Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease

Abstract

Environmental exposure plays a major role in the development of allergic diseases. The exposome can be classified into internal (e.g., aging, hormones, and metabolic processes), specific external (e.g., chemical pollutants or lifestyle factors), and general external (e.g., broader socioeconomic and psychological contexts) domains, all of which are interrelated. All the factors we are exposed to, from the moment of conception to death, are part of the external exposome. Several hundreds of thousands of new chemicals have been introduced in modern life without our having a full understanding of their toxic health effects and ways to mitigate these effects. Climate change, air pollution, microplastics, tobacco smoke, changes and loss of biodiversity, alterations in dietary habits, and the microbiome due to modernization, urbanization, and globalization constitute our surrounding environment and external exposome. Some of these factors disrupt the epithelial barriers of the skin and mucosal surfaces, and these disruptions have been linked in the last few decades to the increasing prevalence and severity of allergic and inflammatory diseases such as atopic dermatitis, food allergy, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, and asthma. The epithelial barrier hypothesis provides a mechanistic explanation of how these factors can explain the rapid increase in allergic and autoimmune diseases. In this review, we discuss factors affecting the planet's health in the context of the 'epithelial barrier hypothesis,' including climate change, pollution, changes and loss of biodiversity, and emphasize the changes in the external exposome in the last few decades and their effects on allergic diseases. In addition, the roles of increased dietary fatty acid consumption and environmental substances (detergents, airborne pollen, ozone, microplastics, nanoparticles, and tobacco) affecting epithelial barriers are discussed. Considering the emerging data from recent studies, we suggest stringent governmental regulations, global policy adjustments, patient education, and the establishment of individualized control measures to mitigate environmental threats and decrease allergic disease.

Keywords: air pollution; climate change; epithelial barrier; exposome; nutrition.

FIGURE 1

Effect of external exposome on epithelial barriers of skin, lung, and intestine. Extreme weather events, wild fires, global warming due to the climate change, air pollution and changes and loss of biodiversity; increased consumption of processed foods, n‐6 fatty acids and genetically modified food; exposure to environmental substances; and the increase in harmful opportunistic pathogens, loss of microbiome diversity and decrease in commensals; disrupts the barriers of skin, lung, and intestine and causes allergic diseases such as asthma, atopic dermatitis, food allergy, and allergic rhinitis. CH₄: methane, NOx: nitric oxides, CO₂: carbon dioxide, CO: carbon monoxide, SO₂: sulfur dioxide, O₃: ozone, GM: genetically modified

FIGURE 2

Health effects of climate change. Climate change causes mental health illness such as anxiety, depression, and post‐traumatic stress; causes respiratory and allergic diseases through air pollution and increased allergens; causes malnutrition through affecting water and food supplies; causes infectious diseases such as vector‐borne (malaria, hantavirus, lyme disease) and water transmitted diseases (cholera, harmful algal blooms); causes cardiovascular diseases, and heat stress due to extreme heat and air pollution

FIGURE 3

Epithelial barrier damaging agents from the environment. Allergens derived from bacteria, virus, and fungus; protease activity of allergens; surfactant, emulsifiers, and enzymes used as food additives; cigarette smoke, nanoparticles, particulate matter, and pollutant gases including nitric oxides, sulfur dioxide, carbon monoxide, carbondioxide, methane, ozone; microplastics irreversibly damage epithelial barriers by disrupting intercellular connections and anchoring of epithelial cells. Zonula occludens 1–3, occludin, claudins, junctional adhesion molecules, E‐cadherin and desmosomes are depicted as damaged epithelial molecules. CH₄: methane, NOx: nitric oxides, CO₂: carbondioxide, CO: carbon monoxide, SO₂: sulfur dioxide, O₃: ozone, ZO: Zonula occludens, JAM: junctional adhesion molecules

FIGURE 4

Environmental factors that play a role in asthma exacerbations. Air pollution with gases (NO_x, SO₂, O₃, CO₂, CO, CH₄) and particulate pollutants (PM2.5 and PM10) emitted from industrial smog and wildfire smog, environmental tobacco smoke, heat waves, sandstorms, and airborne pollen cause asthma exacerbations. Moreover, extreme heat causes early and prolonged pollen discharge, and thunderstorms cause bioaerosols containing potentially allergenic small particles due to the rapid hit of water droplets to the ground. All of these factors may have a direct or indirect effect on epithelial shedding, goblet cell hyperplasia, airway hyperresponsiveness, increased basement thickness, subepithelial fibrosis, extracellular matrix (ECM) deposition, smooth muscle proliferation, and immune cell infiltration in the airways and exacerbate asthma

FIGURE 5

Complex interplay between environmental factors, epithelium, and the immune system. Epithelial cells can secrete IL‐25, IL‐33, and TSLP in response to various stimuli from the environment resulting in a Th2 type shift of the immune response. These cytokines activate dendritic cells and group 2 innate lymphoid cells). ILC2s share many functional similarities with Th2 cells such as the production of IL‐5, and IL‐13 as well as other effector molecules that enhance the Th2 immune response. Eosinophils, basophils, and mast cells are attracted to the area and degranulate. Dysregulation of the epithelial barrier has been hypothesized to cause a leaky epithelium, which causes dysbiosis of the microbial content, decrease of commensals and increase of opportunistic pathogens. The translocation of microorganisms to interepithelial and subepithelial compartments induces inflammation. IL: interleukin, TSLP: thymic stromal lymphopoietin, DC: dendritic cell, ILC2: innate lymphoid cell‐2, EOS: eosinophil, BAS: basophil, MC: mast cell, MBP: major basic protein, ECP: eosinophilic cationic protein, LT: leukotriens, PGD2: Prostaglandin D2, Th0: naive T cell, Th2: T helper 2, Ig E: immunoglobulin E