Vitamin D belongs to the steroid hormone family. It has two major forms, vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol), both of which can be found in foods or supplements, although only vitamin D3 is synthetized in skin [1
]. Indeed, vitamin D3 is mainly produced endogenously in the skin by converting 7-dehydrocholesterol through the action of ultraviolet light B (UVB) of the sun or other UVB sources [2
]. Oral intake of vitamin D is generally limited (oily fish and eggs, vitamin D fortified food), while the majority of it is derived from UVB light action. This links its content not only to dietary intake, but above all to seasonal changes, sun exposure, geographic locations and skin pigmentation [4
]. The steroid hormone precursor vitamin D3 is synthesized within skin and is biologically inactive. Two hydroxylation reactions are required to activate it. The first one forms the 25-hydroxyvitamin D3 [25(OH)D3 or calcidiol] in the liver, then 25(OH)D3 is converted to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol] by the 1α-hydroxylase (CYP27B1) in the kidney. CYP27B1 enzyme is stimulated by parathyroid hormone (PTH) [4
]. Vitamin D has been known for its role in the maintenance and safeguarding of skeletal system integrity. Indeed, biologically active vitamin D enhances calcium intestinal absorption by regulating calcium transport proteins in the small intestine, stimulating osteoclastic maturation and helping bone growth, which in turn supports collagen matrix mineralization [1
The vitamin D receptor (VDR), a nuclear receptor hormone, mediates the biological activity of 1,25(OH)2D3 [4
]. The highly polymorphic VDR belongs to the steroid receptor super family and enables vitamin D to exert its genomic actions [1
Recently, vitamin D has received increased attention, as it was discovered that tissues and cells not involved in mineral and bone metabolism present VDR and vitamin D-activating enzymes. VDR has been reported to be expressed on cell types as antigen-presenting cells and lymphocytes, underlining a possible role of vitamin D as a key modulator of immune and inflammation mechanisms, and suggesting VDR gene polymorphisms to be markers of protection from or susceptibility to autoimmune diseases [3
]. Pleiotropic actions on chronic diseases such as cardiovascular disease, diabetes, neurological disease and autoimmune disease are now under study. Over 900 genes have been reported as regulated by vitamin D [1
]. Although its effect on the immune system and infection is an emerging topic, there has been an increased understanding related to vitamin D as a regulator and signaling component on the immune system [6
Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy triggered by exposure to dietary gluten proteins among individuals genetically predisposed, which affects around 1% of the general population [11
]. CD is a unique autoimmune disease for which gluten has been identified as the environmental trigger. For the disease to occur, the key genetic elements human leukocyte antigen HLA-DQ2 and HLA-DQ8, and the involvement of autoantigen (tissue transglutaminase (tTG)) are required [15
The inducers of the disease are gluten and the alcohol-soluble gliadins it comprises, which are mainly present in specific cereals such as wheat, barley and rye [17
In CD patients, the gluten contained in food products is broken down by specific gastrointestinal enzymes into peptides, which pass through the intestinal epithelial barrier to reach the mucosal lamina propria. The enzyme designated to convert gluten peptides is transglutaminase 2, which recognizes glutamine residues. Glutamine residues are converted into glutamic acid, leading the production of deamidated gluten peptides, which are now able to strongly bind to HLA-DQ2/-DQ8 molecules (the surface restriction elements for gluten-specific CD4+ T lymphocytes). Therefore, gluten peptides behave like antigens inducing an amplified immune response [18
The cited HLA-DQ2/DQ8 molecules are the products of an expression of class II genes by the main histocompatibility complex (HLA system) [19
Beyond genetically predisposed HLA-DQ2/DQ8 haplotypes, another characteristic in CD patients is the autoantibody response expressed against transglutaminase 2. The role of antibodies for transglutaminase 2 in the pathophysiology of CD is not clear, but their serum concentration in CD patients is increased. Autoantibodies play a role in the diagnosis of CD and in monitoring the progression of the disease after beginning a gluten-free diet, which generally reduces serum autoantibodies after a period of months [20
Moreover, celiac disease patients show an altered intestinal mucosa, due to the disassembly of enterocyte tight junctions (which, in physiological conditions, contributes to making the intestinal mucosa a barrier against external agents) [21
Tight junctions are localized in the apical part of enterocytes and are responsible for their connection. Tight junctions are made up of integral membrane proteins such as occluding, claudins and scaffolding proteins (e.g., zonulin) [22
]. Thanks to their capacity to connect enterocytes, tight junctions form a barrier to regulate the transfer of molecules through the intestine. Consequently, a variation in tight junction structure can lead to increased intestinal permeability [21
The characteristic damage that occurs during CD due to gluten exposure develops gradually [23
]. The appearance of lesions characterized by intensified increased intraepithelial lymphocytes, crypt hypertrophy and progressive villous atrophy are the first typical histologic sign of CD. At a macroscopic scale, celiac disease results in malabsorption, diarrhea, bloating and (to variable degrees) undernutrition [24
]. According to Livshits et al., the most widespread intestinal clinical traits are malnutrition, chronic diarrhea and nutritional deficiencies. Today, these traits are disappearing, making way for extra-intestinal presentations such as skin, endocrine, skeletal, hepatic, hematological, thrombophylic, gynecological, fertility, dental, cutaneous, neurological and behavioral abnormalities [25
]. Other extra-intestinal manifestations are osteopenia, osteoporosis, fractures, arthritis and arthralgia [26
]. Currently, gluten-driven symptoms and injuries are occurring at more advanced ages, and latent, hypo-symptomatic or asymptomatic manifestations are becoming amply present [27
Diagnosing CD requires several factors: the presence of clinical signs and symptoms, seropositivity for endomysial or tissue transglutaminase autoantibodies (tTGA), the existence of HLA-DQ2/DQ8 haplotypes and, last but not least, the appearance of histologic lesions characterized by increased intraepithelial lymphocytes, crypt hypertrophy and progressive villous atrophy. However, none of these four criteria are individually sufficient to confirm CD diagnosis [28
While gluten exposure and the presence of specific HLA antigen genotypes are necessary elements for the occurrence of CD, the disease risk is also strictly related to the timing or quantities of gluten consumed, and to the role of other potential pathophysiological factors. Therefore, the genetic predisposition is not enough on its own to be considered the triggering factor of the disease [29
Aside from genetic predisposition, there are additional factors that play important roles in CD. Indeed, genetic background is a mandatory determinant of CD development, but environmental factors (e.g., viral infections) also contribute, such as loss of intestinal barrier function, inappropriate adaptive immune response and an imbalance in gut microbiome [16
]. The role of environmental factors in relation to celiac disease onset is of great interest. In this regard, Ludvigsoon and Green have introduced the concept of a “missing environmental factor” [30
Other than gluten, which is the most important recognized environmental trigger factor, emerging data underline the possible roles of microbiota, time of gluten introduction to children, delivery method, history of breastfeeding, acute viral gastrointestinal infections and micronutrient deficiency in the development of CD [14
]. The emerging extra-calcium role of vitamin D and the increasing interest in its involvement in immune modulation led Tanpowpong and Camargo to postulate that, in genetically predisposed individuals, vitamin D deficiency can play an important role in CD onset in children. In particular, this deficiency can result in a dysregulated immune response that can contribute to an abnormal intestinal mucosa, increasing susceptibility to acute gastrointestinal infection [14
]. Even if the role of vitamin D in celiac disease pathogenesis is not completely known, its potential role in immune regulation could link vitamin D deficiency to this condition, considering that vitamin and mineral deficiencies have been noted both in newly diagnosed CD patients and in CD patients with a gluten free diet (GFD) [12
This review aims to discuss the role of vitamin D in celiac disease onset, considering key findings from literature regarding vitamin D effects on the immune system, 25(OH)D plasma levels, vitamin D supplementation both in pregnancy and in infancy and CD development.
Searches at MEDLINE/PubMed were performed in February 2020 using a combination of keywords addressing “celiac disease”, “vitamin D”, “25-hydroxyvitamin D”, “cholecarciferol”, “vitamin supplement”, “vitamin supplementation”, “pregnancy” and “children”, looking for articles published between 1 January 2010 and 7 February 2020. The following search algorithms were used:
((vitamin D) OR (vit. D) OR (25(OH)D) OR (25-hydroxyvitamin D) OR (cholecalciferol)) AND (celiac disease), which retrieved 428 papers, reduced to 213 with the “last 10 years” filter.
((vitamin D) OR (vit. D) OR (25(OH)D) OR (25-hydroxyvitamin D) OR (cholecalciferol)) AND (celiac disease) AND ((supplementation) OR (supplement)), which retrieved 80 papers, reduced to 57 with the “last 10 years” filter.
((vitamin D) OR (vit. D) OR (25(OH)D) OR (25-hydroxyvitamin D) OR (cholecalciferol)) AND (celiac disease) AND ((pregnancy) OR (pregnant)), which retrieved 21 papers, reduced to nine with the “last 10 years” filter.
((vitamin D) OR (vit. D) OR (25(OH)D) OR (25-hydroxyvitamin D) OR (cholecalciferol)) AND (celiac disease) AND ((infancy) OR (pediatric)), which retrieved 84 papers, reduced to 68 with the “last 10 years” filter.
((vitamin D) OR (vit. D) OR (25(OH)D) OR (25-hydroxyvitamin D) OR (cholecalciferol)) AND (celiac disease) AND ((molecular) OR (in vivo) OR (in vitro)), which retrieved 13 papers, reduced to six with the “last 10 years” filter.
After compiling all of the papers obtained via the research algorithms and eliminating duplicates, the full text of the remaining 44 articles were extensively reviewed on the basis of originality and relevance of each paper to the scope of this review. Thirty-five papers were selected; moreover, 25 papers were added by searching the reference lists of the 35 papers reviewed. A total of 60 articles were considered for this review.
Considering the importance of environmental factors in CD pathophysiology, several aspects are currently under study in order to find a possible association with CD onset. Presently, one important focus of attention relies on birth seasonality, as CD risk seems to increase in infants born during the summer. This aspect could be related to other factors, such as time of gluten ingestion, virus infections, different UV exposures or mother’s vitamin D status during pregnancy, as well as a concomitant presence of these factors. In particular, the emerging extra-calcium role of vitamin D and the increasing interest on its impact on the immune system and intestinal barrier permeability leads to its consideration as an important factor possibly involved in CD onset.
However, there have only been a few fragmentary studies, with different focuses and studied populations. Moreover, the role of supplementation is still uncertain. It is common to routinely consider vitamin D supplementation; however, this has sometimes been considered ineffective.
In light of this, clarifying the role of vitamin D is of great importance. There is a need for larger studies that would take into account variables that can have a role in CD onset (i.e., vitamin D levels of pregnant women, vitamin D supplementation and/or UV exposure), as well as involving different countries. This would be of fundamental importance in order to better explore possible associations and, in particular, to study and evaluate the possible role of vitamin D that could therefore play a key role in terms of prevention and be part of possible new CD prevention strategies.