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.

INTRODUCTION

According to the World Health Organization, approximately 10%–40% of the global population has been diagnosed with at least one of the allergic diseases. Additionally, around 40%–50% of school children have sensitization to at least one allergen.¹ The clinical presentation of atopic diseases often follows a well-described pattern, beginning from atopic dermatitis (AD) and food allergy (FA) in childhood, which can progress to allergic rhinitis (AR) and asthma later in life. This phenomenon is known as the “atopic march (or allergic march).”

The development of allergic diseases has been attributed to complex interactions between genetic and environmental factors. Genetic susceptibility includes an association of well-described gene polymorphisms and allergic disease development.² However, this cannot explain the marked increase in the prevalence of allergic diseases in the short time frame of the last 60 years,³,⁴ suggesting the important role of modern environmental factors in promoting the development of these diseases. Allergy prevalence varies widely across the globe, with higher rates in developed countries.⁵ This could be influenced by several factors, including improved hygiene, changes in dietary habits, the introduction of various toxic chemicals to human lives, and exposure to outdoor and indoor pollutants. A recent meta-analysis of 22 chemical inventories from 19 countries revealed that more than 350,000 new substances had been introduced to human lives since the 1960s, unfortunately with little control over their health effects.⁶ Other contributing factors can include climate change and reduced biodiversity. The “epithelial barrier theory” has been reframed to explain how environmental factors and lifestyle changes can impact human health.⁷,⁸,⁹

The “epithelial barrier theory” proposes mechanisms for developing allergic, autoimmune, and neurodegenerative diseases with inflammation and tissue damage. It accepts and embraces the hygiene and biodiversity hypotheses and links them to epithelial barrier defects and microbial dysbiosis. In addition, it demonstrates possible ways of preventing allergic and autoimmune diseases and suggests future research directions.⁷ Early studies have studied apoptosis of epithelial cells for damaging the epithelial barrier in eczema and epithelial shedding in asthma and chronic sinusitis.¹⁰,¹¹,¹² Around the same time, we started to understand the key roles of epithelial barriers by keeping away the exposome and washing away the inflammatory cells and cytokines.¹³ Following this, epithelial barrier defect has been linked to type 2 response in asthma, chronic rhinosinusitis, and AD.¹⁴,¹⁵,¹⁶ The role of interleukin (IL)-4 and IL-13 as well as T helper (Th) 2 cells and type 2 innate lymphoid cells have been reported.¹⁷,¹⁸,¹⁹

This review discusses the role of the exposome, lifestyle changes, and immunosenescence on epithelial barrier defects caused by damaged epithelial cells, dysregulated inflammatory responses, and microbial dysbiosis. It also discusses the evolution of the hygiene hypothesis and the role of epithelial barrier dysfunction in allergic diseases.

EPIDEMIOLOGY OF ALLERGIC DISEASES

A trend data analysis in the UK between 1971–1991 showed an increased prevalence of hay fever and eczema by 260% and 150%, respectively.⁴ Since 1990, hospital admissions for allergic diseases (anaphylaxis, FA, urticaria, and angioedema) have increased dramatically (Fig. 1).⁴ In contrast, hospital admissions for asthma increased from the early 1960s until the late 1980s and have since fallen and stabilized.⁴,²⁰,²¹,²² Although a plateau has been reached in the prevalence of asthma, AR, and AD in industrialized countries, their prevalence is still on the rise in developing countries.²³,²⁴ The incidence of specific FAs, such as peanut allergy, has increased in Western nations in recent decades.²⁵ In the Global Asthma Network study conducted between 1993 and 2020, the prevalence of current wheeze decreased in low-income countries and increased in lower-middle-income countries, but was stable in upper-middle-income and high-income countries.²⁶ The International Study of Asthma and Allergies in Childhood (ISAAC), conducted between 1996–1997 and 2002–2003, demonstrated a significant increase in the percentage of children and adolescents reporting asthma (Fig. 1).²⁷,²⁸ The variance in the prevalence and severity of asthma, rhinoconjunctivitis, and eczema was observed not only between countries or regions but also between centers within the same country and the same city.²⁷ Those discrepancies could be explained by differences in environmental exposures, socioeconomic conditions, medical treatment availability, etc. In Korean nationwide cross-sectional survey (2008–2017), a 10-year trend study revealed a significant decrease in the prevalence of asthma in infants, preschool children, and the elderly, and in AD in infants and preschool children. Additionally, a significant increase in the prevalence of AR in school-age children, adults, and the elderly, and AD in school-age children and the elderly was observed.²⁹ A systematic review of studies conducted between 1978 and 2016 demonstrated an increased prevalence of AR, conjunctivitis, AD, and FA among children but an inconsistent pattern of asthma in Korea (Fig. 1).³⁰ After the 2000s, a new wave of allergic diseases is taking place, such as FA and anaphylaxis, eosinophilic gastrointestinal disease, particularly esophagitis and drug hypersensitivity and urticaria.³¹,³²,³³

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.

Several lines of evidence have shown that environmental exposures are responsible for the rising prevalence of allergic diseases.⁸,³⁴,³⁵,³⁶ A 10-year follow-up (2008–2018) research conducted in the Polish urban city of Krakow has shown a reduction in the incidence of asthma and AR among children and adolescents, a possible link with improved air quality in the city.³⁴ While exposure to tobacco smoke and fungi on the house wall increased the risk of asthma, mite sensitization was associated with increased risks of AD, AR, and asthma among kindergarten children in Taiwan.⁸ Consumption of certain foods (cereals, pasta, butter, margarine, and potato), physical activity, smoke exposure, and electronic device usage were linked to asthma among young Chinese adults, and parental asthma was the most important intrinsic epidemiological factor for asthma manifestation.³⁵ Children living in areas surrounded by high road density and proximity were at an increased risk of developing atopic eczema, but not asthma or AR, and were more vulnerable to these conditions if they lived in deprived areas in Korea.³⁶ The prevalence of asthma and allergic diseases varies across countries and throughout the years, which could be influenced by the effects of environmental and lifestyle changes.

EVOLUTION OF HYGIENE HYPOTHESIS

Hygiene hypothesis

In 1989, Strachan³⁷ proposed the “hygiene hypothesis” to explain that the lower incidence of infection in early childhood limits the opportunity to prevent allergic diseases (Fig. 2). The paper observed that British children from larger families were less likely to develop hay fever. This could be related to the combined effect of declining family size, household, and high standard of personal cleanliness. In 1988, a year before the paper by Strachan,³⁷ Barker first used the term “hygiene hypothesis” when exploring a positive relationship between high rates of appendicitis and particular patterns of food consumption and infectious diseases.³⁸,³⁹ The findings sparked a surge of interest in the hypothesis, which led to its being explored in various research areas, including autoimmune and allergic diseases. Several birth cohort and family cohort studies reflected the link between allergy occurrence and the number of siblings in the household.⁴⁰,⁴¹ However, a review of 53 articles assessing the causal effect of the number of siblings on the development of allergy and asthma did not reach a definitive conclusion.⁴² Epidemiological data have shown that farm exposure and close contact with the farmyard and animals protect from childhood allergies despite similar genetic ancestries and lifestyles.⁴³ A study of school children from farming communities, the Amish and Hutterites, found that the Amish who practice traditional farming had a lower prevalence of asthma and allergic sensitization in children than the Hutterites who practice industrial agriculture methods. It has to be noted here that it is not only the farming style that differs between the two communities but also the overall modern versus traditional lifestyle, including processed food as well as laundry detergents and cleaning material usage in Hutterites.⁴³

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.

Shortcomings of the hygiene hypothesis have been taken attention during the last few years. For example, water sanitation was established in many Western cities in the 1920s, but the allergy and asthma epidemics started in the 1960s. For the same reason, the protective role of parasite infections has also been questioned. Interestingly, allergic asthma is still rising in “unhygienic” cities in Asia and Africa.⁴⁴ Another limitation of the hygiene and biodiversity hypotheses is that probiotics have yet to prove to be a strong alternative for preventing or treating allergies.⁴⁵ Migrants moving from developing countries to affluent regions demonstrate a rapid increase in asthma and allergic diseases as well as autoimmune diseases, such as type 1 diabetes and multiple sclerosis.⁹,²³,²⁴,⁴⁶,⁴⁷ Studies of migrants who do not develop allergies and asthma suggest that in-house living conditions are a more decisive factor than general public hygiene.⁴⁸ It can be concluded that many of the risk factors associated with FA, AR, AD, and asthma are not directly linked to hygiene but rather to the mode of delivery, antibiotic use, use of different cleaning products, dietary practices, indoor air pollution, and urbanization.⁴⁹,⁵⁰,⁵¹

“Old friends” hypothesis

In the early 2000s, Graham Rook postulated the “old friends” hypothesis, which explains that immunoregulatory microbes that have been accompanied throughout human existence are recognized by the host innate system as harmless or treated as “old friends” (Fig. 2). Continuing exposure to these microbes is necessary for prompt immune activation to prevent immune-mediated diseases. However, reduced exposure to these microbes can cause immune dysregulation.⁵² Farm and rural environments are associated with high microbial load and are thought to reduce the risk of allergy by modulating the immune system. Early exposure to farm environments also influences DNA methylation in genes related to asthma and allergy.⁵³ Nutritional factors, such as breastfeeding, farm milk, and food diversity, may impact both epigenetic modifications and the protective effect of a farm environment on allergic diseases.⁵⁴,⁵⁵ The European cross-sectional study (GABRIEL) showed that early life and long-term exposure to stables and farm milk decreased the development of asthma, hay fever, and atopic sensitization in children living in rural areas.⁵⁶ Other European birth cohort studies, Finnish rural-suburban LUKAS and German urban LISA, observed an association between higher bacterial diversity in early life and reduced risk of AR later in childhood.⁵⁷ The protective effect of a farming environment on sensitization to common allergens lasts into adulthood, but it may also induce sensitization to farm allergens.⁵⁸ It is conclusive that early-life exposure to farming, particularly maternal farming activities during pregnancy or growing up on a farm, shapes lung function development and can benefit allergy.⁵⁹,⁶⁰

Biodiversity hypothesis

The “biodiversity hypothesis” supports previous hypotheses proposing that more contact with natural environments would enrich the human microbiota that maintains immune balance and prevents inflammatory diseases (Fig. 2).⁶¹,⁶² Biodiversity can be defined as complex interactions between species and their macro- and microenvironments.⁶³

A large New Zealand birth cohort suggested that exposure to greenness and vegetation diversity may protect from childhood asthma.⁶⁴ Another cross-sectional ecological Australian epidemiology study has shown a positive correlation between natural and biodiverse environments and beneficial respiratory health outcomes.⁶⁵ The microbiome in nature is more diverse and dynamic and responds to changes in ecological conditions. This can change the microbiome’s balance, significantly impacting the ecosystem and human health. A study has shown that residents in green areas have more diverse and healthy gut microbiota.⁶⁶

Epithelial barrier theory and microbiome

In recent years, there has been a growing understanding of the complex interplay between the epithelial barrier and inflammation. The mechanisms underlying the “epithelial barrier theory” suggest that exposure to harmful substances in the environment can weaken the protective barriers of the skin, airways, and gastrointestinal mucosa, making them prone to bacterial leakage and dysbiosis.⁷,⁶⁷,⁶⁸,⁶⁹ Epithelial barrier defects and microbial dysbiosis have been linked to several immune-related diseases (Fig. 2).⁷⁰,⁷¹,⁷²,⁷³,⁷⁴ The contribution of the microbes, including bacteria, fungi, viruses, archaea, and other microorganisms, and their interactions with the host are essential for the maturation and regulation of the immune system.⁷⁵

The epithelial barrier theory endorses the biodiversity hypothesis by providing clear reasons for the missing biodiversity in chronic inflammatory diseases. Asthma, CRS, and AD have decreased biodiversity and colonized opportunistic pathogens.⁷⁶,⁷⁷ The first reason for reduced biodiversity is because colonizing opportunistic pathogens such as Staphylococcus aureus overwhelm the inflamed areas and cause a decrease in S. epidermidis and S. hominis.⁷⁸ The second reason is a strong antimicrobial response in chronic epithelial barrier leaky areas involving S. aureus and other opportunistic pathogens. The third reason is that opportunistic pathogens have a more robust division capacity than commensals. The fourth reason is that toxic substances not only decrease the epithelial barrier function but also affect the microbial composition of chronically affected tissues.⁷⁹

Commensal bacteria colonizing the oral cavity, skin, airway, and intestinal mucosa perform a protective function by mediating host immunity, directly inhibiting pathogen growth, and competing for colonization.⁸⁰ Once the epithelial barrier is impaired, opportunistic pathogens begin to dominate to cause decreased commensals and microbial diversity, contributing to the onset or development of many chronic immune-mediated and metabolic disorders.⁷¹,⁷²,⁸¹,⁸²,⁸³ Individuals with chronic rhinosinusitis and asthma present dominant pathogenic genera, such as Streptococcus, Haemophilus, Staphylococcus, and Moraxella, in the airway.³⁶,³⁸,⁷⁵ However, changes in commensal bacteria with anti-inflammatory and immunomodulatory properties, including Bifidobacterium spp., Lactobacillus spp., and Akkermansia muciniphila, have also been documented in their gut microbiome.³⁷,⁷⁵,⁸⁴ The abundance of Clostridia class bacteria in the gut differs between healthy and food-allergic twins.⁸⁵ Skin commensal Acinetobacter species may protect against allergic sensitization and lung inflammation by tuning the balance of Th1, Th2, and anti-inflammatory responses to environmental allergens.⁸⁶

Major respiratory viruses found in the airways of children and adults with wheezing and asthma exacerbations include human rhinoviruses (RV) and respiratory syncytial viruses.⁸⁷,⁸⁸ Coronavirus disease 2019 pandemics caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the recent changes in diagnosis, treatment, and seasonality of the viruses might change this situation, and a new equilibrium might be set,⁸⁹,⁹⁰,⁹¹,⁹² especially for patients with asthma.⁹³,⁹⁴ Recurrent viral infections contribute a lot to the temporary epithelial barrier disruption in asthma and AR due to direct effects on various innate immunity mechanisms such as activation of RIG-I inflammasome, damaging infected cells, delaying antiviral responses⁹³ and disrupting tight junctions (TJ) between the cells.⁹⁵,⁹⁶ Additionally, the interkingdom dynamics between the viruses and bacteria on the mucosal barriers might influence the range of epithelial damage and subsequent type 2 or non-type 2 immune response.⁹⁷,⁹⁸,⁹⁹ The type of underlying inflammation at the mucosal barriers might also influence the susceptibility to the infection with RV, SARS-CoV-2, and the subsequent epithelium damage.¹⁰⁰

EXTERNAL EXPOSOME IN EPITHELIAL BARRIER DAMAGE

Climate change and air pollution

Climate change and global warming are becoming major environmental threats to human health, and the changes are now being recognized as potential risk factors for epithelial barrier dysfunction. Climate change can disrupt the function of epithelial cells by increasing exposure to pollutants, elevating pollen emission, and changing its allergenic properties (Fig. 3).¹⁰¹,¹⁰² A retrospective analysis of datasets with 20 years or more from 17 locations across the northern hemisphere showed that increases in daily minimum and maximum temperatures over time were associated with increases in seasonal pollen load and pollen season duration.¹⁰³ Allergens, such as pollens and house dust mite exposure, elicit nasal symptoms and suppress innate antiviral immunity by reducing interferon-λ and pro-inflammatory chemokine responses of airway epithelia.⁹³,¹⁰⁴

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.

Air pollution by ozone, nitrogen dioxide, and diesel exhaust particles induces permeability of human bronchial epithelial cells and facilitates the penetration of allergens and irritants to the submucosa, where they interact with and activate immune cells.¹⁰⁵ Particulate matter (PM) exposures released from wildfires, sand, and dust storms have been associated with asthma, chronic obstructive pulmonary disease, pulmonary embolism, and infections in the lower airway.¹⁰⁶,¹⁰⁷ A possible explanation for PM-related asthma relies on the impact on the airway via disruption of epithelial barrier integrity with downstream effects on the immune system.¹⁰⁷ Other extreme weather events, such as thunderstorms during pollen season, have been observed to induce severe asthma attacks and deaths in patients with pollen allergies.¹⁰⁸

Cigarette smoke induces oxidative stress and epithelial cell death and inhibits epithelial repair processes, leading to several smoke-related lung diseases. Both cigarette smoking and vaping disturb oral, airway, and intestinal microbiota composition and diversity, promoting pathologic changes and impaired mucosal immune responses.¹⁰⁹,¹¹⁰

Detergents and chemicals

Toxic substances in laundry, dishwashing, and household cleaning detergents can damage the respiratory, skin, and gut epithelium (Fig. 3). Professional dishwasher rinse aid caused cellular cytotoxicity and directly impaired barrier integrity of gut epithelial cells by damaging TJ and adherence junction (AJ) expression in daily exposed concentrations.¹¹¹ The alcohol ethoxylates in the rinse aid that remains on washed dishware were identified as a culprit ingredient causing gut epithelial inflammation and barrier damage.¹¹¹ In the bronchial epithelial cells, laundry detergents and rinse residue (containing sodium dodecyl benzene sulfonate) directly disrupted TJ barrier integrity.¹¹²,¹¹³ Transcriptomic analysis of the study revealed that exposure to laundry detergent at high dilution upregulated genes involved in lipid metabolism, apoptosis progress, and cell damage and downregulated genes involved in cell adhesion.¹¹²

Toothpaste containing sodium lauryl sulfate (SLS), the most commonly used detergent, to prevent the growth of some microorganisms and to remove plaques, affected the cell viability in oral epithelial cells.¹¹⁴ SLS is also a frequent ingredient in soaps, cosmetics, and cleansing products. SLS patch on the skin resulted in skin redness, decreased stratum corneum hydration, and skin barrier function.¹¹⁵ It also disturbed skin microbiota, increasing the abundance of pathogenic bacteria (Staphylococcaceae, Enterobacteriaceae, Pantoea) and decreasing skin commensals (Actinobacteria).

Micro-/nanoplastics

Plastic is used extensively in everyday life and can harm humans and the environment. Microplastics (< 5 mm) and nanoplastics (< 0.1 µm) are commonly present in food products, water, cosmetics, discharged health care products, packaging, household goods, etc.¹¹⁶,¹¹⁷ Humans are exposed to micro/nano-plastics via inhalation, ingestion, and skin contact. The smaller particles (inhalable fraction) are absorbed via the pulmonary epithelium and reach the systemic circulation. In contrast, microplastics > 150 µm are not absorbed and remain bound to the intestinal mucosal layer, where they induce local inflammation.¹¹⁶ An advanced in vitro model study observed the translocation of micro/nano-plastics across the lung and intestinal epithelial barrier, activation of pro-inflammatory cells, and disrupted barrier integrity after exposure to micro/nano-plastics (Fig. 3).¹¹⁸ Other cell line model studies have shown that airborne nanoplastics (40 nm polystyrene) induce oxidative stress and inflammatory responses, leading to cell death and epithelial barrier destruction in a size- and duration-dependent manner.¹¹⁹,¹²⁰ While there is limited research on the ability of nanoplastics to penetrate the skin, polystyrene particles with a diameter of 20–200 nm could infiltrate the top layer of the skin at a depth of 2–3 µm.¹²¹

Processed foods

Over time, food processing has evolved significantly in parallel with socioeconomic conditions. Modern food processing methods include canning, packaging, freezing, pasteurization, and adding chemicals. There is a substantial amount of evidence to suggest that a Western diet, characterized by high total and saturated fat, refined sugars, low fiber content, and processed foods, is associated with an increased risk of low-grade intestinal inflammation, dysbiosis, and a reduction of gut microbial diversity, and disturbed gut epithelial barrier function (Fig. 3).¹²²,¹²³ Ultra-processed foods (snacks, drinks, sweets, and formulated foods), certain cheeses, oils, and margarine contain high levels of advanced glycation end products (AGEs). A high dietary intake of AGEs and AGE-forming sugars promotes the development of food allergies due to the misinterpretation of a threat from dietary allergens.¹²⁴ In Phase Three of the ISAAC, participants consuming fast food more than three times per week had an increased risk of developing asthma, rhinoconjunctivitis, and eczema.¹²⁵ Processed foods also contain synthetic colorants and emulsifiers, such as polysorbate 80 and carboxymethylcellulose, to enhance appearance and texture and extend shelf-life. Studies suggest that these products may enhance bacterial translocation across mucosal surfaces, affect the gut epithelial mucous layer, alter microbial composition, and contribute to the development of intestinal inflammation.¹²⁶,¹²⁷,¹²⁸,¹²⁹ Recent study has shown that commonly used food emulsifiers, polysorbate 20 and polysorbate 80, cause cell death at daily-used concentrations, directly impair barrier integrity of gut epithelial cells, and cause molecular toxicity and proinflammation at lower doses.¹²⁹

EPITHELIAL BARRIER DYSFUNCTION IN ALLERGIC DISEASES

The innate immune responses of epithelial cells are essential for maintaining tissue homeostasis. Epithelial cells facilitate mucociliary clearance, produce antimicrobial peptides and inflammatory cytokines, activate mucosal immune cells, and recruit these immune cells to the site of infection and inflammation, constituting a first physical, chemical, and immunological barrier.¹³⁰ Epithelial cells are also involved in tissue repair and remodeling processes by rapidly dividing, migrating, differentiating, secreting growth factors, and degrading extracellular matrix proteins.¹³¹

Studies have shown that opening the epithelial barrier induces inflammatory responses and increased epithelial permeability, creating a vicious cycle that potentiates dysregulated subepithelial immune responses and more exposure to allergens and irritants.⁷⁰,¹³² Cell-cell adhesion complexes (TJ, AJ, desmosome) are the key regulators of paracellular permeability.¹³³ TJs defects and increased epithelial permeability are the main characteristics of chronic airway disease and leaky gut syndrome. Patients with asthma, AD, and FA express lower levels of TJ protein claudin-1 in the skin, bronchial and intestinal epithelium.¹³⁴ AR patients have reduced expression of the transmembrane proteins occludin and claudin-7, associated with exposure to second-hand smoke and urban locations.¹³⁵ It has also been reported that a high-fat diet and antibiotics affect intestinal permeability via altering microbial composition and disrupting intestinal TJs.¹³⁶,¹³⁷ A perturbed gut integrity and permeability allow bacterial translocation into the circulation as further colonization by opportunistic pathogens makes the host more susceptible to inflammation, tissue damage, and chronic diseases.¹³⁸

Epithelial cells release alarmin cytokines (IL-25, IL-33, and thymic stromal lymphopoietin [TSLP]) in response to allergens and infection. These cytokines prime the immune system to produce type-2 immune responses characterized by activation of mast cells, eosinophils, dendritic cells (DCs), Th2, and innate lymphoid 2 cells. In a functional study, IL-33 potentially drives virus-induced asthma exacerbations by suppressing Th1-innate antiviral response without affecting Th2-response (Fig. 4).¹³⁹ Clinical trials evaluating the effect of anti-IL-33 and its receptor ST2 and anti-TSLP in inflammatory allergic diseases have shown improvements in asthma exacerbation, inflammatory biomarkers, and lung function.¹⁴⁰

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.

Epithelial barriers gradually lose integrity with age due to the senescence of epithelial cells, leading to decreased protection from pathogens through the decreased mucociliary function and leakiness through the loss of TJs and tissue damage.¹⁴¹ Senescent epithelial cells increase airway susceptibility to infections or bacterial colonization in aged individuals, exacerbating existing asthma or potentially leading to late-onset asthma.¹⁴¹ Age-associated alterations in DCs affect the function of epithelial cells. The DCs of the elderly secrete tumor necrosis factor-α that affects the function of primary bronchial epithelial cells, promoting airway inflammation.¹⁴² In addition, aging in the lung is associated with chronic low-grade inflammation, characterized by increased IL-1β, IL-6, and IL-8 expression, that contributes to chronic inflammation, tissue damage, airway obstruction and remodeling.¹⁴³,¹⁴⁴,¹⁴⁵ Epithelium from asthmatics airways exhibits activated senescent signaling pathways, such as p16 and p21.¹⁴⁶ In human bronchial epithelial cells, TSLP induced p16 and p21 in a dose-dependent manner.¹⁴⁶ Silencing of these cellular senescence pathways inhibited TSLP-induced remodeling, demonstrating a functional role for senescent epithelial cells in airway remodeling.¹⁴⁶ Chronic rhinosinusitis in elderly patients commonly occurs with nasal polyps and is associated with increased levels of pro-inflammatory markers, tissue neutrophilia and bacterial infection.¹⁴⁷,¹⁴⁸ The reduction in total and specific serum immunoglobulin (Ig)E levels with aging in patients with AR, asthma, and insect allergy suggests that the proportion of atopy may decrease in older adults.¹⁴⁹ However, the association between serum IgE levels and aging in AD is inconsistent.¹⁵⁰ Skin immunosenescence can cause a systematic type 2 inflammatory response by releasing alarmins from damaged epithelial cells and senescent skin stromal cells.¹⁵¹ AD patients with this subtype show frequent allergic sensitization to other airborne and food allergens.¹⁵² In addition, age-associated shifts in the microbiome and the microbiome’s influence on the aging process have been documented.¹⁵⁰,¹⁵³,¹⁵⁴,¹⁵⁵ The correlation between aging and microbiota composition is well established and suggests lower species richness during childhood, more stability and diversity during adulthood, and loss of some beneficial genera in individuals with advanced ages.⁸²,¹⁵³,¹⁵⁵

CONCLUSIONS

In allergic diseases, exposure to harmful environmental substances significantly impacts public health by changing microbial composition and disrupting the skin, respiratory tract, and gut epithelial barrier. Loss of biodiversity and environmental degradation are also directly associated with an increased incidence of allergy. However, as the factors contributing to allergic sensitization and mucosal barrier function are discovered, inventive and rational modifications can be applied to reduce the burden of allergic diseases.

The barrier theory suggests a need for avoidance of the environmental cues and warrants further studies on safe levels of exposure to potentially harmful substances discussed here, such as inhaled and ingested detergents, ingestion of processed foods containing emulsifiers, exposure to PM, diesel exhaust, microplastics, and specific nanoparticles. As Paracelsus said in 1493, “sola dosis facit venenum,” translating to all substances are poisons; everything can potentially become toxic; it merely depends on the dose. There is sufficient epidemiologic evidence from in vitro and ex vivo studies demonstrating that even trace amounts of enzymes and surfactants found in detergents can damage epithelial barriers and increase bacterial translocation. It is recommended that patients with diseases avoid exposure to these substances. There is a need for research into epithelial barriers, immune system, microbiome and environmental interactions, biochemical and molecular mechanisms associated with leaky barriers, and short- and long-term consequences of leaky epithelial barriers to advance our understanding.