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The Role of Vitamin D in Supporting Health in the COVID-19 Era – March 25, 2022


Int. J. Mol. Sci. 2022, 23(7), 3621; https://doi.org/10.3390/ijms23073621
by Alice Albergamo †,Giulia Apprato † and Francesca Silvagno *ORCID
Department of Oncology, University of Torino, 10126 Torino, Italy

The genomic activity of vitamin D is associated with metabolic effects, and the hormone has a strong impact on several physiological functions and, therefore, on health. Among its renowned functions, vitamin D is an immunomodulator and a molecule with an anti-inflammatory effect, and, recently, it has been much studied in relation to its response against viral infections, especially against COVID-19. This review aims to take stock of the correlation studies between vitamin D deficiency and increased risks of severe COVID-19 disease and, similarly, between vitamin D deficiency and acute respiratory distress syndrome. Based on this evidence, supplementation with vitamin D has been tested in clinical trials, and the results are discussed. Finally, this study includes a biochemical analysis on the effects of vitamin D in the body’s defense mechanisms against viral infection. In particular, the antioxidant and anti-inflammatory functions are considered in relation to energy metabolism, and the potential, beneficial effect of vitamin D in COVID-19 is described, with discussion of its influence on different biochemical pathways. The proposed, broader view of vitamin D activity could support a better-integrated approach in supplementation strategies against severe COVID-19, which could be valuable in a near future of living with an infection becoming endemic.
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Table of many trials (from supplementary material)

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Concluding Remarks on Vitamin D Supplementation in COVID-19

The comparison between existing studies is made difficult by the heterogenous patient populations and the differences in treatment protocols. As was highlighted in Section 6.1, due to personal sensitivity to vitamin D activity, it is difficult to establish the proper dosage for an effective treatment of a whole cohort of patients; for this reason, the highest dose of hormone is probably the most appropriate choice, although the negative calcemic effects should be carefully evaluated, and non-calcemic analogs should be tested. It should be noted, however, that a large bolus of vitamin D may have minimal benefit or could even be counterproductive, whereas moderate daily doses in individuals at risk of deficiency would be more beneficial, as highlighted in most recent meta-analyses and reviews [158,159]. In addition to dosage and duration of treatment, it is important to assess the form of the metabolite administered. Cholecalciferol, native vitamin D3, is the most widely tested form due to its large availability and low cost, particularly in developing countries, as well as its relatively safe side-effect profile [144]. On the other hand, calcifediol appears to have advantages over cholecalciferol. Indeed, it does not require hepatic 25-hydroxylation, which can be hampered by liver overload; it has a more reliable intestinal absorption (close to 100%) and can rapidly restore serum concentration of 25(OH)D3 [150]. The advantage of calcidiol administration was reported in osteoporotic patients [160]. Furthermore, the best route of administration and early treatment must be considered, taking into account the clinical characteristics of the patients, baseline 25(OH)D3 levels, and outcome measurement [140,161]. Although some studies considered serum 25(OH)D3 as a negative acute-phase reactant [162], nonetheless, supplementation with the hormone was found to be generally helpful in COVID-19 outcomes. Further, large-scale population studies are needed to confirm the beneficial effects of vitamin D in reducing disease severity and in preventing infection.

Summary of reported mechanisms and targets

  1. Viral entry is hampered; the computational study by Song et al. demonstrated that the interaction of 1,25(OH)2D3 with the SARS-CoV-2 spike RBD (receptor-binding domain) causes a change in the dynamic movement of the binding surfaces between the SARS-CoV-2 RBD and the ACE2 that disrupts their binding [167]. In addition, it was seen that vitamin D and its hydroxyl derivatives bind the active site of TMPRSS2 (the transmembrane serin protease with the function of priming the spike protein) and inhibit SARS-CoV-2 RBD binding to ACE2 to prevent SARS-CoV-2 entry. Moreover, calcitriol downregulates the transcription of ACE2 codifying gene [168].
  2. A recent proteomic study identified 332 human protein targets of the 27 viral proteins [169]. The investigation, carried out by genomics-guided tracing of SARS-CoV-2 targets in human cells, showed that vitamin D alters the expression of 84 genes out of 332 (25%) genes, encoding human proteins prey of 19 viral proteins. These observations suggest that vitamin D, in addition to the inhibition of ACE2 gene expression, may potentially interfere with the functions of 19 out of 27 (70%) SARS- CoV-2 proteins [168]. These analyses support the possibility that vitamin D and VDR are putative mitigation factors of the coronavirus infection.
  3. Virus-triggered RAS imbalance is restored; active vitamin D can modulate the expression of the members of the RAS system in different pathological conditions where the system is altered [93,94,97,170,171]. In fact, in vitro analysis conducted on LPS-treated murine lung cells showed that high concentrations of calcitriol dramatically reduce the effects of LPS on ACE levels and decrease mRNA expression of ATR1 and AngII. Calcitriol also suppresses renin expression, resulting in the inhibition of the ACE/Ang II/AT1R cascade [97]. Moreover, in a study on obese mice, calcitriol administration attenuated acute lung injury complicated with sepsis by promoting the activity of the anti-inflammatory pathway in the RAS. This treatment induced higher ACE2 and MasR expression but lowered AT1R expression and decreased macrophage and neutrophil infiltration in the lung [170]. These studies support the conclusion that the imbalance of the RAS system correlates with the appearance of an uncontrolled inflammatory response [170] which can be reduced by active vitamin D.
  4. The redox balance is maintained; vitamin D regulates the two main players of ROS production and redox defense: NF-kB and glutathione. In COVID-19, the increased levels of AngII generated by the inhibition of ACE2 activate NF-kB, which is responsible for the release of cytokines, enzymes of inflammation, and adhesion molecules. For these reasons AngII is considered an important inflammatory mediator. On the one hand, the NF-kB signaling pathway is partially blocked by active vitamin D [172-174]. On the other hand, ROS generated by the NF-kB signaling pathway are neutralized by the vitamin-D-dependent increased glutathione biosynthesis [33,175] and by the enhanced activity of various ROS-scavenging enzymes controlled by active vitamin D [163].
  5. Mitochondrial oxidative stress is minimized; SARS-CoV-2 infection is associated with altered mitochondrial dynamics with consequent oxidative stress, which can be normalized by active vitamin D, preventing the pro-inflammatory state, cytokine production, and cell death [166]. Indeed, calcitriol through VDR plays a central role in protecting cells from excessive respiration and production of ROS that leads to cell damage [176].


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VitaminDWiki – COVID-19 treated by Vitamin D - studies, reports, videos

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