Epithelial Barrier Theory

Epithelial Barrier Theory in 9 Lectures

Lecture 1: Introduction

“Epihelial Barrier Theory” proposes that increased exposure to epithelial barrier damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. It discusses whether the immune response to dysbiotic microbiota that cross the damaged barrier are involved in the development of these diseases. Almost two billion patients are affected with the epithelial barrier damaging agents. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, celiac disease, and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and autoimmune hepatitis. Finally, distant inflammatory responses due to a ‘leaky gut’ and microbiome changes are suspected in Alzheimer’s disease, Parkinson’s disease, chronic depression and autism spectrum disorders.

Lecture 2: The problem: Pandemic of many chronic noncommunicable diseases starting after 1960s and increasing after 2000s.

The incidence of allergic asthma and atopic dermatitis started to grow to epidemic proportions after the 1960s. Since 2000, the prevalence of food allergy, eosinophilic esophagitis and drug-induced anaphylaxis has risen to epidemic proportions9-11. In addition, a substantial increase in autoimmune and metabolic conditions, such as diabetes, obesity, rheumatoid arthritis, multiple sclerosis and celiac disease has been recorded in industrialized countries since the 1960s, and this trend is still continuing today (Box 1). Several recent studies in animals and humans suggest a connection between increased intestinal barrier leakiness and neurodegenerative and psychiatric disorders such as Parkinson’s disease, Alzheimer’s disease, autism-spectrum disorders and chronic depression. Although they require further evidence, these conditions have substantially increased in prevalence during the same time period as allergic and autoimmune diseases.

Lecture 3: Diseases that epithelial barrier disrupton has ben linked to pathogenesis.

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. 

Lecture 4: Epithelial barrier damaging substances introduced by modern life linked to chronic inflammatory diseases

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 

Lecture 5: Epithelial barrier functions

The epithelial barrier in the airways and gastrointestional system consists of mucus, microbiota, surface liquids, and junctional complexes between adjacent epithelial cells that comprise tight junctions and adherens junctions. The ability of the epithelium to control the balance of tissue damage and repair signals is essential to limit tissue injury and to control the resolution of inflammation during tissue repair. Studies performed on the gut, skin, esophagus, bronchus and sinus have demonstrated that inflammatory responses can be induced as a consequence of an opening of the epithelial barrier, leading to a vicious cycle where the subepithelial inflammation itself continues to keep the barriers damaged and open. Closed epithelial TJs in the mucosal epithelium protect against the exposome, such as allergens, pollutants, microbes and their enzymes and toxins. Open epithelial TJs in the mucosa help to drain immune cells and proinflammatory molecules from the subepithelial inflammation, but at the same time, allow the entrance of foreign substances to deeper tissues.

Lecture 6: Pathogenesis of chronic diseases due to epithelial barrier leakiness

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.

Lecture 7: Link to microbiome and biodiversity: Immune response develops against commensals and opportunistic pathogens in leaky barrier

An important feature of chronic mucosal inflammation is the development of an immune response towards newly colonizing facultative pathogens. When the microbiota that is normally located on the surface of the epithelium translocates to the deeper layers between and beneath the epithelial cells, it stimulates the immune system. Microbial dysbiosis and transepithelial translocation of commensal microbes, as well as further colonization by opportunistic pathogens is a halmark of barrier damaged tissues. A typical example of an opportunistic pathogen that induces a expulsion response in inflammatory tissues is S. aureus, which is the most abundant bacterium that colonizes barrier damaged tissues in the skin and upper respiratory mucosa. After 1980’s a significantly increased colonization of S. aureus in the skin and respiratory mucosa has been observed. An overgrowth of such facultative pathogens also leads to a decrease in the local biodiversity of the microbiome. Breach of the epithelial barrier by S. aureus has been associated with asthma, CRS and atopic dermatitis, and a high prevalence of IgE antibodies specific to S. aureus antigens correlate with severity and disease exacerbation in the same patients. S. aureus colonization further compromises the mucosal barrier, if the epithelium has already been disturbed. In addition to S. aureus, certain facultative pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis have also been associated with barrier leaky tissues.
However, translocated bacteria cannot easily be expulsed and the barrier cannot be closed in this type of a chronic mucosal inflammation, likely because signals from commensal microbes and newly colonizing facultative pathogens are too weak to stimulate an appropriate anti-bacterial response followed by full tissue healing. It does not involve a neutralizing immune response against microbes, so it is more likely to lead to chronicity rather than elimination of the microbes.

Lecture 8: Epithelial barrier theory covers the hygiene hypothesis

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. 

Lecture 9: Barrier theory covers and is linked to biodiversity hypothesis: Immune response to commensals and opportunistic pathogens in leaky epithelial barrier areas cause microbial dysbiosis

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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