Main Text
The global environment has been transformed rapidly in the last six
decades as a direct result of a more westernized, industrialized, and
modernized world. At the same time, humanity has faced a marked increase
in allergic, autoimmune, metabolic and certain neuropsychiatric
diseases, especially in industrialized countries. It is now evident that
exposure to toxic substances together with lifestyle changes due to
urbanization, increased early use of antibiotics, a westernized diet,
and obesity play important roles in the development of these
diseases.1 Despite the extensive progress in
understanding the pathophysiology of allergic and autoimmune diseases,
there is no comprehensive view that can fully explain the reasons behind
the epidemic increase of these conditions worldwide. A comprehensive
review article, introducing ”The Epithelial Barrier Hypothesis” which
aimed to elucidate this phenomenon, was recently
published.1 This hypothesis postulates that
environmental exposure to toxic substances introduced by modern
lifestyle affects the epithelial barrier of the skin, upper and lower
airways and gut mucosa. These substances include detergents, cleaning
products (particularly enzymes and surfactants), microplastics,
nanoparticles, increased ozone and particulate matter concentrations,
cigarette smoke, and food additives (enzymes and emulsifiers). Exposure
to these harmful agents leads to the development of leaky epithelial
barriers, microbial dysbiosis, translocation of bacteria to inter- and
sub-epithelial areas, and tissue microinflammation in and around the
epithelial barriers. “The Epithelial Barrier Hypothesis” also proposes
that the barrier damage caused by the environmental changes is not only
responsible for the development of allergy and autoimmune conditions,
but also a wide range of diseases in which immune responses to
translocated bacteria have systemic effects.1 This
list can be extended by further investigating diseases with microbial
dysbiosis and subepithelial translocation of bacteria and immune
response to commensals or opportunistic bacteria.
The Epithelial Barrier Hypothesis 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.2Since 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.1-3 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.3 Factors that
“keep away” the environmental knox and that “wash away” the toxic
subtances together with inflammation have been proposed. The opening of
epithelial barriers, increased mucus production and mucosal shedding,
representatives of a mechanism that attempts to reduce allergen exposure
(wash-away effect).1,3 It is well known that type 2
cytokines such as IL-4 and IL-13 open the epithelial
barriers.4 Conditions characterized by a systemic type
2 immune response, such as asthma, chronic rhinosinusitis, and atopic
dermatitis, are well-defined by an impaired epithelial
barrier.1,4 “The Epithelial Barrier Hypothesis”
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 urbanization and
industrialization.1 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 Hypothesis presents an overarching idea that also
embraces previous views from the Hygiene, Old Friends, and Biodiversity
hypotheses.1 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 hypothesis
further introduces novel mechanisms for the pathophysiology of
autoimmune diseases, chronic neuropsychiatric conditions, and metabolic
diseases.