shows that 85% of the 100 test subjects with chronic disease (infection and autoimmunity) have elevated levels of calcitriol without high calcium levels, which suggests that the calcitriol isn’t actually doing its job of calcium regulation. It’s elevated for another reason.

The body’s ability to fight against an intracellular infection depends upon the VDR working the way it’s supposed to. That means it’s in the best interest of these organisms to “learn” how to circumvent the system. And that’s just what they do.

the organisms get to go more or less unnoticed. Other organisms besides bacteria that seem to possess this ability include This paper, and many others, hypothesize that bacteria that lack cell walls (like mycoplasma and chlamydia pneumoniae, or bacteria that hide inside cells, like aspergillus, one of the toxic molds, and the Epstein Barr Virus. Lyme and coinfections), can get inside the cell nucleus and hijack the VDR receptor, suppressing its immune modulating function. This means

The body always responds to feedback like this by trying to correct the problem. When the VDR receptor isn’t working as well as it should, it tries to overproduce calcitriol to “wake it up.” In these cases, calcitriol production isn’t limited to just the kidneys anymore, nor is it dependent upon PTH, calcium, and phosphate. It’s a compensatory mechanism.

So high calcitriol isn’t a good thing-it’s (This does evidence that something is broken, in much the same way that high TSH means that the thyroid is no longer responding to signals from the brain telling it to produce thyroid hormone. High calcitriol also typically corresponds to low 25OHVitD, because that’s it’s direct precursor. It’s being depleted in the race to produce ever more calcitiol. not mean that everyone with low 25OHVitD has a chronic infection, though, as I mentioned at the beginning. Most cases of low 25OHVitD are simply due to an interrupted conversion process).

Not only does high calcitriol imply VDR hijacking, but this study shows that high calcitriol is a problem in and of itself. Calcitriol will bind to thyroid receptors, glucocorticoid (cortisol) receptors, and androgen receptors (like testosterone and DHEA), acting as competitive inhibitors, so that the real hormones those receptors are designed for can’t get there. This not only leads to hormone imbalance (like functional hypothyroidism and adrenal fatigue, even if the actual thyroid and cortisol and androgen levels are fine), but those receptors also produce the same natural antibiotic peptides that the VDR receptor does when stimulated by the right hormones. So this compounds the problem, making it that much easier for intracellular organisms to hide from the immune system.

You can test calcitriol and 25OHVitD together in order to determine, or at least imply, whether low vitamin D levels are secondary to chronic infection suppressing VDR function. If calcitriol is elevated without hypercalcemia (high calcium levels), there are also a couple of ways we know of to directly counter the pathogens’ attempts to disrupt the VDR and restore the immune system’s ability to fight back.

Increasing VDR Activity

Many compounds have been found that can stimulate the VDR, but most of them also affect calcium levels, and therefore can’t be used for this purpose. In cases of chronic infection, what you want is a VDR agonist (stimulator) that has no effect on calcium. These include curcumin (which makes sense, since it’s a great anti-inflammatory anyway) and omega-6 fatty acids (and while many of these can be inflammatory if out of balance with omega 3s, Evening Primrose Oil is a good anti-inflammatory option).

But this study shows another surprising option: off-label use of Angiotensin receptor blockers (ARBs) such as olmesartan (usually used as blood pressure medication) increases VDR activity, leading to reduced calcitriol but no effect on calcium levels in a period of weeks. This means the body can go back to producing calcitriol in just the kidneys the way it’s supposed to, because signals are getting where they need to go. Immune system function against intracellular invaders is restored. Even though ARBs are not antibiotics, this effect can be so significant that it can lead to a Herxheimer (die-off) reaction initially, as restored immune function kills the invaders and triggers release of inflammatory cytokines.

If chronic infections are suspected (which they might be for autoimmunity due to molecular mimicry, biotoxin illness, or really any kind of chronic illness), it can be helpful to both check and then track calcitriol (1,25(OH)2D) over the course of treatment. While we should expect calcitriol levels to decrease as organisms are treated directly, we can also directly lower it by improving VDR function.

Originally published at on November 15, 2019.