The effect of obesity on the growth of asthma incidence worldwide

1. Introduction

Asthma and obesity are chronic illnesses that affect world population in epidemic proportions. According to the WHO estimates, overweight affects over 1.9 billion of adults (39% of the world’s adult population), over 340 million of children and adolescents between the age of 5 and 19, and 41 million of children under the age of 5 (WHO, 2016). The WHO estimates that there are over 235 million asthma sufferers worldwide, with over 383,000 deaths from asthma reported in 2015. Global Initiative for Asthma (GINA) reports that asthma affects approximately 1-8% of worldwide populations, depending on the country, with heterogeneous underlying mechanisms involved in the disease development, and with diverse phenotypic manifestations (GINA, 2014).

The incidence of overweight and obesity and of asthma is increasing concurrently worldwide, as shown by epidemiological studies from around the globe, including Europe, Asia, Africa and America (Seidell and Halberstadt, 2015; Brodie-Mendsl and Ekrikpo, 2013; Lee et al., 2016; Dixon et al., 2010). Meta-analysis of a number of prospective epidemiological studies point to the coexistence of both disorders in many patients (Beuther and Sutherland, 2007), while further epidemiological studies have established overweight as a risk factor for development of asthma among worldwide populations (Lee et al., 2016; Ali and Ulrik, 2013; Lugogo et al., 2011; Holguin et al., 2011; Quinto et al., 2011).

Obesity and asthma are complex illnesses, developing as a result of interactions between multiple genetic, environmental and lifestyle factors (Sismanopoulos et al., 2013; Lugogo et al., 2011). Establishing and understanding the relationship between overweight and asthma may have profound consequences for the treatment and prevention of both illnesses. However, the prevalence and nature of this association across different populations and the underlying molecular mechanisms are not yet understood. This thesis will analyse scientific evidence pointing to the obesity as a risk factor for developing asthma and increasing asthmatic symptoms. Furthermore, the present study will examine the current research evidence on the nature of the possible molecular mechanisms that may link asthma and obesity among the affected populations worldwide.

2. The mechanisms underlying the obesity-asthma relationship

Diverse physiological, metabolic and molecular mechanisms and numerous factors are currently studied as the potential mediators of the association between the obesity and asthma (Figure 1). Obesity and overweight and the resulting increased adiposity of internal organs is associated with lower pulmonary function due to adipose tissue expansion, which has been shown in numerous epidemiological studies to increase the risk of asthma across diverse populations, including those of the European, Hispanic and Asian origin (Fenger et al., 2014; Rastogi et al., 2017; Pan et al., 2017; Vatrella et al., 2016). Furthermore, a number of studies point to the metabolic nature of the association between obesity and asthma (Rastogi and Holguin, 2017; Vijayakanthi et al., 2016).BMI and Asthma

Figure 1 The proposed mechanisms of the association between obesity and asthma. The mediators of the relationship between obesity and asthma (factors increasing the risk of asthma) include: decreased pulmonary function, gastrointestinal comorbidities, hormones, oxidative stress, inflammatory response including adipocyte-released pro-inflammatory cytokines and hormones. From Ali and Ulrik (2013).

Although obesity was shown to be an independent risk factor for asthma, it is clear that not all obese individuals develop asthma, suggesting that other factors might play a role, with researchers suggesting that diet, sedentary lifestyle, body composition (fat load), and the level of adiposity-mediated systemic inflammation might all contribute to the development of metabolic dysregulation, which in turn, increases the risk of asthma (Vijayakanthi et al., 2016).

2.1 The role of inflammatory response and metabolic dysregulation

Asthma is a complex disorder associated with airway inflammation, which shows heterogeneous phenotypic presentation and inflammatory mechanisms between patients (Sutherland et al., 2012). The predominant inflammation pattern involves the T-helper type 2 cells (Th2), although studies reveal the existence of other inflammatory profiles involving Th1, Th17 and regulatory T cells, among others (Gelfand and Alam, 2015; Lloyd and Hessel, 2010). The inflammatory phenotype, alongside the presence of absence of obesity in asthma patient can have profound consequences for the effectiveness of treatment, with decreased response to corticosteroid medication observed in obese patients with asthma, as shown in several statistical analyses of patient data (Hawrylak et al., 2014; Forno et al., 2011).

The study by Dixon and Poynter (2016) suggests, that different obesity phenotypes can produce distinct asthma phenotypes in patients affected by both disorders. Furthermore, as revealed in the recent analysis by Ross et al. (2018), distinct asthma-obesity phenotypes can be identified using machine learning approach based on patients’ immunological responsiveness to different treatment modalities. The authors found, that obesity (as determined by BMI percentile) was a critical factor in determining patients’ response to medication (Ibid.). The study by Ross et al., (2018) provided strong evidence on the interaction between obesity and asthma phenotype, as the machine learning approach helped to avoid bias associated with researchers assigning phenotype manually, instead feeding hundreds of variables associated with inflammatory profiles and medication response of the patients into the algorithm. These findings support and expand on earlier epidemiological research showing that obese patients have poorly controlled or more severe asthma, with suggested mechanisms including the role of Th17 and mast cells activation and signalling (Dixon and Poynter, 2016; Liu et al., 2009).

Obesity is understood as a chronic inflammatory disorder, associated with the release of proinflammatory cytokines from adipocytes (adipocytokines), such as IL-6, RANTES (regulated on activation, normal T cell expressed and secreted cytokine) and resistin, which stimulates the secretion of further pro-inflammatory cytokines, including IL-12 and TNFα (Gregor and Hotamisligil, 2011; Matter and Handschin, 2007; Tilg and Moschen, 2006; Silswal et al., 2005). Interestingly, elevated plasma and airway levels adipocytokines have been shown as the risk factors for asthma (Quinto et al., 2011; Jartti et al., 2009; Taildeman et al., 2009). Furthermore, the hormones secreted by the white adipose tissue, leptin and adiponectin are involved in the regulation of inflammatory responses in the body (Lago et al., 2008). Leptin levels are markedly increased in obesity, and that increase has been shown to positively correlate with immunoglobulin E (IgE) levels, airway reactivity and bronchoconstriction induced by exercise in children with asthma (Baek et al., 2011; Mai et al., 2004). Obesity has been shown to worsen inflammation of the airways and increase severity and exacerbations in asthma patients (Fitzpatrick et al., 2012; Sutherland et al., 2008). However, the mechanism of the association between the levels of leptin and other adipocytokines and lung function is subject of ongoing research, with some disagreement between researchers on whether sex has any role in mediating interaction between obesity markers and asthma (Suglia et al., 2011; Sood et al., 2011; Sood et al. 2012). The role of mast cell activation as one of the mechanisms linking obesity and asthma has been proposed by a number of studies, as adipocyte-released RANTES cytokine is a potent chemoattractant of mast cells, which in turn play critical role in the development of allergic inflammation and asthma (Sismanopoulos et al., 2013; Theoharides et al., 2010; Taildeman et al., 2009; Jartti et al., 2009).

Although the association between the obesity and asthma has been established long time ago, the molecular mechanisms that could help to explain this association and its nature remained elusive until recently. However, novel approaches to data analysis help to examine the metabolic and inflammatory profiles of patients with obesity and asthma in unprecedented detail. Liu et al. (2018) used metabolomic approach to identify the metabolic profiles of the obese asthma patients in China and Australia. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) combined with statistical correlation analysis were used to study the profiles of IL-1β, IL-4, IL-5, IL-6, IL-13 and TNFα in sputum, and leptin, adiponectin, and C-reactive protein (CRP) in blood serum, and numerous metabolites in peripheral blood. The authors found significant difference between lean and obese asthmatics in asthma control and in the levels of adiponectin, leptin, IL-1β, IL-4, and IL-13. Furthermore, the levels of 28 metabolites were significantly different in obese asthmatics, compared with non-obese, with significant changes to metabolism of glutamate, aspartate, alanine, caffeine, cyanoamino acid, glycerolipid, glyoxylate and dicarboxylate, biosynthesis of tryptophan, tyrosine and phenylalanine, penthose phosphate pathway. The 18 unique immune and metabolic signatures identified in the study point strongly to the highly specific mechanism of obese asthma, with particular phenotypic profiles of cytokines and metabolites that can be used to differentiate obese-asthma patients from the non-obese. While previous metabolomic studies on Italian and USA populations suggested the existence of unique obese-asthma phenotypes (Maniscalco et al., 2017; Kelly et al., 2017), the study by Liu et al. (2018) was the first to analyse both metabolic and inflammation markers in asthma patients with and without obesity. Furthermore, the unique immune-metabolic profiles were associated with different levels of asthma control, suggesting that the study might have potentially significant implications for therapy of both asthma and obesity.

2.2 Diet as a mediator of the obesity-asthma relationship

An interesting avenue of obesity-asthma research is the role of the Western and westernised diet which is low in fibre and high in sugar and saturated fats, in mediating the association between the obesity and asthma epidemics. Recent research evidence increasingly points to the essential role of diet in maintaining the overall health of the human populations worldwide, as suboptimal diet affects human gut microbiota with potentially serious consequences for the physiological and immunological functions, as shown schematically in Figure 2 (Dreher, 2018; Yap et al., 2018).

The relationship between diet, commensal microbiota and the mucosal immunity

Figure 2 The relationship between diet, commensal microbiota and the mucosal immunity. A – Homeostasis between the microbiota and the immune system is maintained by healthy diet. B – Disorders associated with impaired mucosal immunity (asthma, IBD) are associated with sub-optimal dietary intake of nutrients. SCFA, short-chain fatty acids (metabolites produced by microbiota); ω-6/ω-3, omega-6/omega-3 fatty acid ratio; SFA, saturated fatty acids. From Statovici et al. (2017).

The effect of diet on gut microbiota is profound, due to the complex interaction between the nutrients, gut microbiome and the immune responses across the mucosal surfaces (Statovci et al., 2017). Western diet, which is increasingly popular in developing countries worldwide, is a known risk factor for the development of metabolic diseases, including obesity and diabetes. The effects of the Western diet on the immune cell responses are not yet fully understood (Peterson and Artis, 2014). However, the evidence increasingly points to the interaction between low-fibre diet, microbiota composition and deterioration of mucosal membranes, due to the microbes utilising mucosal membrane glycoproteins as nutrients in the absence of dietary fibre (Desai et al., 2016), which impairs mucosal immune response in the intestines and the airways (Yap and Mariño, 2018; Sullivan et al., 2016). Furthermore, studies in mice show that high-fat and sugar diet-induced obesity leads to development of asthma and airway hyperresponsiveness (AHR, Fricke et al., 2018), while calorie restriction prevents AHR in obese mice (Younas et al., 2019).

Incidentally, westernised diet is the main risk factor for developing the irritable bowel syndrome (IBD) (Uranga et al., 2016; Kamada et al., 2013). Like asthma, IBD is a disorder associated with chronic inflammation of the mucosal membranes, and the incidence of both illnesses is growing rapidly worldwide (Chiba, 2019; Statovci et al., 2017). Genomic and metabolomic studies increasingly point to unhealthy diet as a mediator in the relationship between the obesity and asthma and other disorders associated with impaired immune response of the mucosal surfaces (Macia et al., 2015). The developments in high-throughput Next-Generation Sequencing technologies will further help to better understand the relationship between dietary factors, human microbiota composition and function, and their impact on inflammatory responses across mucosal membranes (Schroeder et al., 2018).

2.3 Genetic factors

While some of the universal metabolic and molecular mechanisms underlying the interaction between obesity and asthma have been identified, the genetic loci associated with the susceptibility to the development of either (or both) asthma and obesity are population-specific. For example, epidemiological studies consistently demonstrate that both asthma and obesity are more prevalent among African Americans than the Americans of European origin (Guerrero et al., 2016).

Epidemiological and genetic studies among the European and Asian populations suggest that shared genetic loci are associated with susceptibility to both the obesity and asthma, for example the 16p11. 2 inversion, which protects against the co-occurrence of asthma and obesity (González et al., 2014). The identified allele shows diverse prevalence among various populations, with 49% prevalence in Europe and only 10% in East Africa, which may explain the differences in the prevalence of obese-asthma phenotype between those groups (Ibid.). Furthermore, studies show that only 5% of the genetic association studies on asthma susceptibility conducted among the populations of European-descent are replicated among the populations of African origin, and this is mirrored by the studies on obesity (White et al., 2013). This highlights the necessity to conduct population-specific studies to identify the genetic factors associated with obesity and asthma among various ethnicities and populations, and several novel genetic loci specific to African American population have been identified in the study by White et al. (2016).

Interestingly, genetic variant on 6q14. 1 associated with increased risk of asthma (49% prevalence among Europeans, 0% among Africans) has been found among the African Americans with admixed European ancestry, showing that not only the ethnicity but also the local history must be considered in identification of new genetic loci (Torgerson et al., 2012). Similarly, genome-wide association study (GWAS) on diverse population with a mixed European-, Native American-, Latino- and African- ancestry identified several novel asthma gene associations, highlighting the importance of studying diverse populations to fully understand the genetic basis of asthma and obesity (Pino-Yanes et al., 2015).

Nevertheless, despite the ethnic/racial differences, the results of genetic association studies among diverse populations support the current consensus regarding the presence of joint asthma- and obesity-susceptibility genetic loci within each population, with the majority of loci identified thus far associated with inflammatory proteins and cytokines (González et al., 2014; White et al., 2016).

3. Discussion

The inflammatory dysregulation underlies the clinical presentation of both the obesity and asthma. However, the metabolic and molecular mechanisms involved in the development and the association between both disorders remained until recently largely unexplained. Nevertheless, recent studies using animal models of asthma and obesity, alongside the epidemiologic and statistical analyses of obese-asthma human populations worldwide provide increasing amount of rich data on the relationship between the two epidemics. Research evidence shows that obese patients have more severe asthma symptoms, including airway and systemic inflammation and worse asthma control, and altered metabolic phenotypes, compared to lean asthma patients (Lugogo et al., 2018). Significantly, altered metabolic profiles of obese patients with asthma have been shown to correlate with inflammatory and clinical phenotypes of asthma (Barros et al., 2017), and those correlations have need shown for diverse populations, including those of Asian and European descent, pointing to the universal underlying mechanisms. Those observations might have significant implications for the development of effective therapeutic interventions and drug development.

The relationship between obesity and asthma is far from straightforward, with considerable research debate currently taking place on the directionality of the interaction. Nevertheless, research evidence to date demonstrates the existence of numerous unique inflammatory and metabolic asthma-obesity phenotypes, alongside the genetic factors specific for given populations, ethnicities and individual patients, and the environmental and lifestyle factors (Kim and Ober, 2019). As demonstrated in the present review, the growing body of research strongly suggests the existence of some universal underlying mechanisms of the association between obesity and asthma, such as the inflammatory and metabolic dysregulation and the role lifestyle and diet (particularly the Western diet, increasingly popular across the populations in developed and developing countries), alongside the more unique, population-specific genetic and lifestyle factors (Yap and Mariño, 2018). This complexity points to the increasing role of precision medicine in future therapeutic interventions for asthma and obesity. Current and future advances in metabolomics and genomics will offer a potential to study the nature of the complex interactions between the host (i.e. the genetic background and metabolic status of an individual) and environment, which leads to development of obesity and asthma, in much greater depth in the future. This will allow to better understand the pathogenesis of both disorders and the nature of their association by exploring the interplay of known and unknown genetic and environmental factors in development of complex obese-asthma phenotypes (Turi et al., 2018; Kelly et al., 2017). Furthermore, the application of -omics data analysis approaches to the growing body of research data on the role of obesity in asthma development will help to evaluate the risk of developing both disorders with greater precision and resolve the current debates on the role of gender and other, perhaps yet unknown, genetic, metabolic or inflammatory factors in the association between obesity and asthma (Turi et al., 2018). Finally, the -omics and precision medicine-based approaches will help to predict the effectiveness of treatment approaches and to develop accurate prognoses for diverse phenotypes of obese-asthmatic patients.

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