In this article, we’re going to look at the 5 main reasons why vitamin D can stay low regardless of whether lots of vitamin D is being taken in through supplements or the diet, or whether a person has lots of sunshine exposure. It’s not that vitamin D supplements don’t work, it’s that there is something else stopping them from working. Scroll down as we uncover what causes low vitamin D even when taking supplements!
What Happens When Your Vitamin D Is Low?
Low levels of Vitamin D have been implicated in a huge range of health issues including cancer, multiple sclerosis, rheumatoid arthritis, diabetes, cardiovascular disease, and autoimmunity. Vitamin D is also arguably the main molecule involved in the healthy functioning of our immune system (1).
Vitamin D’s role in immune function involves controlling immune system inflammation, but also in increasing the body’s ability to kill pathogens. It does this by producing the immune system signaling molecule IL-10, as well as producing the antimicrobial peptides, Defensins and Cathlicidins, used by immune cells to both find pathogens and kill them (1).
It’s no surprise then that for many people it’s a no-brainer to take vitamin D supplements, especially during the winter when there is less sunshine and when people are often outside less. However, there’s a potential problem, and that is that sometimes even when people are taking high-strength vitamin D supplements, or are outside in the sunshine a lot, their vitamin D levels can still stay low.
The simple flowchart below shows the different forms of vitamin D found in the body. Vitamin D precursor is turned into previtamin D3 in the skin by UVB rays from the sun. This is why sunlight is important for Vitamin D production. Then previtamin D3 is turned into cholecalciferol or vitamin D3.
Cholecalciferol or vitamin D3 is the type of Vitamin D we get from food or supplements (although occasionally it’s in the D2 form), so by taking a supplement we can bypass the need for sunshine to produce Vitamin D. D3 is then turned into storage Vitamin D in the liver, this is also known as Calcidiol or as its chemical name, 25 hydroxyvitamin D3, 25(OH)D.
Storage vitamin D is the main type of vitamin D found in the blood and is the type most commonly tested for when we have vitamin D tests. However, we need to turn this form into active vitamin D, which is known as Calcitriol, or by its chemical name 1,25 dihydroxy vitamin D3, 1,25(OH)D to actually use vitamin D.
This conversion most commonly happens in the kidneys. Active vitamin D is the type of vitamin D that exerts the effects we need in our tissues and ultimately what we need to produce.
The 5 Factors That Cause Low Vitamin D Levels
Here are the factors that cause low vitamin D in individuals:
1) Insufficient Calcium Intake
The first reason why Vitamin D can stay low is an insufficient calcium intake. Arguably, Vitamin D’s main role in the body is to allow us to absorb Calcium in the gut.
Active vitamin D, (1,25(OH)), is able to do this by synthesizing the calcium-binding protein known as calbindin in the epithelial cells that line our guts.
Active Vitamin D also forms the 3 types of channels through which calcium moves to be absorbed, which are known as TRPV5 and TRPV6, from the gut to the intestinal cells, and PMCA1b from the intestinal cells into the blood.
If we aren’t getting enough calcium through the diet, then the body has to use more Active Vitamin D in the gut to form more absorption channels. This helps ensure we get as much of the calcium that is in the gut absorbed into the body. This will lead to less storage vitamin D in the blood and on tests because more of it has to be turned into active vitamin D.
It also means there is less active vitamin D available for all of its other roles in the body. By making sure we are getting enough calcium, we can spare vitamin D for use in the immune system as well as for all its other functions, rather than using it for just calcium absorption (2-5).
Whilst adequate calcium consumption is important, it does need to be pointed out that we are not recommending a high calcium intake i.e one higher than the RDA. The RDA is the amount to aim for, what we are trying to do is to avoid not getting enough calcium.
High calcium intake can have potential health problems in itself, in that excess calcium can end up in soft tissues such as the arteries causing calcification, i.e heart disease. Because of this, we recommend avoiding high-dose calcium supplements (6).
The way to make sure you are getting the right amount of calcium is to use a calculator like this. The recommended daily allowance for calcium is 1000mg per day for most adults, although that does increase to 1200mg per pay for women over 50.
Vitamin D is turned from its supplement form as D2 or D3 into the storage form of vitamin D, 25(OH)D, in the liver via the 25-hydroxylase enzyme. Then storage vitamin D is turned into its active form, 1,25(OH)D, in the kidney via the 1-α hydroxylase enzyme.
Both of these enzymes need magnesium to work. The problem is that, according to the National Health and Nutrition Examination Survey (NHANES), 79% of people in the USA don’t get enough magnesium in their diet (7).
Previously low levels of storage Vitamin D and active Vitamin D have been found in subjects with low magnesium levels, and the low levels of vitamin D have been reversed once the subjects are given magnesium supplements (8-9).
Also, some children suffering from Rickets, a disease known to be caused by a lack of vitamin D, who also have low magnesium levels will not respond to huge doses of vitamin D of up to 600,000 IU daily, until magnesium supplements are also given alongside the vitamin D (10).
Further studies using data from the NHANES database show that higher magnesium intakes correlate with higher storage Vitamin D levels (11), as well as also lowering the risk of death from heart disease and colorectal cancer (12).
You can get extra magnesium either through the diet or relatively cheaply through magnesium supplements.
Glutathione is the main antioxidant in the human body. If you are low in glutathione, you will have increased oxidative stress and increased damage to both proteins and fatty acids (13-14).
A 2018 study showed that in both mice and humans, low vitamin D levels also correlated with low glutathione levels. They also found that when subjects or mice were treated with Glutathione or L-Cysteine supplements, their glutathione levels increased and so did their vitamin D levels (15).
Cysteine is used because glutathione is made of 3 amino acids, cysteine, glycine, and glutamate. But cysteine is considered the rate-limiting amino acid needed for glutathione production because there is much less available in the body than the other 2 amino acids.
The authors of the study concluded that low glutathione levels led to low vitamin D because low glutathione increased inflammation, which in turn leads to a downregulation of the genes that are responsible for producing vitamin D. Because Vitamin D can increase the strength of the immune response when we produce a lot of it, it can actually increase the collateral damage caused by the immune system.
The body therefore purposely downregulates Vitamin D production during chronic inflammation such as you would find in obesity or diabetes, to protect the body from further damage.
You can find out your glutathione levels with a simple blood test, and anyone who wants to increase their glutathione levels, or reduce inflammation can supplement with the glutathione precursor N-acetyl cysteine (NAC), or a Liposomal Glutathione supplement. NAC is cheaper than Liposomal Glutathione, but as Glutathione is the active form, the body doesn’t have to make any conversions, so normally the Liposomal Glutathione will produce better results.
If you want to supplement with glutathione, it’s important to choose the liposomal form and not the ordinary form. Liposomal forms allow the glutathione to be absorbed whole, whereas the ordinary form will be mostly broken down into its individual amino acids before being absorbed, making it much less bioavailable.
4) Fat Mass and Exercise
Increased body fat is associated with lower levels of vitamin D (16). The exact reason for this is not fully known, however, because vitamin D is a fat-soluble vitamin it’s thought that increased fat in the body can cause vitamin D to be trapped in fat tissue. This is because excess fat in the cells leads to them become dysfunctional, which means they can’t efficiently release vitamin D. This means that less vitamin D is available for use in the body.
The excess fat mass may also increase levels of the enzyme 24-hydroxylase which deactivates vitamin D and is found in high concentrations in fat tissue (17). In addition to this, because obesity creates chronic low-grade inflammation, the inflammation itself, as we discussed in the previous section on glutathione, may inhibit the production of vitamin D.
Whilst people suffering from obesity can increase their vitamin D levels with supplements, it’s been suggested that they made need 2-3 times the dose as people with a healthy level of body fat (18).
However, in obese people, lifestyle interventions that reduce body fat such as diet changes and exercise can increase vitamin D levels to normal values again (19). Also, exercise can help to increase vitamin D levels in both obese and nonobese individuals. Exercise causes the breakdown of fat tissue and so is able to free vitamin D from fat tissue and allow it to enter circulation so that it can be used (20).
5) Gut Microbiome/Bacteria
Vitamin D is very active in the cells of the gut in both calcium absorption and immune function. It’s been shown that impaired vitamin D functioning can lead to an imbalance in the bacteria of the gut aka the microbiome, and can lead to the formation of excess ‘bad bacteria’. It’s also been found that bacterial imbalance can lead to less vitamin D activity creating a vicious circle (21).
Studies have shown that those with higher levels of active vitamin D were more likely to have ‘good bacteria’ that produce a short-chain fatty acid called butyrate. Butyrate is used by cells of the gut for energy as well as to reduce inflammation and to tighten the junctions between intestinal cells to prevent ‘leaky gut’ (21-23).
Importantly, it seems a lack of good bacteria only reduces levels of active vitamin D, and levels of storage vitamin D can remain normal. So even though the usual vitamin D tests will appear normal, there is actually a low-level vitamin D activity going on.
This means that the good bacteria are involved in turning storage vitamin D into active vitamin D. It’s also an important reason why when testing for Vitamin D you should test for both active and storage vitamin D, rather than just storage vitamin D which is only tested for on the majority of vitamin D tests (21).
Studies have shown that supplementation with probiotics can restore vitamin D activity and reduce inflammation in both mice (24) and humans (25). Probiotic supplementation with Lactobacillus rhamnosus will directly increase butyrate-producing bacteria (26).
So, now you know what causes low vitamin D in people. To get a full picture of your vitamin D status, we recommend testing both your storage and active vitamin D levels. If either is low, and you’re already taking supplements or spending plenty of time outside, then you can look at any of these 5 factors and see if working on them can help improve your vitamin D levels.
Also, if you can’t take the tests, but you’ve been taking vitamin D supplements and haven’t noticed any change in your health, then it’s likely to be one of these things stopping your body from properly using vitamin D.
Related article: What Happened To The Vitamin D Council?
(1) Adrian F Gombart, The vitamin D–antimicrobial peptide pathway and its role in protection against infection, Future Microbiol. 2009 November ; 4: 1151.
(2) Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D defi ciency in calcium deprivation. Nature 1987;325:62 – 65
(3) Davies M, Heys SE, Selby PL, Berry JL, Mawer EB. Increased catabolism of 25-hydroxyvitamin D in patients with partial gastrectomy and elevated 1,25-dihydroxyvitamin D levels. Implications for metabolic bone disease. J Clin Endocrinol Metab 1997;82:209 – 12.
(4) Anderson PH, Lee AM, Anderson SM, Sawyer RK, O ’ Loughlin PD, Morris HA. The effect of dietary calcium
on 1,25(OH) 2D3 synthesis and sparing of serum 25(OH)D3 levels. J Steroid Biochem Mol Biol 2010;121: 288 – 292.
(5) Paul Lips (2012) Interaction between Vitamin D and calcium, Scandinavian Journal of Clinical and Laboratory Investigation, 72:sup243, 60-64
(6) Marisa Brini and Ernesto Carafoli, The Plasma Membrane Ca2+ ATPase and the Plasma Membrane Sodium Calcium Exchanger Cooperate in the Regulation of Cell Calcium, Cold Spring Harb Perspect Biol. 2011 Feb; 3(2): a004168.
(7) Ervin RB, Wang CY, Wright JD, Kennedy-Stephenson J. Dietary intake of selected minerals for the United States population: 1999–2000. Adv Data. 2004;341:1–5.
(8) Fuss, M., COGAN, E., GILLET, C., KARMALI, R., GEURTS, J., BERGANS, A., BRAUMAN, H., BOUILLON, R. & CORVILAIN, J. (1985) Magnesium administration reverses the hypocalcaemia secondary to hypomagnesaemia despite low circulating levels of 25-hydroxy-vitamin D and 1,25-dihydroxyvitamin D. Clinical Endocrinology, 22,807-8 15.
(9) M. FUSS, P. BERGMANN, A. BERGANS, J. BAGON, E. COGAN, T. PEPERSACK, M. VAN GOSSUM AND J. CORVILAIN, CORRECTION OF LOW CIRCULATING LEVELS OF DURING REVERSAL OF HYPOMAGNESAEMIA 1,25-DIHYDROXYVITAMIN D BY 25-HYDROXYVITAMIN D, Clinical Endocrinology (1989), 31, 31-38
(10) Reddy V, Sivakumar B. Magnesium-dependent vitamin-D-resistant rickets. Lancet. 1974;1:963–5.
(11) Xinqing Deng, Yiqing Song, JoAnn E Manson, Lisa B Signorello, Shumin M Zhang, Martha J Shrubsole, Reid M Ness, Douglas L Seidner, Qi Dai, Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III, BMC Med. 2013; 11: 187. Published online 2013 Aug 27
(12) Xinqing Deng, Yiqing Song, JoAnn E Manson, Lisa B Signorello, Shumin M Zhang, Martha J Shrubsole, Reid M Ness, Douglas L Seidner and Qi Dai1, Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III, BMC Medicine 2013, 11:187
(13) Curtis JM, Hahn WS, Long EK, Burrill JS, Arriaga EA, and Bernlohr DA. Protein carbonylation and metabolic control systems. Trends Endocrinol Metab 23: 399–406, 2012.
(14) Dalle-Donne I, Rossi R, Giustarini D, Milzani A, and Colombo R. Protein carbonyl groups as biomarkers of oxi-dative stress. Clin Chim Acta 329: 23–38, 2003.
(15) Sushil K. Jain, Rajesh Parsanathan, Arunkumar E. Achari, Preeti Kanikarla-Marie, and Joseph A. Bocchini, Jr, Glutathione Stimulates Vitamin D Regulatory and GlucoseMetabolism Genes, Lowers Oxidative Stress and Inflammation, and Increases 25-Hydroxy-Vitamin D Levels in Blood: A Novel Approach to Treat 25-Hydroxyvitamin D Deficiency, ANTIOXIDANTS & REDOX SIGNALING, Volume 29, Number 17, 2018
(16) Kyung-Jin Yeum, Bess Dawson-Hughes and Nam-Seok Joo, Fat Mass Is Associated with Serum 25-Hydroxyvitamin D Concentration Regardless of Body Size in Men, Nutrients, 29 June 2018
(17) Li, J.; Byrne, M.E.; Chang, E.; Jiang, Y.; Donkin, S.S.; Buhman, K.K.; Burgess, J.R.; Teegarden, D.
1alpha,25-Dihydroxyvitamin D hydroxylase in adipocytes. J. Steroid Biochem. Mol. Biol. 2008, 112, 122–126.
(18) Andrea Di Nisio, Luca De Toni, Iva Sabovic, Maria Santa Rocca, Impaired Release of Vitamin D in Dysfunctional Adipose Tissue: New Cues on Vitamin D Supplementation in Obesity, The Journal of Clinical Endocrinology and Metabolism · February 2017
(19) Anne Gangloff, Jean Bergeron, Isabelle Lemieux, Angelo Tremblay, Paul Poirier, Natalie Alméras, Jean-Pierre Després, Relationships between circulating 25(OH) vitamin D, leptin levels and visceral adipose tissue volume: results from a 1-year lifestyle intervention program in men with visceral obesity, International Journal of Obesity, March 2019.
(20) A. Hengist,O. Perkin,J. T. Gonzalez,J. A. Betts,M. Hewison,K. N. Manolopoulos,K. S. Jones,A. Koulman,D. Thompson, Mobilising vitamin D from adipose tissue: The potential impact of exercise, Nutrition Bulletin Volume 44, Issue 1, March 2019, Pages 25-35.
(21) Thomas, R.L., Jiang, L., Adams, J.S. et al. Vitamin D metabolites and the gut microbiome in older men. Nat Commun 11, 5997 (2020).
(22) Butyrate Enhances the Intestinal Barrier by Facilitating Tight Junction Assembly via Activation of AMP-Activated Protein Kinase in Caco-2 Cell Monolayers1,2 Luying Peng, Zhong-Rong Li, Robert S. Green, Ian R. Holzman,3and Jing Lin, Butyrate Enhances the Intestinal Barrier by Facilitating Tight Junction Assembly via Activation of AMP-Activated Protein Kinase in Caco-2 Cell Monolayers, J Nutr. 2009 Sep; 139(9): 1619–1625.
(23) Maartje C. P. Cleophas, Jacqueline M. Ratter, Siroon Bekkering, Jessica Quintin, Kiki Schraa, Erik S. Stroes, Mihai G. Netea, and Leo A. B. Joosten, Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males, Sci Rep. 2019; 9: 775.
(24) Shaoping Wu, Sonia Yoon, Yong-Guo Zhang, Rong Lu, Yinglin Xia, Jiandi Wan, Elaine O Petrof, Erika C Claud, Di Chen, Jun Sun,, Vitamin D receptor pathway is required for probiotic protection in colitis, Am J Physiol Gastrointest Liver Physiol. 2015 Sep 1;309(5):G341-9.
(25) Kanhere, M. et al. Bolus weekly vitamin D3 supplementation impacts gut and airway microbiota in adults with cystic fibrosis: a double-blind, randomized, placebo-controlled clinical trial. J. Clin. Endocrinol. Metab. 103, 564–574 (2018)
(26) Roberto Berni Canani, Naseer Sangwan, Andrew T Stefka, Rita Nocerino, Lorella Paparo, Rosita Aitoro, Antonio Calignano, Aly A Khan, Jack A Gilbert, Cathryn R Nagler, Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants , Clinical Trial ISME J. 2016 Mar;10(3):742-50.