Epithelial Barrier Theory

The Story of 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 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 and causes microbial dysbiosis 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 4,5.

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 6,7

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 3,11,17-24. Early reports from the 1960s indicated an increased prevalence of asthma in children and higher hospitalization rates 25-28. After the 2000s, a new wave of epidemics emerged, including food allergy and anaphylaxis, eosinophilic esophagitis, and drug-induced anaphylaxis 29-31. 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 18,32-36.

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 2,37-47. three reasons have been identified for this disruption:

a. Genetical 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 48.  Mutations in filaggrins, polymorphisms in tight junction (TJ) claudin and occludin genes have been reported to play a role on epithelial barrier integrity.37,49

b. 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 3,7.

c. 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. 2,37,44.

3. Microbial dysbiosis:

A healthy microbiota on the surface of the mucosal barrier regulates numerous aspects of barrier homeostasis 50. 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 10. 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 10.

4. 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 51,52. This inability triggers a chronic inflammatory response to harmless microorganisms, decreasing biodiversity and contributing to the development of allergic and autoimmune diseases 10 (Figure 2). 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 53-57.

5. 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  58,59, 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 60,61.

6. 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 62-64. In polyallergic patients, activated and circulating T cells express chemokine receptors and have the capacity to migrate towards various allergic tissues 65. 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 66,67.

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 6-8,68. 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 69. 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 6-8,58,68-82.

Figure 1

The increase in the prevalence and exacerbations of many allergic, autoimmune, metabolic and neurodegenerative diseases was associated with damage to the epithelial layer induced by exposure to infections agents, allergens, particulate matter, diesel exhaust, cigarette smoke, laudry and dishwasher detergents and rinse aids, household cleaners, toothpastes, microplastics, nanoparticles, ozone, processed food additives and emulsifiers and other unidentified chemical substances. Some of these substances may have synergistic effects in the damage of epithelial barriers. Leaky barriers allow the passage of allergens, pollutants, toxins and microbes.

Figure 2:

Pathogenetic events as mechanisms of the epithelial barrier theory: A cascade of events play a role in the pathogenesis of diseases associated with the epithelial barrier theory and development of many chronic noncommunicable diseases. Direct toxicity to epithelium and microbes: Genetic defects in barrier-related molecules or exposure to epithelial barrier-damaging agents cause a disruption of the skin and mucosal tight junction barriers and may also show a direct toxicity to health-promoting commensal microbes. Epithelitis and microbial dysbiosis: It is followed by translocation of microbiota to inter and subepithelial areas and colonization of opportunistic pathogens, such as Staphylococcus aureus (S. aureus), Moraxella catarrhalis, Haemophilus influenzae and pneumococcus bacteria. It is associated with microbial dysbiosis and decreased biodiversity of commensal bacteria. Epithelitis starts with the release of multiple alarmins. Expulsion response: An immune response develops towards commensals and opportunistic pathogens in the gut and respiratory system, and systemic inflammation takes place. Decreased biodiversity takes place because of loss of commensals and colonizing opportunistic pathogens. Migration of inflammatory cells to distant organs: Chronic inflammation in the subepithelial area prevails as one of the main reasons for the development of chronic diseases in the affected tissues. Distant organs are affected because of circulating microinflammation and migration of activated immune system cells to distant organs. Epigenetic regulation and chronicity: An impaired ability to restore the epithelial barrier function due to inflammation and epigenetic changes instigates a vicious cycle of leaky barriers, microbial dysbiosis and chronic inflammation.

References

  1. Akdis CA. Allergy and hypersensitivity: mechanisms of allergic disease. Curr Opin Immunol 2006;18:718-26.
  2. Soyka MB, Wawrzyniak P, Eiwegger T, et al. Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-gamma and IL-4. J Allergy Clin Immunol 2012:1087-96.
  3. Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat Rev Immunol 2021;21:739-51.
  4. Sugita K, Soyka MB, Wawrzyniak P, et al. Outside-in hypothesis revisited: The role of microbial, epithelial, and immune interactions. Ann Allergy Asthma Immunol 2020.
  5. Mitamura Y, Ogulur I, Pat Y, et al. Dysregulation of the epithelial barrier by environmental and other exogenous factors. Contact Dermatitis 2021;85:615-26.
  6. Celebi Sozener Z, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol 2020;145:1517-28.
  7. Celebi Sozener Z, Ozdel Ozturk B, Cerci P, et al. Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease. Allergy 2022;77:1418-49.
  8. Celebi Sozener Z, Ozbey Yucel U, Altiner S, et al. The External Exposome and Allergies: From the Perspective of the Epithelial Barrier Hypothesis. Front Allergy 2022;3:887672.
  9. Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 2001;1:69-75.
  10. Haahtela T, Holgate S, Pawankar R, et al. The biodiversity hypothesis and allergic disease: world allergy organization position statement. World Allergy Organ J 2013;6:3.
  11. Platts-Mills TA. The allergy epidemics: 1870-2010. J Allergy Clin Immunol 2015;136:3-13.
  12. Fahlbusch B, Heinrich J, Gross I, Jager L, Richter K, Wichmann HE. Allergens in house-dust samples in Germany: results of an East-West German comparison. Allergy 1999;54:1215-22.
  13. Akdis CA, Agache,I. (Editors). Global Atlas of Allergy: European Academy of Allergy and Clinical Immunology (EAACI); 2013.
  14. Pawankar R. Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ J 2014;7:12.
  15. Pawankar R, Holgate ST, Canonica GW, Lockey RF, Editors. WAO White Book on Allergy. World Allergy Organization 2011.
  16. Ring J, Akdis C, Lauener R, et al. Global Allergy Forum and Second Davos Declaration 2013 Allergy: Barriers to cure–challenges and actions to be taken. Allergy 2014;69:978-82.
  17. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006;355:2226-35.
  18. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911-20.
  19. Backman H, Raisanen P, Hedman L, et al. Increased prevalence of allergic asthma from 1996 to 2006 and further to 2016-results from three population surveys. Clin Exp Allergy 2017;47:1426-35.
  20. Genuneit J, Seibold AM, Apfelbacher CJ, et al. Overview of systematic reviews in allergy epidemiology. Allergy 2017;72:849-56.
  21. Biedermann T, Winther L, Till SJ, Panzner P, Knulst A, Valovirta E. Birch pollen allergy in Europe. Allergy 2019.
  22. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368:733-43.
  23. Asher MI, Stewart AW, Mallol J, et al. Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One. Respir Res 2010;11:8.
  24. Bjorksten B, Clayton T, Ellwood P, Stewart A, Strachan D, Group IPIS. Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood. Pediatr Allergy Immunol 2008;19:110-24.
  25. Haahtela T, Lindholm H, Bjorksten F, Koskenvuo K, Laitinen LA. Prevalence of asthma in Finnish young men. BMJ 1990;301:266-8.
  26. Anderson HR, Gupta R, Strachan DP, Limb ES. 50 years of asthma: UK trends from 1955 to 2004. Thorax 2007;62:85-90.
  27. Mitchell EA. International trends in hospital admission rates for asthma. Arch Dis Child 1985;60:376-8.
  28. Aberg N. Asthma and allergic rhinitis in Swedish conscripts. Clin Exp Allergy 1989;19:59-63.
  29. Willits EK, Park MA, Hartz MF, Schleck CD, Weaver AL, Joshi AY. Food Allergy: A Comprehensive Population-Based Cohort Study. Mayo Clin Proc 2018;93:1423-30.
  30. Hommeida S, Grothe RM, Hafed Y, et al. Assessing the incidence trend and characteristics of eosinophilic esophagitis in children in Olmsted County, Minnesota. Dis Esophagus 2018;31.
  31. Giavina-Bianchi P, Aun MV, Kalil J. Drug-induced anaphylaxis: is it an epidemic? Curr Opin Allergy Clin Immunol 2018;18:59-65.
  32. Grode L, Bech BH, Jensen TM, et al. Prevalence, incidence, and autoimmune comorbidities of celiac disease: a nation-wide, population-based study in Denmark from 1977 to 2016. Eur J Gastroenterol Hepatol 2018;30:83-91.
  33. Chen X, Wu Z, Wang X, et al. [Prevalence and change of type 2 diabetes mellitus among rural adults in Deqing County, Zhejiang Province in China during 2006-2014]. Wei Sheng Yan Jiu 2017;46:868-87.
  34. Evans C, Beland SG, Kulaga S, et al. Incidence and prevalence of multiple sclerosis in the Americas: a systematic review. Neuroepidemiology 2013;40:195-210.
  35. Pugliatti M, Sotgiu S, Solinas G, Castiglia P, Rosati G. Multiple sclerosis prevalence among Sardinians: further evidence against the latitude gradient theory. Neurol Sci 2001;22:163-5.
  36. Pereira M, Carreira H, Lunet N, Azevedo A. Trends in prevalence of diabetes mellitus and mean fasting glucose in Portugal (1987-2009): a systematic review. Public Health 2014;128:214-21.
  37. De Benedetto A, Rafaels NM, McGirt LY, et al. Tight junction defects in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology 2010:773-86.
  38. Weidinger S, O’Sullivan M, Illig T, et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 2008;121:1203-9 e1.
  39. Schmitz H, Barmeyer C, Fromm M, et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 1999;116:301-9.
  40. Toedter G, Li K, Sague S, et al. Genes associated with intestinal permeability in ulcerative colitis: changes in expression following infliximab therapy. Inflamm Bowel Dis 2012;18:1399-410.
  41. Wawrzyniak P, Wawrzyniak M, Wanke K, et al. Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients. J Allergy Clin Immunol 2017;139:93-103.
  42. Xiao C, Puddicombe SM, Field S, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011;128:549-56 e1-12.
  43. Masterson JC, Biette KA, Hammer JA, et al. Epithelial HIF-1alpha/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis. J Clin Invest 2019;130:3224-35.
  44. Sugita K, Steer CA, Martinez-Gonzalez I, et al. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients. J Allergy Clin Immunol 2018;141:300-10 e11.
  45. Schoultz I, Keita AV. Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function. Cells 2019;8.
  46. Loxham M, Davies DE. Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients. J Allergy Clin Immunol 2017;139:1736-51.
  47. Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol 2014;134:509-20.
  48. Eyerich K, Brown SJ, Perez White BE, et al. Human and computational models of atopic dermatitis: A review and perspectives by an expert panel of the International Eczema Council. J Allergy Clin Immunol 2019;143:36-45.
  49. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011;365:1315-27.
  50. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol 2017;17:219-32.
  51. Altunbulakli C, Reiger M, Neumann AU, et al. Relations between epidermal barrier dysregulation and Staphylococcus species-dominated microbiome dysbiosis in patients with atopic dermatitis. J Allergy Clin Immunol 2018;142:1643-7 e12.
  52. Altunbulakli C, Costa R, Lan F, et al. Staphylococcus aureus enhances the tight junction barrier integrity in healthy nasal tissue, but not in nasal polyps. J Allergy Clin Immunol 2018;142:665-8 e8.
  53. Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 2001;107:607-14.
  54. Sintobin I, Siroux V, Holtappels G, et al. Sensitisation to staphylococcal enterotoxins and asthma severity: a longitudinal study in the EGEA cohort. Eur Respir J 2019.
  55. Sorensen M, Klingenberg C, Wickman M, et al. Staphylococcus aureus enterotoxin sensitization is associated with allergic poly-sensitization and allergic multimorbidity in adolescents. Allergy 2017;72:1548-55.
  56. Friedman SJ, Schroeter AL, Homburger HA. IgE antibodies to Staphylococcus aureus. Prevalence in patients with atopic dermatitis. Arch Dermatol 1985;121:869-72.
  57. Kim YC, Won HK, Lee JW, et al. Staphylococcus aureus Nasal Colonization and Asthma in Adults: Systematic Review and Meta-Analysis. J Allergy Clin Immunol Pract 2019;7:606-15 e9.
  58. Wang M, Tan G, Eljaszewicz A, et al. Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithelial cells. J Allergy Clin Immunol 2019;143:1892-903.
  59. Ogulur I, Pat Y, Aydin T, et al. Gut epithelial barrier damage caused by dishwasher detergents and rinse aids. J Allergy Clin Immunol 2023;151:469-84.
  60. Galli SJ, Starkl P, Marichal T, Tsai M. Mast Cells and IgE can Enhance Survival During Innate and Acquired Host Responses to Venoms. Trans Am Clin Climatol Assoc 2017;128:193-221.
  61. Mukai K, Tsai M, Starkl P, Marichal T, Galli SJ. IgE and mast cells in host defense against parasites and venoms. Semin Immunopathol 2016;38:581-603.
  62. Akdis M, Akdis CA, Weigl L, Disch R, Blaser K. Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation by CLA- memory T cells. J Immunol 1997;159:4611-9.
  63. Jelcic I, Al Nimer F, Wang J, et al. Memory B Cells Activate Brain-Homing, Autoreactive CD4(+) T Cells in Multiple Sclerosis. Cell 2018;175:85-100 e23.
  64. Abernathy-Carver KJ, Sampson HA, Picker LJ, Leung DYM. Milk-induced eczema is associated with the expansion of T cells expressing cutaneous lymphocyte antigen. J Clin Invest 1995;95:913-8.
  65. David BA, Kubes P. Exploring the complex role of chemokines and chemoattractants in vivo on leukocyte dynamics. Immunol Rev 2019;289:9-30.
  66. Czarnowicki T, Krueger JG, Guttman-Yassky E. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march. J Allergy Clin Immunol 2017;139:1723-34.
  67. Han H, Roan F, Ziegler SF. The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol Rev 2017;278:116-30.
  68. Pat Y, Ogulur I, Yazici D, et al. Effect of altered human exposome on the skin and mucosal epithelial barrier integrity. Tissue Barriers 2022:2133877.
  69. Wang Z, Walker GW, Muir DCG, Nagatani-Yoshida K. Toward a Global Understanding of Chemical Pollution: A First Comprehensive Analysis of National and Regional Chemical Inventories. Environ Sci Technol 2020;54:2575-84.
  70. Cullinan P, Harris JM, Newman Taylor AJ, et al. An outbreak of asthma in a modern detergent factory. Lancet 2000;356:1899-900.
  71. Medina-Ramon M, Zock JP, Kogevinas M, et al. Asthma, chronic bronchitis, and exposure to irritant agents in occupational domestic cleaning: a nested case-control study. Occup Environ Med 2005;62:598-606.
  72. Flindt ML. Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. Lancet 1969;1:1177-81.
  73. Adisesh A, Murphy E, Barber CM, Ayres JG. Occupational asthma and rhinitis due to detergent enzymes in healthcare. Occup Med (Lond) 2011;61:364-9.
  74. Jin Y, Lu L, Tu W, Luo T, Fu Z. Impacts of polystyrene microplastic on the gut barrier, microbiota and metabolism of mice. Sci Total Environ 2019;649:308-17.
  75. Michaudel C, Mackowiak C, Maillet I, et al. Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33. J Allergy Clin Immunol 2018;142:942-58.
  76. Aghapour M, Raee P, Moghaddam SJ, Hiemstra PS, Heijink IH. Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure. Am J Respir Cell Mol Biol 2018;58:157-69.
  77. Caraballo JC, Yshii C, Westphal W, Moninger T, Comellas AP. Ambient particulate matter affects occludin distribution and increases alveolar transepithelial electrical conductance. Respirology 2011;16:340-9.
  78. Vita AA, Royse EA, Pullen NA. Nanoparticles and danger signals: Oral delivery vehicles as potential disruptors of intestinal barrier homeostasis. J Leukoc Biol 2019;106:95-103.
  79. Aungst BJ. Intestinal permeation enhancers. J Pharm Sci 2000;89:429-42.
  80. Gullikson GW, Cline WS, Lorenzsonn V, Benz L, Olsen WA, Bass P. Effects of anionic surfactants on hamster small intestinal membrane structure and function: relationship to surface activity. Gastroenterology 1977;73:501-11.
  81. Keita AV, Alkaissi LY, Holm EB, et al. Enhanced E. coli LF82 translocation through follicle-associated epithelium in Crohn’s disease is dependent on long polar fimbriae and CEACAM6-expression, and increases paracellular permeability. J Crohns Colitis 2019.
  82. Roberts CL, Keita AV, Duncan SH, et al. Translocation of Crohn’s disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut 2010;59:1331-9.

References

  1. Akdis CA. Allergy and hypersensitivity: mechanisms of allergic disease. Curr Opin Immunol 2006;18:718-26.
  2. Soyka MB, Wawrzyniak P, Eiwegger T, et al. Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-gamma and IL-4. J Allergy Clin Immunol 2012:1087-96.
  3. Akdis CA. Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions? Nat Rev Immunol 2021;21:739-51.
  4. Sugita K, Soyka MB, Wawrzyniak P, et al. Outside-in hypothesis revisited: The role of microbial, epithelial, and immune interactions. Ann Allergy Asthma Immunol 2020.
  5. Mitamura Y, Ogulur I, Pat Y, et al. Dysregulation of the epithelial barrier by environmental and other exogenous factors. Contact Dermatitis 2021;85:615-26.
  6. Celebi Sozener Z, Cevhertas L, Nadeau K, Akdis M, Akdis CA. Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol 2020;145:1517-28.
  7. Celebi Sozener Z, Ozdel Ozturk B, Cerci P, et al. Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease. Allergy 2022;77:1418-49.
  8. Celebi Sozener Z, Ozbey Yucel U, Altiner S, et al. The External Exposome and Allergies: From the Perspective of the Epithelial Barrier Hypothesis. Front Allergy 2022;3:887672.
  9. Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 2001;1:69-75.
  10. Haahtela T, Holgate S, Pawankar R, et al. The biodiversity hypothesis and allergic disease: world allergy organization position statement. World Allergy Organ J 2013;6:3.
  11. Platts-Mills TA. The allergy epidemics: 1870-2010. J Allergy Clin Immunol 2015;136:3-13.
  12. Fahlbusch B, Heinrich J, Gross I, Jager L, Richter K, Wichmann HE. Allergens in house-dust samples in Germany: results of an East-West German comparison. Allergy 1999;54:1215-22.
  13. Akdis CA, Agache,I. (Editors). Global Atlas of Allergy: European Academy of Allergy and Clinical Immunology (EAACI); 2013.
  14. Pawankar R. Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ J 2014;7:12.
  15. Pawankar R, Holgate ST, Canonica GW, Lockey RF, Editors. WAO White Book on Allergy. World Allergy Organization 2011.
  16. Ring J, Akdis C, Lauener R, et al. Global Allergy Forum and Second Davos Declaration 2013 Allergy: Barriers to cure–challenges and actions to be taken. Allergy 2014;69:978-82.
  17. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006;355:2226-35.
  18. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911-20.
  19. Backman H, Raisanen P, Hedman L, et al. Increased prevalence of allergic asthma from 1996 to 2006 and further to 2016-results from three population surveys. Clin Exp Allergy 2017;47:1426-35.
  20. Genuneit J, Seibold AM, Apfelbacher CJ, et al. Overview of systematic reviews in allergy epidemiology. Allergy 2017;72:849-56.
  21. Biedermann T, Winther L, Till SJ, Panzner P, Knulst A, Valovirta E. Birch pollen allergy in Europe. Allergy 2019.
  22. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368:733-43.
  23. Asher MI, Stewart AW, Mallol J, et al. Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One. Respir Res 2010;11:8.
  24. Bjorksten B, Clayton T, Ellwood P, Stewart A, Strachan D, Group IPIS. Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood. Pediatr Allergy Immunol 2008;19:110-24.
  25. Haahtela T, Lindholm H, Bjorksten F, Koskenvuo K, Laitinen LA. Prevalence of asthma in Finnish young men. BMJ 1990;301:266-8.
  26. Anderson HR, Gupta R, Strachan DP, Limb ES. 50 years of asthma: UK trends from 1955 to 2004. Thorax 2007;62:85-90.
  27. Mitchell EA. International trends in hospital admission rates for asthma. Arch Dis Child 1985;60:376-8.
  28. Aberg N. Asthma and allergic rhinitis in Swedish conscripts. Clin Exp Allergy 1989;19:59-63.
  29. Willits EK, Park MA, Hartz MF, Schleck CD, Weaver AL, Joshi AY. Food Allergy: A Comprehensive Population-Based Cohort Study. Mayo Clin Proc 2018;93:1423-30.
  30. Hommeida S, Grothe RM, Hafed Y, et al. Assessing the incidence trend and characteristics of eosinophilic esophagitis in children in Olmsted County, Minnesota. Dis Esophagus 2018;31.
  31. Giavina-Bianchi P, Aun MV, Kalil J. Drug-induced anaphylaxis: is it an epidemic? Curr Opin Allergy Clin Immunol 2018;18:59-65.
  32. Grode L, Bech BH, Jensen TM, et al. Prevalence, incidence, and autoimmune comorbidities of celiac disease: a nation-wide, population-based study in Denmark from 1977 to 2016. Eur J Gastroenterol Hepatol 2018;30:83-91.
  33. Chen X, Wu Z, Wang X, et al. [Prevalence and change of type 2 diabetes mellitus among rural adults in Deqing County, Zhejiang Province in China during 2006-2014]. Wei Sheng Yan Jiu 2017;46:868-87.
  34. Evans C, Beland SG, Kulaga S, et al. Incidence and prevalence of multiple sclerosis in the Americas: a systematic review. Neuroepidemiology 2013;40:195-210.
  35. Pugliatti M, Sotgiu S, Solinas G, Castiglia P, Rosati G. Multiple sclerosis prevalence among Sardinians: further evidence against the latitude gradient theory. Neurol Sci 2001;22:163-5.
  36. Pereira M, Carreira H, Lunet N, Azevedo A. Trends in prevalence of diabetes mellitus and mean fasting glucose in Portugal (1987-2009): a systematic review. Public Health 2014;128:214-21.
  37. De Benedetto A, Rafaels NM, McGirt LY, et al. Tight junction defects in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology 2010:773-86.
  38. Weidinger S, O’Sullivan M, Illig T, et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 2008;121:1203-9 e1.
  39. Schmitz H, Barmeyer C, Fromm M, et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 1999;116:301-9.
  40. Toedter G, Li K, Sague S, et al. Genes associated with intestinal permeability in ulcerative colitis: changes in expression following infliximab therapy. Inflamm Bowel Dis 2012;18:1399-410.
  41. Wawrzyniak P, Wawrzyniak M, Wanke K, et al. Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients. J Allergy Clin Immunol 2017;139:93-103.
  42. Xiao C, Puddicombe SM, Field S, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011;128:549-56 e1-12.
  43. Masterson JC, Biette KA, Hammer JA, et al. Epithelial HIF-1alpha/claudin-1 axis regulates barrier dysfunction in eosinophilic esophagitis. J Clin Invest 2019;130:3224-35.
  44. Sugita K, Steer CA, Martinez-Gonzalez I, et al. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients. J Allergy Clin Immunol 2018;141:300-10 e11.
  45. Schoultz I, Keita AV. Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function. Cells 2019;8.
  46. Loxham M, Davies DE. Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients. J Allergy Clin Immunol 2017;139:1736-51.
  47. Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol 2014;134:509-20.
  48. Eyerich K, Brown SJ, Perez White BE, et al. Human and computational models of atopic dermatitis: A review and perspectives by an expert panel of the International Eczema Council. J Allergy Clin Immunol 2019;143:36-45.
  49. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011;365:1315-27.
  50. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol 2017;17:219-32.
  51. Altunbulakli C, Reiger M, Neumann AU, et al. Relations between epidermal barrier dysregulation and Staphylococcus species-dominated microbiome dysbiosis in patients with atopic dermatitis. J Allergy Clin Immunol 2018;142:1643-7 e12.
  52. Altunbulakli C, Costa R, Lan F, et al. Staphylococcus aureus enhances the tight junction barrier integrity in healthy nasal tissue, but not in nasal polyps. J Allergy Clin Immunol 2018;142:665-8 e8.
  53. Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P. Total and specific IgE in nasal polyps is related to local eosinophilic inflammation. J Allergy Clin Immunol 2001;107:607-14.
  54. Sintobin I, Siroux V, Holtappels G, et al. Sensitisation to staphylococcal enterotoxins and asthma severity: a longitudinal study in the EGEA cohort. Eur Respir J 2019.
  55. Sorensen M, Klingenberg C, Wickman M, et al. Staphylococcus aureus enterotoxin sensitization is associated with allergic poly-sensitization and allergic multimorbidity in adolescents. Allergy 2017;72:1548-55.
  56. Friedman SJ, Schroeter AL, Homburger HA. IgE antibodies to Staphylococcus aureus. Prevalence in patients with atopic dermatitis. Arch Dermatol 1985;121:869-72.
  57. Kim YC, Won HK, Lee JW, et al. Staphylococcus aureus Nasal Colonization and Asthma in Adults: Systematic Review and Meta-Analysis. J Allergy Clin Immunol Pract 2019;7:606-15 e9.
  58. Wang M, Tan G, Eljaszewicz A, et al. Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithelial cells. J Allergy Clin Immunol 2019;143:1892-903.
  59. Ogulur I, Pat Y, Aydin T, et al. Gut epithelial barrier damage caused by dishwasher detergents and rinse aids. J Allergy Clin Immunol 2023;151:469-84.
  60. Galli SJ, Starkl P, Marichal T, Tsai M. Mast Cells and IgE can Enhance Survival During Innate and Acquired Host Responses to Venoms. Trans Am Clin Climatol Assoc 2017;128:193-221.
  61. Mukai K, Tsai M, Starkl P, Marichal T, Galli SJ. IgE and mast cells in host defense against parasites and venoms. Semin Immunopathol 2016;38:581-603.
  62. Akdis M, Akdis CA, Weigl L, Disch R, Blaser K. Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation by CLA- memory T cells. J Immunol 1997;159:4611-9.
  63. Jelcic I, Al Nimer F, Wang J, et al. Memory B Cells Activate Brain-Homing, Autoreactive CD4(+) T Cells in Multiple Sclerosis. Cell 2018;175:85-100 e23.
  64. Abernathy-Carver KJ, Sampson HA, Picker LJ, Leung DYM. Milk-induced eczema is associated with the expansion of T cells expressing cutaneous lymphocyte antigen. J Clin Invest 1995;95:913-8.
  65. David BA, Kubes P. Exploring the complex role of chemokines and chemoattractants in vivo on leukocyte dynamics. Immunol Rev 2019;289:9-30.
  66. Czarnowicki T, Krueger JG, Guttman-Yassky E. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march. J Allergy Clin Immunol 2017;139:1723-34.
  67. Han H, Roan F, Ziegler SF. The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol Rev 2017;278:116-30.
  68. Pat Y, Ogulur I, Yazici D, et al. Effect of altered human exposome on the skin and mucosal epithelial barrier integrity. Tissue Barriers 2022:2133877.
  69. Wang Z, Walker GW, Muir DCG, Nagatani-Yoshida K. Toward a Global Understanding of Chemical Pollution: A First Comprehensive Analysis of National and Regional Chemical Inventories. Environ Sci Technol 2020;54:2575-84.
  70. Cullinan P, Harris JM, Newman Taylor AJ, et al. An outbreak of asthma in a modern detergent factory. Lancet 2000;356:1899-900.
  71. Medina-Ramon M, Zock JP, Kogevinas M, et al. Asthma, chronic bronchitis, and exposure to irritant agents in occupational domestic cleaning: a nested case-control study. Occup Environ Med 2005;62:598-606.
  72. Flindt ML. Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. Lancet 1969;1:1177-81.
  73. Adisesh A, Murphy E, Barber CM, Ayres JG. Occupational asthma and rhinitis due to detergent enzymes in healthcare. Occup Med (Lond) 2011;61:364-9.
  74. Jin Y, Lu L, Tu W, Luo T, Fu Z. Impacts of polystyrene microplastic on the gut barrier, microbiota and metabolism of mice. Sci Total Environ 2019;649:308-17.
  75. Michaudel C, Mackowiak C, Maillet I, et al. Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33. J Allergy Clin Immunol 2018;142:942-58.
  76. Aghapour M, Raee P, Moghaddam SJ, Hiemstra PS, Heijink IH. Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure. Am J Respir Cell Mol Biol 2018;58:157-69.
  77. Caraballo JC, Yshii C, Westphal W, Moninger T, Comellas AP. Ambient particulate matter affects occludin distribution and increases alveolar transepithelial electrical conductance. Respirology 2011;16:340-9.
  78. Vita AA, Royse EA, Pullen NA. Nanoparticles and danger signals: Oral delivery vehicles as potential disruptors of intestinal barrier homeostasis. J Leukoc Biol 2019;106:95-103.
  79. Aungst BJ. Intestinal permeation enhancers. J Pharm Sci 2000;89:429-42.
  80. Gullikson GW, Cline WS, Lorenzsonn V, Benz L, Olsen WA, Bass P. Effects of anionic surfactants on hamster small intestinal membrane structure and function: relationship to surface activity. Gastroenterology 1977;73:501-11.
  81. Keita AV, Alkaissi LY, Holm EB, et al. Enhanced E. coli LF82 translocation through follicle-associated epithelium in Crohn’s disease is dependent on long polar fimbriae and CEACAM6-expression, and increases paracellular permeability. J Crohns Colitis 2019.
  82. Roberts CL, Keita AV, Duncan SH, et al. Translocation of Crohn’s disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers. Gut 2010;59:1331-9.