Targeting the exposome: does correcting vitamin D deficiency have potential to treat and prevent asthma?

The prevalence of asthma has risen over the last century. Our genome has not changed over this time and therefore changes in the internal and external environment of individuals – their exposome – must underlie rising pathology [1,2]. Research has identified possible causative environmental factors, for example vitamin D insufficiency, air pollution, and obesity. Despite the potential for interventions targeted at ‘correcting’ the individual’s exposome to be cost-effective and extremely safe compared to traditional pharmacotherapies, comparatively few trials have been undertaken of such interventions in asthma. Vitamin D stands out as the environmental factor most rigorously investigated in asthma and lessons learnt from these studies are important in considering other potential treatments for asthma that target the exposome [3]. In humans, vitamin D is in major part naturally produced in the body in a mechanism dependent on the action of sunlight on the skin, and reduced exposure of the skin to sunlight has been suggested to underlie the current epidemic of vitamin D deficiency/insufficiency [4]. Multiple epidemiological studies have identified strong associations between vitamin D deficiency and different aspects of asthma [5]. In support of these associations being biologically important, there are now convincing findings from clinical trialmeta-analyses that show vitaminD supplementation of appropriate patients significantly reduces their rate of exacerbations requiring systemic corticosteroids [3,6,7]. Not only is the effect statistically significantbut also clinically significantwith a recent individual patient data meta-analysis by Jolliffe and colleagues finding an adjusted incidence rate ratio of 0.74 in favor of reduced exacerbations with vitamin D supplementation versus placebo (95% confidence interval 0.56–0.97; p = 0.03) [6]. Not all clinical trials have however shown vitamin D to be beneficial in asthma with discordant trial findings likely a result of heterogeneity in study design and under-powering of some studies – increasing understanding of vitamin D biology has now revealed major considerations for vitamin D supplementation not known when some of the clinical trials were designed [3]. For example, regular dosing appears more beneficial than the infrequent bolus dosing that has been used in some vitamin D trials. Additionally, supplementation appears particularly advantageous in patients who are vitamin D deficient, i.e. in those in whom it corrects their low vitamin D status. In common with other environmental factors, asthmatic patients are affected to variable extent by vitamin D insufficiency/deficiency and the importance of appropriate patient selection in the design of trials that target the exposome is becoming more apparent. There remains skepticism about why vitamin D, traditionally known for its role in bone health, is advantageous in asthma but crucially there is a wealth of translational research demonstrating mechanisms by which vitamin D could be beneficial. Asthma exacerbations result from a noxious insult to the airways, most typically a viral infection, on top of a background of uncontrolled T helper lymphocyte subtype 2(Th2-) type cytokine-mediated airway inflammation. Therefore, vitamin D may be reducing exacerbations by having a protective effect against respiratory tract infections and/or by ameliorating underlying Th2-type inflammation, and vitamin D has been shown to bemechanistically capable of both. Vitamin D enhances cellular production of antimicrobial peptides, such as cathelicidin, with antiviral actions [8,9] and clinical evidence strongly supports an antimicrobial effect of vitamin D. For example,Martineau et al. have shown in a recentmeta-analysis that vitamin D can reduce the incidence of acute respiratory tract infections [10]. Underlying Th2-type airway inflammation in asthma is thought due todysregulated immune responses to inhaled aeroallergens in many patients and due to Alarmin cytokine-mediated pathways in some patients. Vitamin D has been shown to promote multiple types of regulatory T cell including those expressing FoxP3 and those secreting interleukin(IL-) 10, as well as enhancing expression of other immunomodulatory molecules such as CD200 and CD73, whilst suppressing effector T cells such as those of Th17 subtype [11,12]. Consistent with this, Heine and colleagues have in mice shown vitamin D deficiency to increase specific Immunoglobulin E (IgE) responses in an allergen sensitization model, with vitamin D supplementation enhancing allergen immunotherapy [13]. Of particular importance is the capacity of vitaminD to enhance corticosteroid sensitivity in asthma. Sutherland and colleagues have shown a positive correlation in asthmatic patients between serum vitamin D levels and dexamethasone-induced mitogenactivated protein kinase phosphatase-1 expression [14].