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

KEYWORDS:

• Asthma
• exposome
• regulatory T cell
• respiratory tract infection
• vitamin D

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 trial meta-analyses that show vitamin D supplementation of appropriate patients significantly reduces their rate of exacerbations requiring systemic corticosteroids [3,6,7]. Not only is the effect statistically significant but also clinically significant with 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 be mechanistically 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 recent meta-analysis that vitamin D can reduce the incidence of acute respiratory tract infections [10].

Underlying Th2-type airway inflammation in asthma is thought due to dysregulated 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 vitamin D 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 mitogen-activated protein kinase phosphatase-1 expression [14]. Chambers and colleagues have shown giving oral calcitriol, the active form of vitamin D, to steroid-refractory severe asthmatics can restore both the clinical and immunological IL-10 response to corticosteroids [12].

Vitamin D also inhibits inflammatory pathways induced by Alarmin cytokines such as IL-33, for example by promoting secretion of the soluble decoy receptor sST2 and inhibitory effects on responder cells [3,15].

Clinical evidence that supplementation of patients with vitamin D can suppress underlying Th2-type airway inflammation is less robust but there is good evidence that vitamin D supplementation can enhance the pro-regulatory actions of corticosteroids in severe asthma [12]. That vitamin D can act on diverse cell types is not surprising given the frequency of vitamin D response elements in genes throughout the genome and across a multitude of cell types. In many ways the secosteroid vitamin D is a master regulator of immunological responses, comparable in breath and importance of action to corticosteroids that form the backbone of asthma pharmacotherapy.

Exacerbations are associated with worse health-related quality of life [16] and even short courses of oral corticosteroids are associated with significant side effects [17], underlying the importance of reducing asthma exacerbations. However, day-to-day asthma symptoms also negatively impact on patient health. The beneficial effect of vitamin D supplementation on quality of life and lung function in asthma above and beyond exacerbation reduction is less certain [7]. Of major importance to patients are daily symptoms related to symptomatic airway narrowing and there is less evidence for any action of vitamin D supplementation to reduce day-to-day airflow obstruction. However, vitamin D has been shown to have the capacity to inhibit airway smooth muscle pro-inflammatory responses and proliferation, both contributory to airways obstruction [18]. Severe vitamin D deficiency in asthma is also often associated with nonspecific constitutional symptoms and musculoskeletal chest pains, and there is additional evidence that vitamin D supplementation of appropriate individuals reduces nonspecific musculoskeletal pains [19].

In addition to a role in preventing asthma exacerbations in patients with known disease, there is also emerging evidence for a role for vitamin D in primary prevention of asthma. Two recent major clinical trials have investigated whether enhanced vitamin D supplementation of pregnant women can reduce the incidence of asthma in their offspring [20,21]. The results from the first 3 years of follow-up are promising for a beneficial effect of vitamin D; however, it also appears that the most benefit may be in mothers who are vitamin D sufficient both at the start of and during the pregnancy [22]. Accompanying translational mechanistic studies have provided strong evidence of the beneficial effect of vitamin D on the developing immune system [20,23].

Given the strong evidence for vitamin D supplementation of insufficient individuals in asthma, the question then follows of why vitamin D supplementation at therapeutic dose is not more prominent in asthma treatment guidelines? Historically there was concern about safety of vitamin D supplementation; however, trials have not indicated any significant safety issues [7]. Reluctance to include vitamin D supplementation in management strategies may actually relate to it being a vitamin supplement rather than a prescription-only medicine. The prescription of and adherence to any therapeutic intervention is significantly affected by whether the treatment is congruent with the doctor’s and patient’s health beliefs respectively. That vitamin D supplementation is part of widespread nutritional supplementation with multivitamins in many people but separately, at higher dose, a medical pharmacotherapy in appropriate individuals is confusing for many patients and health-care workers. Many people believe an adequate vitamin D status is simply a matter of a good diet or multivitamin supplements without understanding that the major natural source for vitamin D is sunlight and that most multivitamins contain relatively low concentrations of vitamin D. Despite media interest, the public continues to have limited understanding of vitamin D biology, and mismatches between believed and actual personal vitamin D status are common [24]. Uncertainty and skepticism around vitamin D supplementation is negatively influencing attitudes to prescriptions of vitamin D treatments [25]. Similar issues relating to health beliefs and attitudes toward nonprescription medical therapies compared to traditional pharmacotherapies are prominent in other treatments targeted at the exposome, such as strategies to avoid personal pollution exposure and prescriptions of exercise therapy. The immunological, scientific basis for treatments that target the exposome needs to be emphasized to the medical profession and public to align these treatments with their health beliefs.

In summary, epidemiological evidence indicates that the modifiable environmental factor of vitamin D insufficiency/deficiency has a significant negative impact on asthma control with laboratory translational research demonstrating mechanisms by which vitamin D has the capacity to reduce asthma exacerbations and improve asthma control. Of particular importance are the actions of vitamin D to promote steroid-sensitive regulatory T cells and inhibit Alarmin-mediated inflammation. Recent meta-analyses of clinical trial data have produced significant evidence that correcting vitamin D deficiency is beneficial in asthma. Daily vitamin D supplementation to correct deficiency is a safe and beneficial part of our medication armamentarium in asthma, underpinned by well-characterized immunological actions.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This article was not funded.