Epithelial Barrier Theory in 9 Lectures

Overall, conditions (approximately 2 billion patients), which are caused or exacerbated by damaged epithelia fall into three categories: 1) Chronic conditions where local barrier defects cause pathology in affected skin and mucosal tissues, such as in allergic diseases, inflammatory bowel and celiac disease; 2) Chronic autoimmune and metabolic conditions in which leaky barriers and microbial dysbiosis in the gut contribute to disease onset and exacerbations, such as in type 1 and type 2 diabetes, obesity, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, hepatitis and systemic lupus erythematosus; 3) Chronic conditions in which gut barrier defects and microbial translocation are associated with neurodegenerative or psychiatric conditions, such as autism spectrum disorder, chronic depression, stress-related psychiatric disorders, Parkinson’s disease and Alzheimer’s disease, although causal relationships remain to be proven. The research is going on and there is a lot to add to these table.

Tables

A number of allergens, pathogens and environmental toxins can damage the epithelial barrier. These include allergens derived from dust mites, certain bacteria, fungi, viruses, toxins contained in laundry, dishwashing and household cleaning agents. Moreover, surfactants, enzymes and emulsifiers in processed food, cigarette smoke, particulate matter, diesel exhaust, ozone, nanoparticles and microplastics have been shown to damage the epithelial barrier (Table 2-Table3). These substances are encountered by humans as a consequence of industrialization, urbanization and modernization

Exposure to barrier damaging agents or genetic deficiency in barrier molecules cause colonization of opportunistic pathogens and epithelial inflammation. Microbiome migrates deeper inside the epithelium and gets in contact with basal epithelial cells and stimulates the immune system. Opportunistic pathogens, such as S aureus, Moraxella, Haemophilus, Pneumococcus are colonized and translocate beneath the epithelium. An Immune response develops against the commensals and opportunistic pathogens and leads to the development of microbial dysbiosis. Microbial dysbiosis and the translocation of commensals and opportunistic pathogens across epithelial barriers typically intiates a type 2 immune response, characterized by a predominance of TH2 cells, ILC2s and eosinophils. The aim here is to expulse the microbes that are going deeper between and even below the epithelium. The epithelium cannot fully repair and close the barrier, instigating a vicious circle of leaky barriers, microbial dysbiosis and chronic inflammation.

Exposure to barrier damaging agents or genetic deficiency in barrier molecules cause colonization of opportunistic pathogens and epithelial inflammation. Microbiome migrates deeper inside the epithelium and gets in contact with basal epithelial cells and stimulates the immune system. Opportunistic pathogens, such as S aureus, Moraxella, Haemophilus, Pneumococcus are colonized and translocate beneath the epithelium. An Immune response develops against the commensals and opportunistic pathogens and leads to the development of microbial dysbiosis. Microbial dysbiosis and the translocation of commensals and opportunistic pathogens across epithelial barriers typically intiates a type 2 immune response, characterized by a predominance of TH2 cells, ILC2s and eosinophils. The aim here is to expulse the microbes that are going deeper between and even below the epithelium. The epithelium cannot fully repair and close the barrier, instigating a vicious circle of leaky barriers, microbial dysbiosis and chronic inflammation.

The relatively recent onset of the epidemics of allergic, autoimmune and metabolic conditions leads to the question what might underlie their development. A prominent hypothesis is the hygiene hypothesis, which proposes that certain microorganisms protect against inflammatory diseases, and that their loss, due to hygiene measures, results in an increase in allergy, asthma and autoimmunity. Several extensions to the hygiene hypothesis have been proposed. One is the ‘old friends’ hypothesis’, which suggests that some microbial species have co-evolved with humans and their surrounding animals and have protective functions. Several shortcomings of the hygiene hypothesis have been discussed during the last decades and suggest that these hypothesis do not fully explain the rise in allergic and autoimmune disease. These include the fact that water sanitation was established in many western cities in the 1920s, but allergy and asthma epidemics only started in the 1960s. The protective role of parasite infections that increase biodiversity has been questioned for the same reason. In addition, allergic asthma is still on the rise in some cities in Asia and Africa that have low standards of hygiene. Another limitation of the hygiene hypothesis and biodiversity hypothesis is that probiotics are not viable alternatives for the prevention or treatment of allergies. Moreover, studies of migrants who move 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. It appears that domestic living conditions, increased birth by ceserian sections, antibiotic usage, dietary practices, urbanization, indoor air pollution are more prominent factors compared to general public hygiene.

Reduced biodiversity and alterations in the composition of the gut and skin microbiota always go parallel with leaky barriers and are associated with various inflammatory conditions listed in Table 1. Young children at risk of developing allergies have gut microbiome dysbiosis with an overall reduced microbiome diversity. General microbial deprivation appears to be a risk factor for immune dysregulation and impaired tolerance.An outgrow of facultative pathogens, such as S. aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis leads to decreased biodiversity and may contribute to the development of allergic diseases. The microbiome can flourish through contact with all the elements linked to the hygiene hypothesis, such as pets, farm animals and siblings. It has been demonstrated that asthmatic children exhibit an aberrant immune response by the time they reach school age. Blood samples taken before asthma development, when they were infants, showed T cell production of IL-5, IL-17 and IL-10 to H. influenzae, M. catarrhalis and S. pneumoniae. These findings support an abnormal T cell immune response against pathogenic bacteria during early life, which precedes the development of asthma. It is not difficult to speculate that early colonization of these microbes in deeper tissues is the main denominator of dysbiosis.Recent studies suggest that microbes themselves, fecal transplantation or related products can be used to remodel the body’s response to alleviate or cure diseases. Special diets that release SCFA, as measured from fecal SCFA levels, have been suggested to be protective in diabetes, allergies, asthma and inflammatory bowel disease. In addition, fiber, tryptophan and omega-3 fatty acid content in food have been demonstrated to have an enhancing role in mucosal tolerance to foods in gastrointestinal tissues in various models and pediatric cohorts.
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