Epithelial Barrier Theory: The Role of Exposome, Microbiome, and Barrier Function in Allergic Diseases

Abstract

Allergic diseases are a major public health problem with increasing prevalence. These immune-mediated diseases are characterized by defective epithelial barriers, which are explained by the epithelial barrier theory and continuously emerging evidence. Environmental exposures (exposome) including global warming, changes and loss of biodiversity, pollution, pathogens, allergens and mites, laundry and dishwasher detergents, surfactants, shampoos, body cleaners and household cleaners, microplastics, nanoparticles, toothpaste, enzymes and emulsifiers in processed foods, and dietary habits are responsible for the mucosal and skin barrier disruption. Exposure to barrier-damaging agents causes epithelial cell injury and barrier damage, colonization of opportunistic pathogens, loss of commensal bacteria, decreased microbiota diversity, bacterial translocation, allergic sensitization, and inflammation in the periepithelial area. Here, we review scientific evidence on the environmental components that impact epithelial barriers and microbiome composition and their influence on asthma and allergic diseases. We also discuss the historical overview of allergic diseases and the evolution of the hygiene hypothesis with theoretical evidence.

Keywords: Allergy; asthma; barrier; climate; environment; exposome; exposure; microbiome; microbiota; pollution.

Fig. 1. Epidemiology of allergic diseases. The prevalence of allergies increased to epidemic levels, starting with asthma, as reported in the UK. A nearly 10-fold increase in pediatric asthma was observed in Australia, the UK, New Zealand, Canada, and the USA. Increased prevalence of allergic diseases since 1978 has been reported in different studies.

AD, atopic dermatitis.

Fig. 2. Hypotheses for the development of allergic diseases. The hygiene hypothesis proposes a relationship between the incidence of allergic diseases and lower exposure to infection. ‘Old friends’ hypothesis explains the correlation between allergic disease development and exposure to immunoregulatory microbes at early ages. The biodiversity hypothesis defines the link between a biodiverse environment and health. Epithelial barrier theory proposes the interplay between environmental harmful substances and epithelial barrier dysfunction.

Fig. 3. External exposome factors that can impact the skin, lungs, and gut epithelial barrier defects. Climate change causes extreme weather events and results in the loss of biodiversity. Polluted air leads to changes in the composition and diversity of the microbiome. Processed foods promote the development of intestinal inflammation and microbial dysbiosis. Chemicals damage barrier integrity and increase the risk of infection. Microbial dysbiosis can lead to an overgrowth of harmful bacteria and damage the epithelial barrier. The role of these exposomes in epithelial barrier damage has been well-documented in allergic diseases, including asthma, allergic rhinitis, atopic dermatitis, and food allergy.

Fig. 4. Mechanisms of epithelial barrier theory. Perturbed gut integrity and permeability facilitate bacterial translocation and opportunistic pathogen colonization. Damaged epithelial cells produce TSLP, IL-25, and IL-33, followed by activation of immune cells. Type-2 cytokines and degranulation of mast cells exacerbate the inflammation and further attenuate barrier function.

DC, dendritic cell; TSLP, thymic stromal lymphopoietin; IL, interleukin; Ig, immunoglobulin.