Vitamin D requires Gut-microbiome activation to work

Vitamin D helps regulate calcium and phosphate in the body to maintain our bones, teeth, and muscles. Nowadays, studies confirm the beneficial effects of Vitamin D on the bowel[1], heart, skin, cell overgrowth, and blood sugar.[2]

Vitamin D and maintaining immune defenses are also correlated [3]. Current research found that over 80% of 200 COVID-19 patients in Spain had Vitamin D deficiency [4]. Further limited studies and meta-analyses have observed that Vitamin D seems to reduce symptoms of COVID-19 as compared to standard care [5]. However, more substantial data is needed to support its impact in decreasing mortality rates of hospitalized patients.

We now know that there is evidence to back up the benefits of Vitamin D in the body. Still, the research community debates its ability to prevent diseases. In particular, one study concluded that Vitamin D supplementation did not improve the bone strength of old adults in the US [6]. Another clinical trial concluded that Vitamin D supplementation did not prevent cancer and cardiovascular disease in aging adults [7].

These mixed findings on the benefits of Vitamin D have been a mystery to scientists, until now. Researchers at the University of California (UC) San Diego recently revealed a possible explanation for this discrepancy and a new understanding of Vitamin D bioavailability [8].

The Inactive Form of Vitamin D

Like any other substance, Vitamin D comes in several forms. Typically, researchers determine Vitamin D levels in the body by conducting standard blood tests, which only detect an inactive form of Vitamin D stored in the body called 25 hydroxyvitamin D or 25(OH)D.

The body benefits from Vitamin D only when the inactive precursor metabolizes into its active form - 1,25 dihydroxyvitamin D or 1,25(OH)D. So no matter the amount of sun exposure or supplementation you take in, you only gain the benefits once activation of Vitamin D occurs in the body.

UC San Diego researchers have suggested that the Vitamin D paradox, where studies failed to establish a correlation in Vitamin D supplementation, blood inactive Vitamin D status, and positive health outcomes, might be due to scientists measuring in the blood 25(OH)D, the inactive form of Vitamin D, rather than its active form 1-25(OH)D.

Gut Microbiome and Vitamin D Link

In addition, UC San Diego researchers found a consistent association between 1-25(OH)D levels, the active form of Vitamin D, and the diversity and number of bacteria in the gut microbiome. In contrast, 25(OH)D, the precursor form of the vitamin, had a weak correlation with the “friendly” gut bacteria. The link between active Vitamin D levels and gut microbiome trumps other factors investigated in the study, such as antibiotic use, ethnic background, and even location.

Butyrate and Vitamin D Metabolism

The study also pointed out that participants with the highest levels of active Vitamin D have the most gut bacteria that produce butyrate. This short-chain fatty acid results from bacteria feeding on fibre and has been known to have potential benefits to support the gut lining, maintain the gut microbiome, and further support a competent immune system [9].

Researchers believe that butyrate-producing gut bacteria, rather than high quantities of inactive Vitamin D, control Vitamin D activation, which could explain these seemingly contradicting findings

Contrary to prior logic, participants living in sunnier places did not have significantly higher levels of active Vitamin D as other participants, despite synthesizing high amounts of inactive Vitamin D through the skin. Researchers believe that butyrate-producing gut bacteria, rather than high quantities of inactive Vitamin D, control Vitamin D activation, which could explain these seemingly contradicting findings.

Moreover, there is increasing evidence that the microbiome and immune system are interconnected and that active Vitamin D and butyrate may play extensive roles in this dynamic [10].

All of this points to butyrate helping our body transform the inactive precursor to the active form of Vitamin D, allowing us to reap all the benefits for optimal well-being.


Vitamin D supplementation and sunlight appear to be insufficient for optimal Vitamin D bioavailability and turnover. We need to encourage our bodies through gut microbial diversity, including butyrate-producing bacteria, to directly influence Vitamin D metabolism to its active form. Consequently, supplementing Vitamin D with butyrate ensures that we get all the benefits of Vitamin D to promote a sound mind and body while maintaining a favourable gut microbiome to support our immunity and overall well-being.

[1] Barbáchano, A., Fernández-Barral, A., Ferrer-Mayorga, G., Costales-Carrera, A., Larriba, M. J., & Muñoz, A. (2017). The endocrine vitamin D system in the gut. Molecular and Cellular Endocrinology. 453, 79–87.

[2] Bikle, D. D. (2016). Extraskeletal actions of vitamin D. Annals of the New York Academy of Sciences. 1376(1), 29–52.

[3] von Essen, M. R., Kongsbak, M., Schjerling, P., Olgaard, K., ØDum, N., & Geisler, C. (2010). Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nature Immunology. 11(4), 344–349.

[4] Hernández, J. L., Nan, D., Fernandez-Ayala, M., García-Unzueta, M., et al. (2020). Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection. The Journal of Clinical Endocrinology & Metabolism. 106(3), e1343–e1353.

[5] Shah, K., Saxena, D., and Mavalankar, D. (2021). Vitamin D supplementation, COVID-19 and disease severity: a meta-analysis. QJM: An International Journal of Medicine. 114(3), 175-181.

[6] LeBoff, M. S., Chou, S. H., Murata, E. M., Donlon, C. M., (2020). Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA‐3 TriaL (VITAL). Journal of Bone and Mineral Research. 35(5), 883–893.

[7] Manson, J. E., Cook, N. R., Lee, I. M., Christen, W., et. al. (2019). Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. New England Journal of Medicine, 380(1). 33–44.

[8] Thomas, R. L., Jiang, L., Adams, J. S., Xu, Z. Z., Shen, J., Janssen, S., Ackermann, G., Vanderschueren, D., Pauwels, S., Knight, R., Orwoll, E. S., & Kado, D. M. (2020). Vitamin D metabolites and the gut microbiome in older men. Nature Communications. 11(1).

[9] Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., et. al. (2013). Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 504(7480), 446–450.

[10] Yamamoto, E. A., & Jørgensen, T. N. (2020). Relationships Between Vitamin D, Gut Microbiome, and Systemic Autoimmunity. Frontiers in Immunology. 10.

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