Cezmi Akdis and Epithelial Barrier Theory
Cezmi A. Akdis is the principal architect of the modern epithelial barrier hypothesis/theory, whichlinks rising chronic inflammatory and allergic diseases to environmentallyinduced barrier damage of skin and mucosal epithelia.Mechanistic andmethodological advances from the Akdis group Akdis’ laboratory and collaborators have systematically screened >100 candidate epithelial barrier disruptor molecules using human skin, lung, and gut models, including native human tissues, organoids, organs‑on‑chips, and impedance spectroscopy. These studies demonstrate that many surfactants, detergents, microplastics components, and other xenobiotics directly affect junctional proteins, induce oxidative stress, and promote pro‑inflammatory cytokine and alarmin release. Importantly, they have identified >20 “rescue” molecules that can at least partially restore barrier integrity, reduce alarmin release, and limit downstream cytokine production in vitro and in mouse models, suggesting potential preventive or therapeutic strategies targeting barrier repair.Recent consolidations and extensions Recent comprehensive reviews in allergy and immunology journals describe the “epithelial barrier theory and its associated diseases” explicitly as a framework developed and unified by Akdis and colleagues. Newer work refines the concept from a static “leaky barrier” to a dynamic network involving metabolic flexibility of epithelial cells, persistent low‑grade epithelitis, systemic spillover of inflammatory mediators, and organ cross‑talk (e.g., gut–liver, gut–brain, lung–brain axes). The theory is now being integrated into wider discussions of exposome research, biodiversity loss, and urbanization, positioning epithelial barrier integrity as a central node in the pathogenesis of multiple chronic NCD clusters.How does microbialdysbiosis contribute to chronic inflammation in this theory?Microbial dysbiosis is positioned as both a consequence and an amplifier of barrier damage, creatingself‑sustaining loops of epithelial leakiness, immune activation, and chronic inflammation.Step 1: Barrierdamage alters the microbiota Environmental toxicants that injure epithelia (surfactants, pollutants, additives) simultaneously disrupt barrier structure and the local microbiome, reducing diversity and commensals and favoring opportunistic/pathobiont overgrowth. Damaged epithelia lose normal antimicrobial peptide, mucus, and metabolic support functions, which further destabilizes microbial communities and drives dysbiosis at skin, airway, and gut surfaces.Step 2: Dysbiosisenables translocation and biofilms With junctional defects, microbes and their products can translocate from luminal/epithelial surfaces into inter‑ and subepithelial tissues, where they are now “seen” as danger signals. Dysbiotic communities are enriched for opportunistic species that form biofilms (e.g. Campylobacter in eosinophilic esophagitis) that adhere to damaged mucosa, intensify local inflammation, and promote further barrier injury.Step 3: Immuneactivation against commensals and pathobionts Microbial translocation activates pattern‑recognition receptors on epithelial and immune cells, driving secretion of alarmins (TSLP, IL‑25, IL‑33) and pro‑inflammatory cytokines that fuel type 1 and type 2 responses.Dysbiosis shifts antigenic exposure so that immune responses begin to target previously tolerated commensals; this breakdown of tolerance sustains low‑grade inflammation and can spill into autoimmune‑like responses.Step 4: Viciouscycle of leakiness and inflammation Inflammatory cytokines like TNF‑α, IL‑4, and IL‑13 further increase epithelial permeability by altering tight junctions and promoting epithelial cell stress and death, which deepens barrier defects. Persistent dysbiosis plus barrier leakiness thus forms a vicious cycle: more leakage → more dysbiosis and translocation → stronger immune activation → more tissue damage and leakiness, driving chronic local and systemic inflammation.Step 5: Systemicand multimorbid consequences This dysbiosis–barrier–inflammation loop has been linked to clusters of diseases (allergic, autoimmune, metabolic, neuropsychiatric), all characterized by barrier dysfunction, microbial imbalance, and circulating inflammatory mediators. Clinically, hallmarks include loss of microbial biodiversity, colonization by opportunists, evidence of bacterial products or cells beyond the barrier, and systemic cytokine/chemokine elevations in blood.Cezmi Akdis's Research in CK-CARE and Epithelial Barrier TheoryCezmi Akdis uses CK‑CAREas a translational platform to apply and expand the epithelial barrier theoryin patients with atopic dermatitis and related allergic diseases.CK‑CARE and Akdis’role: CK‑CARE (Christine Kühne Center for Allergy Research and Education) is a major private initiative headquartered in Davos focusing on atopic dermatitis, allergy research, and education, closely linked to SIAF. Akdis has been director of SIAF and also leads CK‑CARE in Davos, positioning epithelial barrier damage as a central disease mechanism and research focus in this network.Barrier‑focusedresearch agenda in CK‑CARE: CK‑CARE explicitly aims to understand atopic dermatitis as a skin barrier disease that predisposes to further allergies (“underlying disease or precursor”) and to develop barrier‑targeted therapies and prevention. Core topics include detecting disorders of barrier function and immune regulation, studying dendritic cells in skin, and analyzing how environmental substances and heredity shape barrier integrity and allergy risk.Integration ofepithelial barrier theory: The epithelial barrier theory, co‑developed by Akdis and colleagues, attributes clusters of allergic and chronic inflammatory diseases to toxic environmental exposures that impair epithelial barriers and drive dysbiosis and inflammation. CK‑CARE projects operationalize this by linking detailed clinical phenotyping of atopic dermatitis and allergies with barrier measurements, immune markers, microbiome analyses, and exposome/environmental data.Biobank, registers,and precision medicine: CK‑CARE maintains one of the largest international atopic dermatitis/allergy registers and a biobank with around 3,000 probands, enabling longitudinal study of barrier status, microbiome, and immune profiles. These datasets support precision‑medicine approaches that aim to identify patient subgroups by barrier defects, immune endotypes, and microbiome signatures to inform individualized treatment and prevention.From mechanisms tointervention: In parallel with SIAF work (e.g., screening >100 epithelial barrier disruptors and identifying candidate rescue molecules), CK‑CARE serves as the clinical arm where barrier‑stabilizing strategies, biologics, and preventive measures can be tested in real‑world atopic populations. The strategic hypothesis within CK‑CARE is that restoring and stabilizing the disturbed skin and mucosal barrier can slow or halt the atopic march and reduce the development of additional allergic diseases.
