Vitamin D and gut health: the missing link?

Vitamin D deficiency is the most common nutritional deficiency in the world. In addition to affecting the bones, the extraskeletal effects of this vitamin are aimed at the immune system, muscles, heart and blood vessels, nervous system and brain.

The „sunshine vitamin” is attracting great attention of scientific community and lay people for the past three decades, and the interest does not seem to diminish, on the contrary,it seems like new discoveries arise all the time. Vitamin D is a powerful hormone, one of the few molecules we can synthesize in our body with the help of sunrays. It is considered conditionally essential, meaning that we can provide enough vitamin D for the body without ingestion through food. But in some situations the synthesis is insufficient and we require supplementation. The problem is that those situations are in fact very common, considering that almost half of the global population has a deficiency or insufficiency of vitamin D. Nevertheless, vitamin D deficiency is the most common nutritional deficiency in the world. Low levels are noticed especially during the autumn, winter and early spring in individuals who are not taking food supplements or medications containing vitamin D1. Vitamin D receptors (VDR) are found in the tissues of most organs and organ systems. Extraskeletal effects of vitamin D are aimed at the immune system, muscles, heart and blood vessels, nervous system and brain.

The most challenging attribute of vitamin D is immunomodulatory action. After ingestion or skin synthesis, 25­OH vitamin D is metabolized to produce the endocrine hormone, 1,25 dihydroxyvitamin D (1,25(OH)2D). This form of vitamin D regulates gene expression in various targeted tissues by interacting with the vitamin D receptor (VDR) ­ a ligand­activated transcription factor2. Interestingly, the most responsive target tissue is the intestine. The well ­ known role of vitamin D in the intestine is control of calcium metabolism by regulating the intestinal calcium absorption. But it is only one part of this interaction. Scientific data show that other functions of the intestine are regulated by the biological actions of 1,25(OH)2D through the VDR. Vitamin D status and VDR activity in the intestine impacts the integrity and function of gut barrier, suppression of colon carcinogenesis, re­ gulation of intestinal stem cells, and inhibiting gut inflammation3

Vitamin D and vitamin D receptors (VDRs) play a role in regulating the microbiome of the digestive and respiratory systems in both health and disease. The body of scientific evidence shows that vitamin D is one of the protagonists in the complex interplay between intestinal microbiota and immune system modulation2. Vitamin D status in the gut, and low vitamin D concentrations in the blood are associated with increased intestinal permeability and consequent metabolic endotoxemia associated with low­grade inflammation. The use of vitamin D can affect the composition of the intestinal microbiota, and the results of in vitro research show that vitamin D enhances the ability of macrophages to suppress Escherichia coli . In animal models of mice deficient in vitamin D or in those with inactive VDR receptors, dysbiosis develops, which favors intestinal and metabolic disorders, and presents a risk for development of various diseases and conditions. The synergy of probiotics and vitamin D in humans is supported by the results of a randomized placebo­controlled study published in 2013. showing that the use of vitamin D in combination with the probiotic strain L.reuteriresulted in a 25% increase in vitamin D levels in the blood4

The first studies that indicated the synergistic effect of the use of probiotics (LactobacillusreuteriDSM 17938) and vitamin D3 were conducted on children with asthma in 20165. More recent interventional clinical studies observe the use of this combination on adult patients in very diverse indications. For example, the combination of vitamin D and probiotics showed a beneficial effect on mental health and hormonal, inflammatory and oxidative stress markers in women with polycystic ovary syndrome (PCOS)6. Furthermore, this combination was investigated in patients with schizophrenia and a favorable clinical and metabolic effect was recorded7. A double­blind clinical study published in 2018 showed that the combination of vitamin D and probiotics can be effective in patients with type 2 diabetes and coronary heart disease, and the beneficial effects were reflected in mental health, inflammatory parameters, and regulation of glycemia and lipids in the subjects8. Indications in which the use of a combination of vitamin D and probiotics certainly makes sense are inflammatory bowel diseases (especially ulcerative colitis) and non­alcoholic fatty liver disease, as well as in pregnant women with gestational diabetes, children with type 1 diabetes and obesity9,10

FIGURE 1 Interpretation of vitamin D levels in blood in specific ranges

Cardiometabolic diseases might be linked to vitamin D deficiency through microbiota. A combination of vitamin D insufficiency or deficiency and dysbiosis may contribute to the progression of cardiometabolic diseases. Adequate vitamin D status has a beneficial effect on gut microbiota, therefore preventing the progression of development and progression of metabolic syndrome11.

Multiple investigations indicate that the gut microbiota could play a role in the onset and progression of colorectal cancer (CRC). Furthermore, low levels of vitamin D (vitD) in the bloodstream are linked to an increased risk of CRC as well as poorer prognosis. Nevertheless, the relationship between these two factors remains unclear. One possibility is that vitD supplementation could have an impact on the composition of the gut microbiota, and that the microbiota could play a role in mediating the effects of supplementation12

The short guide to vitamin D supplementation

Vitamin D replacement therapy increases the concentration of 25(OH)D in the blood, and the increase depends on the body weight of the individual and the initial concentration of 25(OH)D.

Control of vitamin D replacement therapy is laboratory monitoring of concentration 25(OH) vitamin D in the blood and achieving a target value of ≥75 nmol/L (30ng/mL) for adults13 and ≥50 nmol/L (20 ng/mL) for children14. Preferred values for various the extraskeletal effects of vitamin D can be significantly higher and range up to 150 nmol/L, and interpretations of other ranges and limit toxic concentrations are presented in Figure 1.

The concentration of 25(OH)D in the range of 75–100 nmol/L is usually achieved by the replacement Therapy with doses in the range od 2.000 to 4.000 IU of vitamin D3 per day. Achieving blood concentration greater than 100 nmol/L requires the use of higher doses.

For the purpose of preventive use, vitamin D is usually dosed in the range of 800 – 2,000 IU per day, and the dose is adjusted depending on age and risk factors. The dose of 400–1000 IJ/day is recommended for infants, 1.000–1.500 IJ/day for children from 1 to 10 years, 1.500–2.000 IJ/day for adolescents and 2.000–4.000 IU/day for adults15. The same range of daily doses is used as maintenance dose in people who have reached the desired vitamin concentration D in blood (75­125 nmol/L). If the replacement therapy is applied to people who are obese or have malabsorption, the daily dose should be increased two to three times.

In laboratory-confirmed vitamin D deficiency (concentration in blood < 75 nmol/L) a dose of 6.000 IU per day is used for the duration 8 weeks, but the duration of therapy can vary between 4 and 12 weeks, depending on the starting value of the concentration of 25(OH)D in the blood and risk factors. Patients with malabsorption syndromes, obesity or using pharmacotherapy that interfere with the metabolism of vitamin D, can apply doses of up to 10.000 IU per day over a longer period of time, under medical supervision.

References:

1 Sassi F, Tamone C, D'Amelio P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients. 2018;10(11):1656.

2 Luthold RV, Fernandes GR, Franco­de­Moraes AC, Folchetti LG, Ferreira SR.Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals. Metabolism. 2017;69:76­86.

3 Fleet JC. Vitamin D and Gut Health. Adv Exp Med Biol. 2022;1390:155­167.

4 Jones ML, Martoni CJ, Prakash S. Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25­hydroxyvitamin D: a post hoc analysis of a randomized controlled trial. J Clin Endocrinol Metab. 2013;98(7):2944­51.

5 Miraglia Del Giudice M, Maiello N, Allegorico A, Iavarazzo L, Capasso M, Capristo C, Ciprandi G. Lactobacillus reuteri DSM 17938 plus vitamin D3 as ancillary treatment in allergic children with asthma. Ann Allergy Asthma Immunol. 2016;117(6):710­712.

6 Ostadmohammadi V, Jamilian M, Bahmani F, Asemi Z. Vitamin D and probiotic co-supplementation affects mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome. J Ovarian Res. 2019;12(1):5.

7 Ghaderi A, Banafshe HR, Mirhosseini N, Moradi M, Karimi MA, Mehrzad F, Bahmani F, Asemi Z. Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients. BMC Psychiatry. 2019;19(1):77.

8 Raygan F, Ostadmohammadi V, Bahmani F, Asemi Z. The effects of vitamin D and probiotic co­supplementation on mental health parameters and metabolic status in type 2 diabetic patients with coronary heart disease: A randomized, double­blind, placebocontrolled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):50­55.

9 Jamilian M, Amirani E, Asemi Z. The effects of vitamin D and probiotic co-supplementation on glucose homeostasis, inflammation, oxidative stress and pregnancy outcomes in gestational diabetes: A randomized, double­blind, placebo­controlled trial. Clin Nutr. 2019;38(5):2098­2105.

10 Sun J. Dietary vitamin D, vitamin D receptor, and microbiome. Curr Opin Clin Nutr Metab Care. 2018;21(6):471­474.

11 Sukik A, Alalwani J, Ganji V. Vitamin D, Gut Microbiota, and Cardiometabolic Diseases­A Possible Three­Way Axis. Int J Mol Sci. 2023 Jan 4;24(2):940.

12 Trovato C, Zampino MG, Corso F, Bellocco R, Raimondi S, Rescigno M, Gandini S. Colorectal cancer, Vitamin D and microbiota: A double­blind Phase II randomized trial (ColoViD) in colorectal cancer patients. Neoplasia. 2022;34:100842.

13 Vranešić Bender D, Giljević Z, Kušec V, Laktašić Žerjavić N, Bošnjak Pašić M, Vrdoljak E, et al. Smjernice za prevenciju, prepoznavanje i liječenje nedostatka vitamina D u odraslih. Liječ Vjesn 2016;138:121-132. 8.

14 Braegger, C., Campoy, C., Colomb, V., Decsi, T., Domellof, M., Fewtrell, M., Hojsak, I., Mihatsch, W., Molgaard, C., Shamir, R., Turck, D., van Goudoever, J. Vitamin D in the Healthy European Paediatric Population. J Pediatr Gastroenterol Nutr. 2013; 56 (6), 692­701

15 National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment Osteoporosis. Developed by the NOF 2009, updated January 2010.