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The epithelial barrier theory posits that environmentally induced barrier dysfunction, driven by modern industrial and urban exposures, leads to compromised surfaces of the exposed tissues accompanied by epithelial activation and barrier dysfunction, microbial dysbiosis, loss of commensal bacteria, opportunistic pathogen colonization, bacterial translocation, inflammation and immune dysregulation. While toxic chemical exposures have been the primary focus of barrier research, temperature extremes\u2014now intensified by anthropogenic warming, altered weather patterns and regional climatic variability\u2014may similarly disrupt epithelial structure and function. Heat and cold can alter tight-junction regulation, induce mitochondrial and endoplasmic reticulum stress, oxidative stress, apoptosis and modify cytokine and chemokine profiles, thereby weakening barrier defenses and enhancing susceptibility to pollutants, allergens and pathogens. These effects may be amplified by co-exposures such as humidity fluctuations, UV radiation, wildfire smoke and increased pollutant loads associated with floods, droughts and other environmental catastrophes. Shifts in the exposome, including contamination of water systems and food chains, further link temperature-related barrier injury to rising rates of noncommunicable diseases (NCDs). Clinical and epidemiological evidence supports associations between heat waves and disease exacerbations, between cold exposure and infectious or allergic responses, and between altered weather patterns and growing prevalence of NCDs. This review synthesizes mechanistic, environmental and epidemiological data to highlight extreme temperatures as critical drivers of epithelial barrier dysfunction and global disease burden.<\/jats:p>","DOI":"10.1007\/s00281-026-01087-8","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:06:36Z","timestamp":1792508796000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extreme temperatures and the epithelial barrier theory"],"prefix":"10.1007","volume":"48","author":[{"given":"Ismail","family":"Ogulur","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huseyn","family":"Babayev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Zeyneloglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ceren","family":"Bicer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanni","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"D\u2019Avino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manru","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Maldonado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Hotie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sena","family":"Ardicli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yagiz","family":"Pat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00fcbeccel","family":"Akdis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari C.","family":"Nadeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezmi A.","family":"Akdis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"1087_CR1","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1038\/s41591-024-03452-2","volume":"31","author":"P Masselot","year":"2025","unstructured":"Masselot P, Mistry MN, Rao S, Huber V, Monteiro A, Samoli E, Stafoggia M, de\u2019Donato F, Garcia-Leon D, Ciscar JC, Feyen L, Schneider A, Katsouyanni K, Vicedo-Cabrera AM, Aunan K, Gasparrini A (2025) Estimating future heat-related and cold-related mortality under climate change, demographic and adaptation scenarios in 854 European cities. 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She is on the Scientific Advisory Board of Stanford University-Sean Parker Asthma Allergy Center, CA; Advisory Board member of LEO Foundation Skin Immunology Research Center, Copenhagen, and Scientific Co-chair of the World Allergy Congress (WAC) Istanbul, 2022, and Scientific Programme Committee Chair, EAACI. K.N. currently reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS); Stock options from IgGenix, Seed Health, ClostraBio, Cour, Alladapt; Consultant for Excellergy, Red tree ventures, Regeneron, and IgGenix; Co-founder of Alladapt, Latitude, and IgGenix; National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers; patents include, \u201cMixed allergen composition and methods for using the same,\u201d \u201cGranulocyte-based methods for detecting and monitoring immune system disorders,\u201d and \u201cMethods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders.\u201d C.A.A. has received research grants from the Swiss National Science Foundation, European Union (EU CURE, EU Syn-Air-G), Novartis Research Institutes (Basel, Switzerland), Stanford University (Redwood City, Calif), Seed Health (Boston, USA), AO Research Institute (Davos, Switzerland) and SciBase (Stockholm, Sweden). He is the Co-chair for the EAACI Guidelines on Environmental Science in Allergic Diseases and Asthma; Chair of the EAACI Epithelial Cell Biology Working Group. Serves on the Advisory Boards of Sanofi\/Regeneron (Bern, Switzerland, New York, USA), Stanford University Sean Parker Asthma Allergy Center (CA, USA), Novartis (Basel, Switzerland), GlaxoSmithKline (Zurich, Switzerland), Bristol-Myers Squibb (New York, USA), Seed Health (Boston, USA) and SciBase (Stockholm, Sweden). C.A.A. is the Editor-in-Chief of Allergy. All other authors have no conflicts to disclose.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"22"}}