Epithelial Barrier Theory

Review Articles

Yazici, D., Ogulur, I., Kucukkase, O. et al. Allergo J Int 31, 91–102 (2022). hMps://doi.org/10.1007/s40629-022-00211-y

The “epithelial barrier hypothesis” proposes that genetic predisposition to epithelial barrier damage, exposure to various epithelial barrier–damaging agents and chronic periepithelial inflammation are responsible for the development of allergic and autoimmune diseases. Particularly, the introduction of more than 200,000 new chemicals to our daily lives since the 1960s has played a major role in the pandemic increase of these diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defence against external factors. A leaky epithelial barrier initiates the translocation of the microbiome from the surface of affected tissues to interepithelial and even deeper subepithelial areas. In tissues with a defective epithelial barrier, colonization of opportunistic pathogens, decreased microbiota biodiversity, local inflammation, and impaired regeneration and remodelling takes place. A dysregulated immune response against commensals and opportunistic pathogens starts. Migration of inflammatory cells to other tissues and their contribution to tissue injury and inflammation in the affected tissues are key events in the development and exacerbation of many chronic inflammatory diseases. Understanding the underlying factors that affect the integrity of epithelial barriers is essential to find preventive measures or effective treatments to restore its function. The aim of this review is to assess the origins of allergic and autoimmune diseases within the framework of the epithelial barrier hypothesis. Read more.

Yazici, D., Ogulur, I., Pat, Y. et al. Seminars in Immunology, https://doi.org/10.1016/j.smim.2023.101846

Since the 1960 s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The “Epithelial Barrier Theory” postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body’s primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory. Read more.

Pat, Y. , Ogulur, I. Allergy. 2021 Nov;76(11):3560-3562. doi: 10.1111/all.14899. Epub 2021 May 28. PMID: 33982305.

The Epithelial Barrier Theory is rooted in studies from the beginning of the century that demonstrate immune-mediated epithelial barrier damage in chronic allergic inflammation. One of the first findings regarding the immune-mediated epithelial barrier damage was made in atopic dermatitis and allergic contact dermatitis patients. Skin infiltrating T cells were demonstrated to induce keratinocyte apoptosis, leading to eczema development, a skin barrier defect.1 Since then, many studies have elaborated on the concept of type 2 immunity mediated barrier damage in various diseases such as asthma, chronic rhinosinusitis, and colitis.2,3 Type 2 immunity, which is the default defence against parasites and venoms, plays a crucial role in epithelial barrier regulation. It was proposed in 2006 that the thickening of the airway basement membrane forms a barrier below the leaky epithelium between the environment that may include a dysbiotic microbiome and toxic substances and inner tissues to prevent the entry of harmful components.2 Factors that “keep away” the environmental knox and that “wash away” the toxic substances together with inflammation have been proposed. The opening of epithelial barriers, increased mucus production, and mucosal shedding are representatives of a mechanism that attempts to reduce allergen exposure (wash-away effect).2,3 It is well known that type 2 cytokines such as IL-4 and IL-13 open the epithelial barriers.4 Conditions characterised by a systemic type 2 immune response, such as asthma, chronic rhinosinusitis, and atopic dermatitis, are well-defined by an impaired epithelial barrier.3,4 “The Epithelial Barrier Theory” takes into account five facts: the steep increase in allergic and autoimmune diseases, the evidence of epithelial barrier disruption in these conditions, microbial dysbiosis and bacterial translocation, immune response to commensals and opportunistic pathogens, and changes in environmental exposure due to urbanisation and industrialisation.3 In the last century, humanity has faced new environmental challenges, including poor air quality, climate change, and increased use of toxic substances such as detergents, nanoparticles, and microplastics. These biological and chemical insults disrupt the barrier integrity and cause the release of epithelial cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin, which leads to a type 2 immune response in affected organs in asthma, rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, food allergy, and atopic dermatitis.5,6

The Epithelial Barrier Theory presents an overarching idea that also embraces previous views from the Hygiene, Old Friends, and Biodiversity hypotheses. It includes all previous mechanisms and brings a promising rationale to explain the sudden increase of chronic noncommunicable inflammatory diseases observed in the last six decades. It offers new ideas for diagnosis, treatment, and prevention of diseases associated with epithelial barrier leakiness. Moreover, the theory further introduces novel mechanisms for the pathophysiology of autoimmune diseases, chronic neuropsychiatric conditions, and metabolic diseases. Read more.

Pat Y, Ogulur I, Yazici D, et al. Tissue Barriers. 2023 Oct 2;11(4):2133877. Doi: 10.1080/21688370.2022.2133877. Epub 2022 Oct 19. PMID: 36262078; PMCID: PMC10606824.

Topic: summarizing the effects of human-induced environmental damage on global ecosystems and human health through the context of epithelial barrier theory

Pollution in the world and exposure of humans and nature to toxic substances is continuously worsening at a rapid pace. In the last 60 years, human and domestic animal health has been challenged by continuous exposure to toxic substances and pollutants because of uncontrolled growth, modernization, and industrialization. More than 350,000 new chemicals have been introduced to our lives, mostly without any reasonable control of their health effects and toxicity. A plethora of studies show exposure to these harmful substances during this period with their implications on the skin and mucosal epithelial barrier and increasing prevalence of allergic and autoimmune diseases in the context of the “epithelial barrier theory”. Exposure to these substances causes an epithelial injury with peri-epithelial inflammation, microbial dysbiosis and bacterial translocation to sub-epithelial areas, and immune response to dysbiotic bacteria. Here, we provide scientific evidence on the altered human exposome and its impact on epithelial barriers.

The change in human exposome: The main threats to nature and human health

Anthropocene refers to the current geological epoch in which human activities significantly affect the Earth’s geology and ecosystems. Since the industrial revolution, the proposed beginning of anthropogenic influences, the human impact on the nature has become more evident and the consequences such as anthropogenic climate change, habitat destruction, and environmental pollution are now threatening the Earth’s ecosystem and human health. 1,6,12-20 According to current reports, population sizes of species in the nature have decreased by 60% between 1970 and 2014 and extinction rates are 100 to 1000 times higher than previous background rates.21

The term exposome describes all the environmental exposures individuals are facing during their lifetime.4 These factors can be divided into three categories: general external environment, specific external environment, and host-dependent internal environment.22 The general external environment includes a wider socioeconomic environment such as climate, urban-rural environment, and educational level. However, specific external environment includes more individual factors such as lifestyle, pollutant exposure, and infections. However, the host-dependent internal environment includes both biological effects of external exposure and biological responses such as metabolic factors, inflammation, and oxidative stress.4,23,24 There have been alarming changes in the exposome in the last 70 years brought about by industrialization, urbanization, and modernization as exemplified by studies indicating human exposure to nearly 200,000-350,000 new chemicals.4,5,10 Since the 1950s, the amount of plastic production has increased nearly 200 times, and it is estimated that the total amount of plastic produced worldwide by 2017 reached approximately 8.3 billion metric tons.13,15,25 Today the human body is continuously exposed to a wide range of potentially harmful substances, such as PM, DEP, cigarette smoke, NP, MP, nanoparticles, ozone, nitric oxide (NO), nitrogen dioxide(NO2), carbon monoxide (CO), sulphur dioxide(SO2),  household cleaners, laundry and dishwasher detergents, toothpaste, surfactants and emulsifiers in processed food, and pesticides   (Figure 2). 1 Annual global deaths from pollution-related diseases are estimated at 9 million, still more than COVID-19-related deaths, mostly in underdeveloped countries.6,17

Ambient and indoor air pollution

Air pollution is one of our era’s biggest menaces as it contributes to climate change and is a leading cause of respiratory diseases.26 According to the World Health Organization’s (WHO) World Global Ambient Air Quality Database, 91% of the global population is exposed to poor air quality.27,28 Ambient air pollution alone is responsible for an estimated 3.7 to 4.2 million annual deaths worldwide. 6 Air pollution is a complex mixture of gaseous and particulate components. Gaseous components include NO, NO2, SO2, CO and ozone. 29 Air and aquatic PM originates from both natural and anthropogenic sources. Natural sources include dust, including desert dust, sea salt, and forest fires. In contrast, anthropogenic sources include traffic, power plants, factories, wood, and coal-burning emissions. 30 Studies suggest that air pollution aggravates cardiovascular and respiratory diseases and is associated with the development or progression of asthma, diabetes, reproductive, and various neurocognitive diseases.31-33 PM is classified according to particle size (PM0.1, PM2.5, and PM10). Epidemiological studies indicate that exposure to ambient PM pollution has increased over the past ten years coinciding with increased drug use, high fasting plasma glucose, and high body mass index.14 In the last 40 years, atmospheric black carbon concentration (which is a PM2.5) generated as a by-product of incomplete combustion of fossil fuels, biofuels, and biomass, has shown a substantial increase of 1.57 times (from 0.70 μg/m3 in 1980 to 1.10 ± 0.22 μg/m3 in 2019) with an annual increase by 1.52% in China.34 Moreover, it was reported that there was an independent association between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality.35 According to a meta-analysis, there is a positive and statistically significant link between the onset of asthma and exposure to black carbon, NO2, PM2.5 and PM10, well-known traffic-related air pollution constituents. 36 Ambient air pollution, especially PM, is considered a neurotoxicant and impairs cognitive functions, learning abilities, and neurodevelopment. It is thought to be associated with depression, vascular dementia, and stroke. Along with urban PM, wildfire PM has also been associated with morbidity and mortality. An increased risk of hospitalization and emergency room visits for asthma, chronic obstructive pulmonary disease (COPD), and respiratory tract infection has been reported in individuals exposed to wildfire PM. 19 Among other air pollutants, exposure to oxides of nitrogen affects the central nervous system and contributes to neurological disorders.37 During COVID-19 restrictions, the atmospheric levels of air pollutants associated with traffic emissions including oxides of nitrogen, SO2, and CO, and primary PM levels decreased due to the quarantine and lock-down measures imposed by the governments. In contrast, secondary PM levels remained unchanged or even increased during the same period.38

Indoor pollution is a major problem, as pollution levels are often twice as high then outdoors and people spend 80-90% of their lives indoors.39 Household air pollution is estimated to be responsible for 2.9-4.3 million deaths per year worldwide.2 Thanks to social and economic development, household air pollution has declined in the last ten years. 14 Although the risk exposure to tobacco use is declining, it is still responsible for more than 8 million deaths annually of which 1.2 million are from second-hand smoking,40 mostly affecting low- and middle-income countries. 5,40

Micro- and nano- plastic pollution

The use of plastics has rapidly grown as these materials offer a low production cost and high stability and durability. However, plastic waste poses a threat to nature as most plastics are non-biodegradable. It is estimated that in 2015 globally 66-90 million metric tonnes of miss managed plastic waste are produced and every year 8 million tonnes of plastic waste are escaped to the oceans.25,41 When plastic waste enters the environment, it breaks down into small fragments and particles such as MPs (1 mm to 5 mm) and NPs (1 nm to 1000 nm).13,42 The degradation products can be detected in the air, water, and sediment.13,16 It is reported that nano- and MPs are harmful to aquatic species, such as zooplankton, bivalves, and small fish.13 Moreover, NPs can penetrate living organisms and eventually enter the human food chain.13,15 In addition, humans are exposed to airborne NPs through the airways and in contact with the skin.15 

Processed foods: harmful additives in foods

The modern food industry provides a wealth of supply and diversity made possible by the incorporation of food additives, such as synthetic colorants, preservatives, stabilizers, surfactants, emulsifiers, and texturizers. There is mounting evidence suggesting that processed foods that contain food additives and advanced glycation endproducts (AGEs) due to heat processing disrupt the integrity of the epithelial barrier, a key pathological feature in the development of allergic and autoimmune diseases.1,43  The consumption of processed food has been associated with all-cause mortality, obesity, metabolic syndrome and depression.44 In addition, food contamination is possible by contact with dishware that has residues from cleaning products, such as detergents and anionic surfactants.7,45,46

Anthropogenic climate change

Anthropogenic activities are responsible for global warming,47-49 with a mean temperature increase of 0.2°C per decade.18 A recent study predicts global warming of 2.6 °C (1.9 °C to 3.7°C) by 2100, taking into account only the current energy policies and measures being developed by the countries participating in the Paris agreement. Nonetheless, the authors noted that warming can be limited to 1.9–2.0°C if all the conditional and unconditional pledges of the Paris agreement are met in full and on time.50 The generation of large quantities of greenhouse gases has been a key driver of climate change, in particular carbon dioxide emissions. Moreover, deforestation cripples the Earth’s natural ability to remove atmospheric CO2, further aggravating global warming and causing extreme weather events.26,51 In the future, increases in morbidity and mortality are estimated due to climate change-related adverse effects such as heat-related illnesses, poor air quality, and undernutrition due to reduced food quality and security.18 It should be noted that the global risks from toxic pollution and climate change are highly correlated, with low- and middle-income countries being the most affected by both.17 Read more.