Gastrointestinal food allergy (GFA), an adverse immune-mediated reaction to food proteins, is the major cause for digestive system dysfunctions in children and is linked to multiple gastroenteropathies such as eosinophilic oesophagitis and gastroenteritis, irritable bowel syndrome, and inflammatory bowel diseases.1 The prevalence of food allergy has been increasing among children living in both developed and developing countries with dramatic impacts on the quality of life of affected children, and financial burdens on the families and social health care systems. There are no proactive treatments available for food allergy. Consequently, the mainstay of therapy is the choice of avoidance.2 Although risk factors and aetiology for food allergy still remain unknown, multiple factors may trigger the escalating trend in the past decade. Studies have revealed that vitamin D may be the important modifiable environmental and social factor for food allergy.3

Vitamin D deficiency and insufficiency is common among children and infants.4,5 Vitamin D is a sterol hormone with well-established function for regulating mineral and bone homeostasis. Mounting evidence supports vitamin D associates with allergic immune responses by regulating the functions of immune cells such as dendritic cells, T and B lymphocytes, mast cells,6–9 with an overall immunosuppressive effect on allergens-triggered hypersensitive immune reaction. Vitamin D and vitamin D receptor (VDR)-mediated signalling also involve in the proliferation of intestinal mucosal epithelial cells and maintaining intact intestinal barrier. Low serum vitamin D level or decreased intestinal VDR signalling can cause impaired intestinal barrier integrity and increase exposure to pathogens from intestinal lumen, and predispose to more-severe and persistent intestinal injury in murine colitis.10–12 The increased permeability and persistent inflammation in gut contribute to the pathological process of GFA.1

Several observational studies suggested that low vitamin D status is associated with the occurrence or the pathological process of food allergy. Low serum vitamin D in pre-neonatal, neonate, or pregnant women was related to increased incidence rate of childhood food allergy or sensitisation,13,14 and infants with challenge-proven food allergy as well as food-sensitised infants with severe atopic dermatitis have low serum vitamin D.15,16 How serum vitamin D status correlates with immunological changes in children who are affected by GFA is less investigated. In this study, we determined serum vitamin D status and its relationship with immunological and clinical outcomes in children with symptomatic GFA.

Forty-nine GFA children and 21 age-matched healthy children were included in this study. There was no significant difference of age, gender, and body mass index (BMI) between these two groups (Table 1). Serum 25OHD levels in the GFA children ranged from 36.5 to 156.4nmol/L with a mean value of 91.2nmol/L. For comparison, serum 25OHD levels in age-matched healthy controls were 92.2nmol/L (ranged from 32.6 to 145.6nmol/L). However, low 25OHD (<75nmol/L, or 30ng/mL) were common in both GFA and control groups (Table 1). In general, GFA children had elevated total IgE and/or blood eosinophil numbers.

Serum concentration of 25OHD in the GFA children varied widely. The mean 25OHD level in the children with low 25OHD was significantly lower than those with normal 25OHD levels (≥75nmol/L) (Table 2). We noticed that GFA children with low 25OHD level had increased total IgE (IgE>166.3kU/L) and persistent blood eosinophilia after one-week food-allergen avoidance, while the eosinophil numbers in those with normal 25OHD rapidly decreased to normal range. The GFA children showed improvement and disappearance of gastrointestinal symptoms upon allergen avoidance (Table 2), but those with low 25OHD had delayed symptomatic resolution compared to those with normal 25OHD level (OR=3.51, 95% CI 1.00–12.36, P=0.048). Additionally, the GFA children with low 25OHD were older and had lower BMI than the 25OHD normal group. There was no difference in circulatory Treg subpopulation in GFA children with low and normal 25OHD. The age and BMI had no effects on total IgE, Tregs, and eosinophil numbers.

We analysed the associations between 25OHD and immunological characteristics of GFA children with elevated total IgE. As shown in Table 3, children with low 25OHD had higher total IgE, lower circulatory Tregs, and persistent blood eosinophilia (Table 3). Furthermore, bivariate relationship analysis showed serum 25OHD concentration correlated inversely with total IgE (Fig. 1A), but positively with circulatory Treg population (Fig. 1B).

Figure 1.

Correlations between serum 25OHD and total IgE and circulatory Tregs in gastrointestinal food allergic children (GFA) with elevated IgE. (A) Serum 25OHD concentration has an inverse correlation with total IgE. (B) Serum 25OHD concentration has a positive correlation with circulatory Treg cell population.

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The prevalence of vitamin D insufficiency is very common.4,20,21 Low vitamin D status has been linked to a variety of disorders. We showed here that GFA children who have low serum vitamin D tend to have higher total IgE and persistent eosinophilia after withdrawal of the offending allergens. IgE and eosinophils have essential roles in type I hypersensitivity, which manifests in various allergic diseases, including food allergies. It was observed that improving vitamin D status in pregnancy or early infancy reduces the development of allergic disease in high-risk infants by inhibiting cytokine profiles associated with allergy.22 In mice, vitamin D deficiency causes IgE elevation and eosinophilia in neonatal allergic disease.23 Vitamin D plays a role in the regulation of immuno-surveillance and maintenance of immunological homeostasis in the gut through IgE-mediated hypersensitive immune responses, including inhibition of IgE production,7 reduction of release of cytotoxic granules by eosinophils,24 and eosinophils migration.25 Therefore, low vitamin D status may adversely affect gut immunological homeostasis in children suffering from GFA.

Another aspect of vitamin D on gut allergic immune response correlates with its capacity to promote the development or to enhance the activity of Tregs, a CD4+ T lymphocytes subgroup that is specialised for immune suppression in normal immune system and is crucial in controlling immune responses as well as maintaining the homeostasis of the immune system.26 The induction of Tregs is a key event in tolerance to food allergens.27 We found that the Treg population was lower in the low vitamin D group. Vitamin D can promote T lymphocyte to Treg transition and induces the development of Tregs via inducing an immature state of tolerogenic dendritic cells, the major cells for presenting antigens to T cells, by inhibiting their differentiation and maturation.28 Vitamin D status positively correlates with regulatory T cell function.9 In pregnant women, vitamin D deficiency impairs Treg cell function and elevates IgE receptor-expressing B cells.29 It is therefore of significance in monitoring vitamin D status of children with digestive system disorders including GFA.

In summary, our study provides novel information in that it is one of very few studies investigating whether lower vitamin D correlates with higher hypersensitive immune response in GFA children. Although the numbers were small, we were able to demonstrate that delayed resolution of eosinophilia and gastrointestinal symptoms was associated with low vitamin D status. Therefore, vitamin D normalisation could be beneficial for children who suffer from GFA.

The study was funded by a grant from Nanjing Municipal Department of Science and Technology (ZKX130391 to GY).

The authors declare no financial or other issues that might lead to conflict of interests. The author for correspondence is in possession of related documents of this study. All authors read and approved the manuscript.