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Epithelial Barrier Theory
The Epithelial Barrier Theory is a comprehensive explanation for the global, epidemic-level rise in chronic health conditions over the past 65 years. The theory, postulated by Cezmi Akdis, proposes that exposure to toxic substances introduced by industrialization and modern lifestyle changes disrupts the epithelial barrier of the skin, upper and lower airways, and gut mucosa, triggering an inflammatory immune response that can initiate or aggravate many chronic inflammatory diseases.

Background
The surfaces of our skin, respiratory tract, and gut are all lined with protective cellular layers known as epithelial barriers. Intact epithelial barriers are crucial for homeostasis, as they protect host tissues from infections, environmental toxins, pollutants and allergens. Many of the chemical agents found in common consumer products (including toothpaste, shampoo, detergents, and processed foods), are known to damage these critical barriers, increasing permeability to bacteria, toxins, pollutants and allergens. When epithelial barriers are disrupted (or “leaky”), substances and microbes can pass into deeper tissues, where they don’t belong and trigger an immune/inflammatory response that can initiate or aggravate many chronic inflammatory diseases.

These diseases like asthma, rhinitis, atopic dermatitis, food allergy, inflammatory bowel disease, diabetes, rheumatoid arthritis, and chronic depression are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel with urbanization and industrialization. This steep increase in chronic, non-communicable diseases has been linked to changes in hygiene, decreased bacterial and worm infections, less microbial and food diversity, increased allergen exposure, changes in indoor environment, and nutrition.

Akdis’s Epithelial Barrier Theory posits that the increase in barrier-damaging agents linked to industrialization, urbanization and modern life underlies the global rise in allergic, autoimmune, neuropsychiatric chronic conditions that now affect more than two billion people worldwide.

Characteristics of the Epithelial Barrier Theory

 * 1) Increased prevalence over the last 60 years: The sharp rise in the prevalence of allergic and autoimmune diseases suggests that environmental factors are impacting our immune system.       Early reports from the 1960s indicated an increased prevalence of asthma in children and higher hospitalization rates.    After the 2000s, a new wave of epidemics emerged, including food allergy and anaphylaxis, eosinophilic esophagitis, and drug-induced anaphylaxis.   Interestingly, the increase in autoimmune diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis, and celiac disease, began in the 1960s, and this trend continues in developing countries.
 * 2) Disturbed epithelial barriers: Evidence of epithelial barrier disruption in these conditions suggests that our body's first line of defense against harmful pathogens is not functioning correctly. Epithelial barrier damage has been demonstrated in most cases through direct biopsies of affected tissues.        Three reasons have been identified for this disruption:
 * 3) * Pathogenetic events as mechanisms of the epithelial barrier theory.jpgical defects and mutations in barrier proteins: In the skin, the stratum corneum forms a relatively stronger barrier with its filaggrin repeats and other molecules such as loricrin, involucrin and  hornerin. Mutations in filaggrins, polymorphisms in tight junction (TJ) claudin and occludin genes have been reported to play a role on epithelial barrier integrity.
 * 4) * Direct exposure to pollutants, chemicals, and other environmental factors that are in the exposome can disrupt the epithelial barriers and affect the microbiome and immune system.
 * 5) * Inflammation in the affected epithelial barriers takes place in asthma, atopic dermatitis, rhinitis, sinusitis and colitis activates the epithelial cells, and these epithelial cells open their barriers.
 * 6) Microbial dysbiosis: A healthy microbiota on the surface of the mucosal barrier regulates numerous aspects of barrier homeostasis. However, reduced biodiversity and alterations in the composition of gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic diseases, inflammatory bowel disease, type 1 diabetes, and obesity. Dysbiosis refers to an imbalance in the microorganisms residing in our tissues, with microbial dysbiosis and bacterial translocation being linked to the development and exacerbation of allergic and autoimmune diseases.
 * 7) Immune response to commensal bacteria and opportunistic pathogens: In areas with leaky epithelial barriers, the immune system struggles to distinguish between harmful and harmless microorganisms.  This inability triggers a chronic inflammatory response to harmless microorganisms, decreasing biodiversity and contributing to the development of allergic and autoimmune diseases. In addition, immune response to S. aureus, an opportunistic pathogen is taking place in most of the atopic dermatitis, chronic rhinosinusitis and asthma patients and a high prevalence of IgE antibodies correlates with the disease severity.
 * 8) Peri-epithelial inflammation, epithelitis, and expulsion response: Individuals with leaky epithelial barriers exhibit local inflammation in their epithelial cells, referred to as  "epithelitis". Epithelitis is the initial event that attracts proinflammatory cells to the damaged epithelial barrier area, prompting the immune system to expel tissue-invading commensals and opportunistic pathogens through a process called the "expulsion response”, similar to an essential defense mechanism against helminth parasites.
 * 9) Migration of inflammatory cells to distant organs: Immune cells activated at leaky barrier sites can migrate to distant organs, causing inflammation in those areas. Moreover, increased inflammatory mediators in the circulation, namely, “circulating microinflammation”, consisting of acute phase reactants, chemokines, and cytokines, can be detected. There are clear examples of inflammatory cell migration from barrier leaky areas to diseased tissues. Cutaneous lymphocyte antigen-expressing T cells can get activated in the gut with food allergen exposure and then migrate to skin and exacerbate atopic dermatitis.   In polyallergic patients, activated and circulating T cells express chemokine receptors and have the capacity to migrate towards various allergic tissues. This mechanism could be responsible for the atopic march of allergic diseases, sequentially manifesting as atopic  dermatitis, food allergy, asthma, and allergic rhinitis during childhood.

Harmful environmental substances that disturb epithelial barriers
Exposure to harmful environmental substances can disturb epithelial barriers, leading to leaky epithelial barriers, microbial dysbiosis, bacterial translocation to inter- and sub-epithelial areas, and tissue microinflammation in and around the barriers. The term "exposome" refers to all environmental factors individuals encounter throughout their lifetime. These factors are categorized into three groups: the general external environment, the specific external environment, and the host-dependent internal environment. The general external environment includes factors such as climate, urban-rural settings, and education level, while the specific external environment comprises individual factors like lifestyle choices, exposure to pollutants, and infectious diseases. The host-dependent internal environment encompasses both the biological effects of external exposure and biological responses, such as metabolic factors, inflammation, and oxidative stress.

Over the last 60 years, industrialization, urbanization, and technological advancements have significantly changed the exposome, raising concerns about their health effects on humans and animals. A recent meta-analysis of 22 chemical inventories from 19 countries revealed that more than 350,000 new substances have been introduced to human lives since the 1960s, with little control over their health effects. Many of these substances may have become pollutants or entered the daily exposome. Unfortunately, 50,000 of them are publicly unknown due to confidential submissions, and nearly 70,000 have been ambiguously described.

Since the 1950s, plastic production has increased nearly 200-fold, with an estimated 8.3 billion metric tons produced worldwide by 2017. Consequently, the human body is continuously exposed to a variety of potentially harmful substances, including particulate matter, diesel exhaust particles, cigarette smoke, nano and microplastic, nanoparticles, ozone, NO, NO2, CO, SO2, household cleaners, laundry and dishwasher detergents, toothpaste, surfactants, emulsifiers, preservatives in processed food, and pesticides.