Extreme temperatures and the epithelial barrier theory.

Extreme temperatures are now recognized as significant global health threats, driving morbidity and mortality across diverse diseases by compromising epithelial barrier integrity and causing periepithelial inflammation. 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-now intensified by anthropogenic warming, altered weather patterns and regional climatic variability-may 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.