Epithelial Barrier Theory

Original articles

Negative impact of common food emulsifiers on gut health

Mechanisms of gut epithelial barrier impairment caused by food emulsifiers polysorbate 20 and polysorbate 80

Ogulur I, Yazici D, Pat Y, Bingöl EN, Babayev H, Ardicli S, Heider A, Rückert B, Sampath V, Dhir R, Akdis M, Nadeau K, Akdis CA. Allergy. 2023 Aug 2. doi: 10.1111/all.15825.

Compounds present in everyday consumer products like processed foods, detergents, household cleaners and cosmetics have the potential to damage the protective cellular linings of the skin, respiratory tract and gut, which are referred to as epithelial barriers. This impairment can lead to microbial dysbiosis, bacterial migration, chronic microinflammation, and immune dysfunction. The concept of the epithelial barrier theory suggests that the widespread use of these barrier-damaging agents, including emulsifiers, surfactants, preservatives, and microplastics, is a key factor behind the significant and global increase in chronic health condition observed over the past 65 years.

Polysorbates are a type of nonionic surfactant often used in food preparation to improve the texture and consistency of foods, as well as to act as an emulsifier to help mix ingredients that might not otherwise blend well, such as oil and water. Originally incorporated as a food additive during mid-20th century, their utilization has since become widespread globally. Today, they are found in a wide range of processed foods, including ice cream, baked goods, salad dressings, and sauces, at concentrations up to 1%.

A comprehensive study by Ogulur et al. demonstrated the impact of P20 and P80, the most common types of polysorbates used in foods, on epithelial barriers and inflammatory response. Using human models, such as induced pluripotent stem cell-derived human intestinal organoids, colon organoids, organ-on-a-chips, and liquid-liquid interface cultures, it was revealed that P20 and P80 damage the gut barrier. This disruption is due to cell death and molecular toxicity, as well as the triggering of numerous genes and proteins that stimulate inflammatory responses in epithelial cells (known as ‘epithelitis’). The food emulsifiers also triggered a range of cellular processes, including tissue damage, alterations in cell signaling and communication, and induced inflammation. The study highlights that these effects occurred even at doses much lower than those approved for public use.

Considering that a defective epithelial barrier can facilitate the entry of allergens and induce an inflammatory response that can initiate or aggravate many chronic inflammatory diseases, the need to further evaluate the health hazards of these barrier-damaging compounds –– and the search for safer alternatives –– is all the more urgent. Read more.

Disrupted epithelial barriers as a predictor of severe COVID-19 development

Yazici D, Cagan E, Tan G, Li M, Do E, Kucukkase OC, Simsek A, Kizmaz MA, Bozkurt T, Aydin T, Heider A, Rückert B, Brüggen MC, Dhir R, O'Mahony L, Akdis M, Nadeau KC, Budak F, Akdis CA, Ogulur I. Allergy. 2023 Jul 8. doi: 10.1111/all.15800.

According to the epithelial barrier theory, the disruption of epithelial barriers by environmental and toxic agents results in microbial dysbiosis, bacterial translocation to subepithelial areas and local or systemic immune/inflammatory response to environmental agents, allergens and microbes. Chronic conditions like allergic, autoimmune and metabolic diseases have been linked to such events. Hyperinflammation, hyperactivated immune responses (known as the cytokine storm), cellular infiltration and organ damage are hallmarks of severe COVID-19 infections.

The compromised epithelial barrier facilitates the translocation of microbiota and their secreted metabolites, thus initiating or exacerbating inflammatory cascades in many inflammatory diseases. A comprehensive study by Yazici et al. provides evidence that compromised epithelial barrier function is predicting severe COVID- 19, in line with the epithelial barrier theory. In this study, the amount of bacterial DNA leakage to circulation was analyzed and the link between disrupted epithelial barriers and an excessive inflammatory response was demonstrated. Major inflammatory proteins, including AREG, AXIN1, CLEC4C, CXCL10, CXCL11 and TRANCE correlated strongly with bacterial translocation and can be used to predict and discriminate severe COVID-19 cases from healthy controls and mild cases. Interestingly all of these analyses were done at the time of hospital admission even before severe symptoms occurred demonstrating that there is a link between certain protein biomarkers and disease progression from moderate to severe COVID-19 and death. These findings emphasize the value of early detection of biomarkers of epithelial barrier leakiness and bacterial translocation as indicators of poor disease outcome. They have implications on other infections, chronic diseases and may change the daily clinical practice and facilitate early therapeutic interventions. Read more.

Spatial and single-cell RNA-sequencing, the cutting-edge technologies for the investigation of the disease pathogenesis

Mitamura Y, Reiger M, Kim J, Xiao Y, Zhakparov D, Tan G, Rückert B, Rinaldi AO, Baerenfaller K, Akdis M, Brüggen MC, Nadeau KC, Brunner PM, Roqueiro D, Traidl-Hoffmann C, Akdis CA. Allergy. 2023 Aug;78(8):2215-2231. doi: 10.1111/all.15781.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases affecting the lives of more than 500 million people worldwide. Representative symptoms are dry, itchy, sensitive skin with redness with the skin barrier dysfunction. Recent advances, including single-cell RNA-sequencing analyses, showed the details of AD’s molecular and immunological characterization. However, even within the realm of single-cell studies, the dimensions of spatial arrangement were unclear.

The human body has approximately 200 different cell types. Spatial transcriptomics is a novel technology that integrates whole transcriptomics data and information on the localization of the cells. To investigate how do these cells converse and collaborate within the skin’s intricate landscape, Mitamura et al. collected gene expression information from more than 16,000 spots in tissue from AD patients and healthy controls. This study identified the detailed cell-cell crosstalk in the AD skin. Besides, the combination of the result of cutting-edge technologies (Spatial transcriptomics, single-cell transcriptomics, targeted multiple proteomics) demonstrated AD specific CCL13+, CCL18+, M2 macrophages, activated dendritic cells (CCR7+, CCL17,  LAMP3+), and activated fibroblast (CCL19+, TNC+, COL6A5+). The spatial transcriptome identified the interaction between these M2 macrophages, dendritic cells, fibroblasts, and T cells. Moreover, serum levels of TNC and CCL18 showed positive correlation with AD severity, suggesting that they are possible candidate biomarkers for AD.

Identifying the AD-specific activated cells and demonstrating their cellular interactions may lead to unknown pathogenesis of AD and novel treatment for AD. Implementing the findings in other areas, especially the epithelial layer, is a promising approach for investigating the mechanism of epithelial barrier dysfunction. Read more.

Negative impact of professional dishwasher rinse aid on gut health

Ogulur I, Pat Y, Aydin T, Yazici D, Rückert B, Peng Y, Kim J, Radzikowska U, Westermann P, Sokolowska M, Dhir R, Akdis M, Nadeau K, Akdis CA. J Allergy Clin Immunol. 2023 Feb;151(2):469-484.

According to the epithelial barrier theory, exposure to many toxic substances in humans and animals damages the epithelium, the thin layer of cells that covers the surface of our skin, lungs and intestine. A number of diseases, including food allergy, esophagitis, gastritis, diabetes, obesity, fatty liver, autoimmune hepatitis, liver cirrhosis, rheumatoid arthritis, multiple sclerosis, autism spectrum diseases, chronic depression, Alzheimer’s and Parkinson’s diseases have been linked to defective epithelial barriers in the digestive system and dysbiosis in the microbiota particularly in the gut. In general, it has been proposed that damaged epithelial barriers contribute to the pathogenesis of two billion patients.

Professional dishwashers have become the state of the art for dishwashing in public places including restaurants, schools, military and hotels throughout the whole world. A comprehensive study by Ogulur et al. demonstrated the toxicity of professional dishwasher rinse aids. The substance responsible for this damage was pinpointed as alcohol ethoxylates present in the rinse aid. Using human models, such as induced pluripotent stem cell-derived human intestinal organoids, organ-on-a-chips and liquid-liquid interface cultures, the health hazard of exposure to professional and household dishwasher detergent and rinse aid, and its individual components on cytotoxicity, barrier function, transcriptome and protein expression was investigated.

A worldwide commonly used ingredient, alcohol ethoxylates in the professional dishwasher rinse aid was killing gut epithelial cells in 1:20’000 dilutions. The underlying mechanisms of the epithelial barrier disruption in response to professional dishwasher rinse aid are cell death in high doses and epithelial barrier opening in low doses together with activation of multiple genes and proteins that induce inflammatory responses in the exposed cells. One of the most exciting findings of the present study is after a finalized dishwashing, the researchers were able to extract a significant amount of remaining toxic substances from the washed and ready to use dishware. These findings, which mark the beginning of intestinal epithelial disruption and inflammatory responses in many chronic diseases, may have an important impact on public health. It is now so important to make the public aware of this toxicity and take immediate measures as apparently this substance is commonly used in professional dishwashers. Read more.

Electrical impedance spectroscopy, an efficient method for skin barrier detection

Rinaldi AO, Korsfeldt A, Ward S, Burla D, Dreher A, Gautschi M, Stolpe B, Tan G, Bersuch E, Melin D, Askary Lord N, Grant S, Svedenhag P, Tsekova K, Schmid-Grendelmeier P, Möhrenschlager M, Renner ED, Akdis CA. Allergy. 2021 Oct;76(10):3066-3079.

Rinaldi AO, Morita H, Wawrzyniak P, Dreher A, Grant S, Svedenhag P, Akdis CA. Allergy. 2019 Oct;74(10):1934-1944. doi: 10.1111/all.13824.

The quantitative assessment of the skin barrier’s integrity in vivo holds significant potential across various clinical applications, encompassing diagnosis, ongoing monitoring, preventative measures, and the evaluation of therapeutic interventions. Both invasive and non-invasive techniques have been developed to investigate the functionality of the skin barrier. Among the non-invasive approaches, examples include the measurement of skin hydration, colorimetry, skin surface pH, and sebometry. However, these methods offer limited insights into diverse skin attributes and states, lacking a direct measurement of the skin barrier’s performance. A widely employed technique, known as trans-epidermal water loss (TEWL), is susceptible to the influence of various environmental factors. Its accuracy is dependent upon factors such as humidity, temperature, and the level of skin hydration.

Electrical impedance spectroscopy (EIS) emerges as a promising non-invasive solution for assessing skin barrier function in vivo. By gauging the tissue’s electrical impedance across various frequencies, EIS furnishes insights into the structural integrity of the skin, thereby revealing its underlying pathophysiological condition. The distinctions in cell size, shape, orientation, compactness, intercellular fluid caused by inflammation and membrane structures between normal and pathological tissues are encapsulated within the impedance measurements. Noteworthy EIS applications encompass the identification of malignant tissues in melanoma, breast, prostate, and skin, as well as the characterization of tissue alterations subsequent to ischemia.

A pivotal breakthrough by Rinaldi et al. spotlighted EIS as a means to probe epithelial barrier function in vivo. Our initial studies conducted on mice showcased EIS’s utility and reliability in pinpointing skin barrier impairments. Upon experimentally inducing skin barrier damage through procedures like tape stripping and the topical application of proteases (papain, trypsin, cholera toxin), an evident drop in skin electrical impedance was observed. This trend exhibited an inverse correlation with TEWL.

Moving to a clinical milieu, EIS exhibited its prowess in quantifying the skin barrier’s status among patients with atopic dermatitis (AD). The tool demonstrated commendable specificity and sensitivity in distinguishing between healthy controls, non-lesional skin of AD patients, and the lesional skin of those afflicted with AD. EIS further facilitated the assessment of skin lesion recovery post-treatment, with strong correlations established between EIS measurements, disease scoring systems like SCORAD, pruritus scores, and even the tandem repeat count of FLG genes.

The spectrum of potential clinical applications for EIS is broad. A notable proposition is its utilization in identifying infants at a heightened risk of developing AD through a swift, non-invasive assessment. This, in turn, could enable the recommendation of preemptive measures to fortify the skin barrier and mitigate exposure to environmental factors. In the context of AD, where a pressing need exists for novel monitoring tools to forecast exacerbations and gauge lesion response to therapy, EIS emerges as a valuable candidate. By bridging the gap between objective disease assessment and lesion monitoring, EIS holds significant promise in advancing dermatological care.