†These authors contributed equally.
Academic Editor: Elad Tako
Vitamin D is essential for the regulation of the immune system. In recent years, the role of vitamin D in the control of several autoimmune conditions such as inflammatory bowel disease (IBD), celiac disease, type 1 diabetes mellitus (T1DM), and others has been investigated. The aim of this review was to define the level of knowledge on vitamin D’s role in these disorders, as well as the preventive and therapeutic role of vitamin D supplementation. Relevant studies published over the last 20 years were identified via a PubMed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) search using the keywords: vitamin D, autoimmune disease, and prevention. Vitamin D deficiency or impaired function of the enzymes necessary for its activity has been shown to affect the onset and severity of the autoimmune diseases examined. Vitamin D supplementation appears useful in the support therapy of IBD. Its role in celiac disease, autoimmune hepatitis, T1DM, and autoimmune thyroiditis is unclear. In conclusion, further studies are needed to define whether vitamin D is a cause or a result of the most common autoimmune, extra-skeletal diseases, such as IBD. Vitamin D should be provided to all newborns during their first year of life. Afterwards, the vitamin D supplementation regimen should be tailored to the presence of risk factors for vitamin D deficiency and/or specific disease.
Genetic, immunological, hormonal, environmental, or microbial factors can trigger the development of autoimmune diseases. It has been demonstrated that low vitamin D levels are associated with the development of many illnesses (including upper respiratory tract, enteric, and urinary infections), and that these concentrations may underpin the onset of autoimmune disease. Many autoimmune disorders, such as inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes mellitus (T1DM), are more common in northern latitudes where sun exposure is limited, and vitamin D insufficiency is more prevalent . This is because vitamin D promotes the function of immune cells and the generation of antimicrobial peptides in the immune system [2, 3, 4, 5, 6]. The aim of this study was to summarize knowledge regarding the relationship between low vitamin D levels and the most common autoimmune diseases and to investigate the possibilities of supplementing vitamin D in prevention or treatment.
Relevant studies published over the last 20 years were identified via a PubMed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) search using the keywords, or combinations of keywords: vitamin D, autoimmune disease, and prevention. The most common autoimmune diseases were afterwards used as search terms to review literature data regarding the role of vitamin D in their pathogenesis. Particular emphasis was placed on primary prevention studies, undertaken prior to any evidence of autoimmunity. Additional papers were identified by reviewing reference lists of relevant publications. Non-English publications were excluded. A systematic approach to study selection was not implemented. Instead, data were extracted based on their relevance to the topic.
Cholecalciferol, or vitamin D3, is primarily generated in the skin from a precursor, 7-dehydrocholesterol, via a photoconversion pathway mediated by ultraviolet B. This is the primary route of vitamin D3 production, although it may also be received from other sources, such as food (in conjunction with vitamin D2) (Table 1, Ref. ) or vitamin supplements .
|Food||Vitamin D amount (IU)|
|Salmon, trout, cod||30–1500/100 g|
|Cod liver oil||400/5 mL|
|Egg yolk||20/100 g|
|IU, international unit.|
Once synthesized, vitamin D attaches to vitamin D-binding protein (VDBP) and
undergoes two successive hydroxylations: the first in the liver, mediated by
cytochrome P450R1 and minimally by other enzymes, and the second in the kidney,
catalyzed by CYP27B1. Once activated, 1,25(OH)2D exerts its functions by binding
to its nuclear receptor, the vitamin D receptor (VDR), which is found in a
variety of tissues such as the skin, parathyroid, adipocytes, and the intestine
. It modulates plasma calcium content in the bloodstream by stimulating the
development of osteoclast precursors into mature osteoclasts and enhancing the
expression of calcium channels to promote dietary calcium absorption . Recent
studies have shown vitamin D-activating enzyme systems and VDRs in immune system
cells such as dendritic cells, monocytes/macrophages, and lymphocytes [2, 8].
Vitamin D downregulates major histocompatibility complex (MHC) class II and
co-stimulatory molecules (such as CD40, CD80, and CD87) on dendritic cells,
resulting in decreased activation of CD4+ T cells. Furthermore, vitamin D
inhibits dendritic cell cytokine production, notably interleukin (IL) 23, which
promotes T helper cell development into Th17 cells. Vitamin D also increases
IL-10 expression . Some Toll-like receptors are expressed on the surface of
monocytes and macrophages and stimulate the expression of VDRs and CYP27B1 when
they bind to microbial (bacterial, viral, or fungal) components. CYP27B1 enters
the cell and transforms 25-hydroxyvitamin D (25(OH)D) into the active form of
vitamin D. Within the cell, 1,25(OH)2D stimulates the formation of antimicrobial
peptides such as cathelicidin and defensin 2, while also regulating the
expression of the DEFB4 gene via the transcription factor nuclear factor
The gut microbiota has an increasingly recognized role in the genesis of
autoimmune diseases. The microbiota is made up of bacteria, viruses, fungi, and
other microbial agents and comprises the entirety of commensal, symbiotic, and
pathogenic microorganisms found in the gut. There are approximately 2.8
Vitamin D has been shown to influence the makeup of the microbiota. Previous research has demonstrated that a lack of vitamin D owing to dietary restriction, the absence of CYP27B1 or the VDRs stimulates the growth of Bacteriodetes and Proteobacteria [15, 16]. In a cross-sectional study of healthy subjects, vitamin D consumption was linked to an abundance of Prevotella and Bacteroides . In addition to Prevotella, lower amounts of Haemophilus and Veillonella, both from the phyla Proteobacteria and Firmicutes, were found [16, 17]. In a study that compared biopsies obtained from endoscopic examinations in patients on vitamin D3 supplementation for 8 weeks, it was discovered that the upper gastrointestinal tract had a greater richness of different species, with a reduction in Proteobacteria and an increase in Bacteroidetes, whereas the lower gastrointestinal tract and feces had no difference in the composition of the microbiota before and after supplementation .
Bacteria can also impact vitamin D metabolism; for example, Streptomyces griseolus CYP105A1 converts vitamin D3 to 1,25(OH)D via two hydroxylation processes distinct from those discussed above . Ruminococcus torques (Firmicutes) and Mycobacterium tuberculosis both have homologous CYP27A1 and CYP27B1 proteins .
Despite this, it remains unclear how vitamin D supplementation or deficiency impacts the microbiota of autoimmune disease patients. Genetic predisposition influences all aspects of vitamin D activity, intestinal barrier integrity, and immune activation. A lack of vitamin D enhances permeability of the intestinal barrier and immunological activity.
It has been speculated that vitamin D, and particularly its insufficiency, is linked to the emergence of autoimmune diseases [1, 11]. Below is reported the most recent evidence on the role of vitamin D in the genesis of some of the most frequent autoimmune diseases, such as IBD, celiac disease, autoimmune hepatitis, T1DM, and autoimmune thyropathy.
IBDs, which include Crohn’s disease (CD), ulcerative colitis (UC), and IBD unclassified, are chronic inflammatory disorders with periods of activity and clinical remission. Given its function in immune system homeostasis, particularly at the intestinal level, vitamin D has been suggested to be capable of affecting the clinical activity of IBD .
The intestinal epithelium is the first line of defense, and its integrity is dependent on vitamin D, among other elements. It has been demonstrated that animals with VDR deletion at the intestinal epithelial level had clinically more severe colitis, with worsened apoptosis and enhanced mucosal response of Th1 and Th17 . In contrast, vitamin D supplementation decreased the severity of colitis in both wild-type and Cyp knock-out mice, who are nonproducers of endogenous 1,25(OH)2D, in a model of acute colitis generated by sodium dextran sulfate. Furthermore, transgenic mice expressing human VDR in intestinal epithelial cells demonstrated better resistance to colitis induction than wild-type mice . Du et al.  demonstrated that in inflammatory conditions, intestinal VDR is downregulated, which is related to elevated local CYP27B1 expression, as a protective effect for lowering inflammation and boosting VDR signaling. In fact, animals given antibiotics but unable to upregulate CYP27B1 suffered more severe colitis. Furthermore, elevated vitamin D levels appear to be associated with higher serum cathelicidin concentrations and decreased inflammation in UC patients. In a study conducted by Brandvayman et al. , no significant relationship was found between low vitamin D levels and seasonal patterns in disease onset in children; however, in the case of flares, a higher frequency was observed in June and a lower frequency in April (p = 0.016), with significantly lower vitamin D levels as compared to those tested during remission . Low 25(OH)D levels have been linked to a higher incidence of active illness . Notably, low vitamin D levels were seen even in IBD patients in clinical remission . This might be owing to the effect of medicines on micronutrient absorption; for example, glucocorticoids diminish calcium, zinc, and phosphorus absorption and utilization and change vitamin D metabolism. Low or inadequate vitamin D levels are also connected with an increased requirement for admission and surgery in this group of subjects .
Vitamin D supplementation in IBD patients may be compromised due to malabsorption; hence, substantial doses of vitamin D are typically necessary to attain optimum serological levels. The optimal dose strategy to treat vitamin D deficiency and maintain adequacy in IBD patients, however, is still being discussed . In pediatric IBD patients, 2000 international unit (IU)/day of vitamin D3 for 6 months was found to be more effective than 400 IU/day or vitamin D2 dosages up to 2000 IU in raising blood 25(OH)D concentrations above 30 ng/mL [24, 25]. Oral dosages of 2000 IU/day vitamin D3 and 50,000 IU/week vitamin D2 for 6 weeks were both well-tolerated and superior to 2000 IU/day vitamin D2 in boosting blood 25(OH)D concentrations in IBD patients with vitamin D insufficiency . Simek et al.  discovered that two weekly vitamin D3 administration regimens for 6 weeks (5000 IU/10 kg/week, maximum weekly dose of 25,000 IU, and maximum cumulative dose of 150,000 IU versus 10,000 IU/10 kg/week, maximum weekly dose of 50,000 IU, and maximum cumulative dose of 300,000 IU) were safe and effective in correcting vitamin D status in IBD children with hypovitaminosis D. Current recommendations on vitamin D supplementation and status in pediatric IBD patients are summarized in Table 2 (Ref. ).
|Vitamin D status check||At diagnosis and at least yearly (serum 25(OH)D levels)|
|Vitamin D supplementation||Continuous and at least 1000–1500 IU/day (higher doses than those recommended for age)|
|To be done after achieving vitamin D sufficiency (in case of deficiency)|
|Vitamin D treatment (deficiency)||Daily 2000–4000 IU/day vitamin D for |
|Vitamin D treatment (deficiency and poor compliance to daily treatment)||Intermittent bolus doses for a cumulative dose of |
|IU, international unit.|
Supplementing with vitamin D has been shown to improve disease symptoms. It should be noted that if such individuals have genetic variants or VDR malfunction, supplementation may be changed .
Vitamin D supplementation and VDR’s anti-inflammatory action are both linked to
the gut microbiota. First, there is dysbiosis in IBD patients . CD patients
typically have a decrease in the phylum Firmicutes, particularly
Faecalibacterium prausnitzii, and a rise in Bacteroidetes and
Proteobacteria. The microbiota of UC patients is distinguished by a low
number of butyrate-producing bacteria and an enhanced Bacteroides
fragilis/Faecalibacterium prausnitzii ratio, which is linked with a poor
anti-inflammatory response . Low amounts of Faecalibacterium
prausnitzii in the stool have been linked to flares; at normal quantities, they
boost IL-10 production while decreasing IL-12 and interferon-
Celiac disease is a chronic autoimmune enteropathy caused by an immune response provoked by gluten in those who are genetically prone to it. It has been proposed that vitamin D insufficiency in childhood may contribute to the etiology of celiac disease by causing incorrect immunological responses, aberrant intestinal mucosal integrity, and reduced local defense against microbial pathogens . A link between sun exposure and celiac disease pathogenesis has been proposed, suggesting that celiac disease is more frequent in northern than in southern latitudes in the United States . Maternal vitamin D supplementation, as well as maternal and neonatal vitamin D status, were not found to be associated with the risk of celiac disease in children [35, 36].
Patients with celiac disease have lower vitamin D levels than healthy people [1, 37]. Furthermore, patients on a gluten-free diet (GFD) had greater vitamin D levels, with values more equivalent to those reported in healthy controls as compared to patients on a free diet. There is no difference in VDR genotypes between celiac disease patients and controls . The microbiome, which may be important in the development of celiac disease, plays an important role. The microbiome of healthy adults varied from that of celiac patients who have not removed gluten from their diet, and patients on a GFD had a considerable drop in Lactobacillus and Bifidobacterium in the study by Nistal et al. . Furthermore, another study found that pediatric celiac disease patients have a greater incidence of pro-inflammatory and gram-negative bacteria in the duodenum upon diagnosis than controls . As previously stated, vitamin D regulates the gut flora, and a lack of it can increase the evolution of celiac disease through these changes. In addition, celiac disease is linked to gastrointestinal infections. Rotavirus infections in children and Campylobacter infections in adults, as well as antibiotic exposure and early childhood illnesses, are risk factors . Vitamin D deficiency is known to enhance susceptibility to infections. It has also been demonstrated that chronic vitamin D and VDR deficiency might worsen celiac disease and influence prognosis .
Based on the research thus far, it is unclear if vitamin D is a contributing factor or a result of celiac disease. Bittker et al.  claimed that the high levels of 1,25(OH)2D (as opposed to 25(OH)D, which is low in patients with celiac disease) found in non-GFD patients may be considered a risk factor for celiac disease onset for a variety of reasons, including the association between prolonged oral vitamin D supplementation and an increased risk of celiac disease. The same cytokines, chemokines, and toll-like receptors are upregulated after high doses of vitamin D as well as throughout the disease .
Autoimmune hepatitis is a disorder defined by an autoimmune reaction initiated by autoantibodies generated against the liver parenchyma, resulting in liver inflammation and, if not treated promptly, progression to cirrhosis and liver failure. In addition, Tao et al.  evaluated the relationship between low vitamin D levels and indicators of T-cell inflammation/subset in a retrospective study on a cohort of adult patients with autoimmune hepatitis. In this study, patients with low vitamin D levels had an increase in inflammatory response, oxidative stress, and a reduction in T cell subsets. These alterations were significantly different in patients with impaired liver function compared to those with autoimmune hepatitis but normal liver function. The amount of 25(OH)D in individuals with autoimmune hepatitis was found to correlate adversely with inflammatory factors (hs CRP, TNF, IL-6) and oxidative stress factor (malondialdehyde) and positively with CD3+ and CD4+ counts, superoxide dismutase, and total antioxidant capacity . Furthermore, a mutation in the FokI gene at the beginning codon of vitamin D receptor exon 2 alters mRNA transcription and replication of VDR, reducing receptor function and leading to immunosuppression, which is the cause of autoimmune hepatitis.
T1DM is a polygenic autoimmune disease characterized by a total lack of insulin
secretion. Several studies  have given light on the link between vitamin D and
this condition. VDRs have been discovered at the pancreatic islet cell membrane,
implying a function in glucose regulation . Thus, vitamin D administration
may slow the course of previously diagnosed T1DM by boosting pancreatic beta-cell
secretion or by immunomodulatory actions. Maretzke et al.  examined
meta-analyses, systematic reviews, and randomized controlled trials that found an
inverse relationship between vitamin D supplementation in childhood and the
likelihood of developing T1DM. According to these findings, supplementing with
vitamin D during pregnancy has no influence on the risk of T1DM in children.
However, all of the previous studies are of poor quality. There is insufficient
evidence to support vitamin D supplementation as primary prophylaxis . Data
on supplementing during pregnancy are debatable, and no indication of protection
has been demonstrated . Epidemiological studies, on the other hand, have
shown that patients geographically farther from the equator or in locations with
longer winters had a higher risk of developing T1DM, indicating the protective
role of vitamin D in the genesis of T1DM. Gregoriou et al. 
conducted a high-quality systematic review that included seven randomized
clinical trials in which alfacalcidol or vitamin D3 supplementation (0.25–0.5
Vitamin D is crucial in autoimmune thyroid disorders. Experiments in animal
models have revealed that vitamin D insufficiency (25(OH)D
In summary, it is still unknown if vitamin D insufficiency is a cause or a result of autoimmune illness. The role of vitamin D supplementation and its consequent success in the therapy of autoimmune thyroid disease remains debatable.
The role of vitamin D has been thoroughly proven, not only in calcium-phosphorus metabolism but also in immune system modulation. More studies, particularly randomized clinical trials, are needed to determine if vitamin D has a causative or consequential role in these extra-skeletal autoimmune diseases since no clear evidence has been found yet. In the management of autoimmune diseases in terms of prevention or treatment, the role of vitamin D should be considered, especially in at-risk categories and/or in the presence of predisposing genetic factors.
CA and CR designed the study. VD, GLP, GPM and AC performed the literature research. VD and GLP wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
This research received no external funding.
The authors declare no conflict of interest.
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