The epithelial barrier theory proposes a comprehensive explanation for the origins of allergic and other chronic noncommunicable diseases

Abstract

The epithelial barrier theory proposes that modern environmental exposures compromise skin and mucosal surfaces, initiating local inflammation that propagates systemically. The theory integrates epidemiological trends, molecular mechanistic data, and emerging clinical data to show how everyday exposures cause the development and exacerbation of more than 70 chronic noncommunicable diseases. A canonical epithelial cell and barrier injury cascade takes place, generating oxidative stress with increased reactive oxygen species, the release of alarmins, and multiple chemokines and epithelial barrier disruption. The damage to epithelial barriers occurs together with microbial dysbiosis. The alerted immune system fuels various immune activation loops involving multiple cells and chemokines and links barrier leakiness to atopic, autoimmune, metabolic, and neuropsychiatric disease clusters. Supporting the one health concept, abundant exposure of domestic animals and pets to the same groups of toxic substances related to their diseases has recently become more evident. The prevalence of these preventable diseases showed an increase in parallel to industrialization and modernization and epidemiologic exposure to culprit substances throughout the whole world, with a substantial public health burden reaching trillions of dollars each year.

Impact statement.

Modern environmental exposures compromise epithelial barriers, triggering inflammation, microbial dysbiosis, and chronic disease clusters—atopic, autoimmune, metabolic, neuropsychiatric. These preventable conditions now affect millions and impose a public health and economic burden of trillions annually in healthcare costs and lost productivity.

Exposure to common noxious agents (1), including allergens, pollutants, and micro‐nanoplastics, can cause epithelial barrier damage (2) in our body's protective linings. This may trigger an immune response to our microbiome (3). The epithelial barrier theory explains how this process can lead to chronic noncommunicable diseases (4) affecting organs, such as the gut, lungs, brain, and joints.

Abbreviations

AD, atopic dermatitis

AIM2, absent‐in‐melanoma 2 inflammasome

AJ, adherens junction

AMPK, AMP‐activated protein kinase

APAF‐1, apoptotic protease‐activating factor‐1

ASC, apoptosis‐associated speck‐like protein with CARD

ATM/ATR, ataxia‐telangiectasia mutated/Rad3‐related kinases

ATP, adenosine triphosphate

BMP, bone morphogenetic protein

CaMK II, calcium/calmodulin‐dependent protein kinase II

CAR, coxsackie‐ and adenovirus receptor

CHOP, C/EBP homologous protein

CLE, confocal laser endomicroscopy

CXCL/CXCR, C‐X‐C chemokine ligand/receptor

DAMP, damage‐associated molecular pattern

DNA/dsDNA, deoxyribonucleic acid/double‐stranded DNA

DSS, dextran sodium sulfate (colitis model)

EIS, electrical impedance spectroscopy

EMT, epithelial‐to‐mesenchymal transition

ER, endoplasmic reticulum

ETC, electron transport chain

G‐CSF, granulocyte colony‐stimulating factor

GPx4, glutathione peroxidase 4

HDAC, histone deacetylase

HIF‐1α, hypoxia‐inducible factor‐1 alpha

HMGB1, high‐mobility‐group box 1

IBD, inflammatory bowel disease

IFN, interferon

IL, interleukin

ILC/ILC2/ILC3, innate lymphoid cell/group 2/group 3

JAM, junctional adhesion molecule

JNK, c‐Jun N‐terminal kinase

LIMK, LIM‐domain kinase

MLCK, myosin light‐chain kinase

MMP, matrix metalloproteinase

MOMP, mitochondrial outer‐membrane permeabilization

mROS, mitochondrial reactive oxygen species

NCD, noncommunicable disease

NF‐κB, nuclear factor κ‐light‐chain‐enhancer of activated B cells

NK cell, natural killer cell

NLRP3, NACHT‐LRR‐PYD‐domain protein 3 inflammasome

OXPHOS, oxidative phosphorylation

P2Y13, purinergic receptor P2Y13

PEG, polyethylene glycol

PM/PM2.5, particulate matter/≤ 2.5 μm particles

PPAR, peroxisome‐proliferator‐activated receptor

PRR, pattern‐recognition receptor

ROS, reactive oxygen species

SDS/SLS, sodium dodecyl sulfate/sodium lauryl sulfate

SIRTs, sirtuin deacetylases

SMA, smooth‐muscle actin

SMAC, second mitochondria‐derived activator of caspases

TEER, transepithelial electrical resistance

TEWL, transepithelial water loss

Th1/Th2/Th17, T‐helper‐1/‐2/‐17 cells

TJ, tight junction

TLR, Toll‐like receptor

TNF, tumor necrosis factor

TSLP, thymic stromal lymphopoietin

UC, ulcerative colitis

UPR, unfolded protein response

VOCs, volatile organic compounds

ZEB, Zinc‐finger E‐box‐binding protein

ZO‐1, zonula occludens‐1

The past six decades have witnessed a dramatic and concerning rise in the prevalence of many chronic noncommunicable diseases (NCDs), reaching pandemic proportions globally [1]. Seeking explanations for this trend, research beginning around 2000, particularly focusing on the mechanisms of type 2 inflammatory diseases like eczema, asthma, and chronic rhinosinusitis (CRS), highlighted the critical role of epithelial cell death and subsequent chronic barrier defects. These initial studies revealed that epithelial dysfunction led to peri‐epithelial inflammation driven by both innate and adaptive immunity [2, 3, 4].

Early understanding framed epithelial barrier functions primarily as ‘keeping away’ harmful agents like allergens, toxins, pollutants, and microbes by acting as a physical, chemical, and immunological barrier. Additional concepts included ‘washing away’ the inflammation by opening epithelial barriers and draining the inflammatory cells and cytokines to the lumens of mucosal surfaces and outside the skin, and ‘suppression’ of inflammation via regulatory cells and cytokines active during type 2 inflammation or high‐dose allergen exposure in healthy individuals [5, 6]. The following studies demonstrated compromised epithelial barriers in conditions like asthma, atopic dermatitis (AD), and CRS, exposure to barrier‐toxic substances, and the effects of type 2 immune responses, particularly cytokines IL‐4 and IL‐13 [7, 8, 9, 10]. Genetic predispositions have been suggested in all of these diseases, which may form the background for increased inflammation or barrier defects; however, they alone are not sufficient to explain the substantial increase after the 1960s and 2000s [11].

Building on this foundation, subsequent work identified specific lifestyle‐related and environmental substances capable of damaging epithelial barriers, including common detergents, household cleaning substances, chlorine, toothpaste, food emulsifiers, pesticides, air pollutants and micro‐nanoplastics. These agents were shown to induce epithelial damage, trigger the release of alarmins, and provoke tissue inflammation [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. Compromise of these critical barriers not only triggers local pathological processes, but can also lead to systemic consequences as damaging agents, microbial components, or inflammatory mediators disseminate from the initial site of injury. This systemic spread is crucial for understanding the link between localized epithelial damage and the development or exacerbation of diseases in distant organs (Table 1). This body of work culminated in the formulation of the broader ‘epithelial barrier theory’. This theory posits that widespread exposure to environmental agents linked to industrialization, urbanization, and modern life compromises the integrity of epithelial barriers [1]. This dysfunction often occurs alongside microbial dysbiosis—characterized by a decrease in beneficial commensal microbes and colonization by opportunistic pathogens—and facilitates bacterial translocation into deeper tissues, initiating the cascade of dysbiosis, immune responses, and inflammation central to the epithelial barrier theory (Fig. 1). The resulting tissue and systemic inflammation, coupled with immune dysregulation, are proposed as key underlying factors contributing to the increasing prevalence and exacerbation of allergic, autoimmune, metabolic, neuroimmune, and other chronic inflammatory diseases [1, 23]. Despite growing awareness, there remains a significant need to advance the scientific understanding of the factors and molecular pathways involved in epithelial barrier leakiness and to inform policymakers about the potential detrimental effects of implicated substances.

Table 1.

Systemic translocation and distant organ effects of selected effectors following epithelial barrier damage.

Effectors	Primary barrier site(s) of entry/damage	Evidence/mechanism of systemic translocation or spread	Examples of distant organs/systems affected & observed/hypothesized effects	Selected key references
Micro‐ and nanoplastics (e.g., polystyrene particles)	Gastrointestinal tract, airways, skin (potential)	Direct epithelial penetration (e.g., M‐cell uptake in the gut); potential lymphatic and bloodstream dissemination following breach; documented transplacental transfer	Placenta: Accumulation within placental tissue Liver: Hepatotoxicity, inflammation, metabolic dysregulation (potentially via gut–liver axis) Other organs (potential): Spleen, kidney, brain (based on particle biodistribution); induction of systemic inflammation, oxidative stress in various tissues	[19, 58, 95, 111, 136]
Particulate matter (PM) (from air pollutants)	Lungs, airways, nasal epithelium	Translocation of ultrafine particles from alveoli into systemic circulation; potential olfactory nerve transport from the nasal cavity to the brain	Cardiovascular system: endothelial dysfunction, atherosclerosis, hypertension Brain: Neuroinflammation, potential contribution to neurodegenerative diseases (e.g., multiple sclerosis), cognitive impacts Liver: Inflammation, fibrosis (potentially involving gut–lung–liver axis interactions) Systemic: Increased chronic systemic inflammation and oxidative stress	[25, 134, 152]
Microbial products & translocated microbes (e.g., LPS, PAMPs, whole bacteria/fungi from dysbiotic microbiota)	Gastrointestinal tract (‘leaky gut’), airways, skin	Compromised epithelial tight junctions and overall barrier integrity leading to passage of microbial components or whole microbes into the submucosa, lymphatics, and systemic circulation	Liver: Nonalcoholic fatty liver disease (NAFLD/NASH), autoimmune hepatitis, fibrosis (via gut–liver axis) Joints: Inflammatory arthritis (e.g., rheumatoid arthritis, ankylosing spondylitis via gut–joint axis) Brain: Neuroinflammation, anxiety, depression, autism spectrum disorders, Parkinson's disease, Alzheimer's disease (via gut–brain axis) Pancreas/islets: Autoimmune diabetes (Type 1) Adipose Tissue: Inflammation, formation of ‘creeping fat’ in IBD Systemic: Chronic low‐grade inflammation, metabolic syndrome, development/exacerbation of autoimmune diseases	[1, 24, 56, 183, 216, 217, 218, 219, 220, 221, 222, 223, 224]
Alarmins (IL‐33, TSLP, IL‐25, other DAMPs), Pro‐inflammatory Cytokines (IL‐1β, TNF‐α, IL‐6)	Any damaged epithelial site (skin, gut, airways)	Release from damaged/activated epithelial cells and resident immune cells into local tissue microenvironment, with subsequent spillover into systemic circulation	Systemic: Contribution to and maintenance of chronic low‐grade systemic inflammation; priming or exacerbation of inflammatory responses in distant organs/tissues (e.g., demonstrated gut–lung axis and skin–gut axis effects in allergic inflammation); modulation of systemic immune cell activity and trafficking; fever; acute phase protein responses	[1, 16, 18, 20, 21, 57, 86, 139, 182, 190, 234, 235, 246]

Fig. 1.

Epithelial barrier damage caused by multiple damaging substances leads to the release of alarmins, microbial dysbiosis and subepithelial infiltration of commensal and dysbiotic microorganisms. The resulting immune response triggers inflammation, which leads to further epithelial barrier damage and the propagation of a vicious cycle. The loss of tolerance to microorganisms, activation of effector immune cells and release of pro‐inflammatory cytokines into the circulation may decrease the threshold/trigger multiple chronic inflammatory diseases at distant sites.

Recent research has identified 68 diseases that align with this theory [23]. Many of these conditions, such as asthma, AD, CRS, allergic rhinitis, eosinophilic esophagitis (EoE), inflammatory bowel disease (IBD), and celiac disease, are characterized by inflammation localized to the affected organ's epithelial tissue. Another category includes metabolic and autoimmune diseases like obesity, diabetes mellitus, rheumatoid arthritis, multiple sclerosis, fatty liver disease, autoimmune hepatitis, systemic lupus erythematosus, and ankylosing spondylitis. While these conditions manifest systemically or in organs distant from primary barrier sites, they are often associated with chronic mucosal inflammation involving gut or lung barrier defects or conditions like periodontitis [1, 24, 25]. These are thought to be mediated through inter‐organ axes like the gut–thyroid, gut–joint, gut–liver, and gut–brain pathways, contributing to diseases, such as Hashimoto's thyroiditis, Graves' disease, osteoarthritis, obesity, diabetes, and liver cirrhosis [23]. Furthermore, accumulating evidence suggests a link between increased intestinal barrier permeability (‘leaky gut’) and neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, stress‐related psychiatric conditions, autism spectrum disorders, and chronic depression [1].

Athletes and highly active individuals are exposed to numerous factors that can compromise epithelial barrier integrity and microbiome health. Intense physical exertion stresses multiple organs, leading to inflammation and tissue damage [26]. Harmful exposures include cleaning agents, chlorine in pools, air pollutants, microplastics, and additives in processed high‐calorie sports foods. These factors, combined with sleep disturbances, frequent travel, and hygienic stressors, heighten the risk of barrier dysfunction, particularly in the skin, gut, and respiratory tract [27]. Athletes in winter and water sports are especially vulnerable due to high exposure to airborne and chlorinated substances [27].

While moderate exercise improves microbiota diversity, enhances gut barrier function, and reduces inflammation that benefits conditions like cardiovascular disease, diabetes, and obesity [28, 29, 30, 31, 32, 33, 34, 35], elite‐level physical stress may reverse these advantages [36, 37]. Exercise‐induced oxidative stress, immune shifts (e.g., increased Th2 and reduced Th1/Treg), and gastrointestinal symptoms reflect the vulnerability of overstressed athletes [38]. Despite these risks, elite athletes who maintain optimal hygiene, nutrition, and recovery can mitigate some damage [39, 40].

The well‐being of humans, animals, and the environment is inherently interconnected, as acknowledged by the ‘One Health Concept’, an integrated and holistic approach designed to sustainably balance and optimize the health of people, animals, and ecosystems [41, 42, 43]. The conceptual framework of the epithelial barrier theory can be effectively extended to domestic animals within an integrative scope [41]. This issue is especially critical in livestock species, considering the high consumption of animal‐derived products as a major protein source in human nutrition. Furthermore, companion animals living in close proximity to humans are similarly (and in some cases more extensively) exposed to chemicals and environmental pollutants associated with modernization and urbanization, such as detergents, surfactants, air pollutants, and food additives, including a high and increasing burden of micro‐nanoplastics exposure [41].

Notably, large‐scale analyses have identified skin disorders and enteropathies as common conditions in dogs [44], highlighting the potential contribution of chemical‐induced epithelial barrier disruption to their rising prevalence. Due to their barefoot contact with household surfaces, especially via furless paw pads, they may absorb higher doses of these substances [45]. Conditions like canine AD, often affecting high‐contact areas like paws and axillae, support this risk [41]. Pets also face chemical exposure through grooming behaviors, such as licking paws or using pet toothpaste containing surfactants like sodium lauryl sulfate (SLS). Additionally, animals are vulnerable to airborne pollutants, including ozone, volatile organic compounds, and microplastics, particularly those closer to ground level, such as small dog breeds [41]. Indoor environments pose continuous exposure risks, especially for exclusively indoor animals like cats. The widespread use of plastic‐based pet products and frequent cleaning in multi‐pet households further heighten exposure. Moreover, poisoning from insecticides, rodenticides, and household chemicals remains a consistent threat, with several reports documenting such toxic events in domestic animals [46, 47]. Addressing environmental pollution and related risks to human and animal health requires a coordinated, collaborative, cross‐sectoral action and a global strategy within the One Health Framework [48].

This article synthesizes current evidence on the cellular and molecular mechanisms by which environmental stressors compromise epithelial barriers. It elucidates how modern toxins disrupt barrier integrity and traces these disturbances to the development of more than 70 chronic NCDs and their immunological sequelae. The discussion is framed within the ‘One Health’ paradigm, underscoring the cross‐species importance of safeguarding epithelial barrier function for human and animal health alike.

Substances that cause epithelial barrier damage

After the chemistry revolution, urbanization and modernization have introduced widespread human exposure to numerous chemicals and substances since the 1960s (Table 2). A significant development was the introduction of potent anionic surfactants and enzymes into laundry detergents to enhance cleaning, which coincided with epidemiological observations linking occupational detergent exposure to asthma, rhinitis, and AD [1]. Experimental studies investigating the effects of highly diluted laundry detergent, even 50 000‐times dilution, on bronchial epithelial cells revealed transcriptomic signatures indicative of an inflamed, damaged barrier attempting to heal, characterized by increased IL‐33 expression, upregulation of genes related to lipid metabolism, oxidative stress, and cell survival, and downregulation of genes associated with cell adhesion, extracellular matrix, and wound healing [16]. Worryingly, residual active detergents and surfactants can persist in fabrics even after rinsing, potentially impairing epithelial tight junctions (TJs) upon contact [16]. Common surfactants like sodium dodecyl sulfate (SDS) and sodium dodecylbenzene sulfonate, found in countless cleaning products, soaps, shampoos, and cosmetics, have demonstrated the ability to injure lung and skin epithelial TJs even at very high dilutions [14]. This raises concerns about ongoing daily exposure risks.

Table 2.

Key environmental agents, their categories, common sources, and mechanisms of epithelial barrier disruption.

Category	Substance	Common sources	Primary epithelial target/direct damaging effect	Key cellular pathways affected	Selected key references
Detergents & surfactants	SDS (sodium dodecyl sulfate), anionic surfactants, laundry detergents, dishwasher detergents rinse aids	Household cleaning products (laundry, dishwashing), personal care items (soaps, shampoos, toothpaste)	Disruption of cellular membranes (plasma, mitochondrial, ER), direct damage to tight junctions (TJs) and adherens junctions (AJs), reduced transepithelial electrical resistance (TEER), epithelial cell death	Mitochondrial damage, ROS production, ATP depletion, ER stress, unfolded protein response (UPR), inflammasome activation, cytoskeletal contraction, junctional opening, apoptosis, necrosis, release of alarmins (IL‐33, TSLP), eosinophilic inflammation, potentially ferroptosis	[14, 16, 20, 22, 57, 86]
Food emulsifiers	Polysorbate 20, polysorbate 80, carboxymethyl cellulose, lecithin	Processed foods, food additives.	Increased intestinal permeability, disruption of mucus layer, changes in surface tension, direct cellular toxicity to epithelial cells	Mitochondrial damage via PPAR, β‐oxidation, ROS production, ER stress and UPR, pro‐inflammatory cytokine release, inflammasome activation via ROS, apoptosis	[21, 53, 54, 69]
Micro‐ & nanoplastics	Polystyrene particles	Environmental contamination (water, air, soil), food chain, drinking water, cosmetics	Reduced intestinal mucus secretion; Direct gut barrier damage and increased permeability; epithelial cell penetration; protein binding & conformational changes; lipid bilayer destabilization	Lysosomal damage and enzyme leakage, ROS via NADPH oxidase activation, mitochondrial damage and ROS generation, ER stress (particle accumulation, impaired protein folding), inflammasome activation, ferroptosis, apoptosis, pyroptosis	[19, 58, 59, 60, 95, 111, 131, 150, 151, 254]
Air pollutants	Particulate matter (PM, PM2.5), ozone, diesel exhaust, cigarette smoke components	Combustion processes (traffic, industry), airborne dust, smoke, indoor/outdoor air	Compromised barrier integrity in airway and nasal epithelia, oxidative stress, inflammation, epithelial cell death	Mitochondrial damage and ROS generation, ER stress (PM‐induced Ca++ dysregulation), inflammasome activation (NLRP3), ferroptosis (PM), DNA damage, release of alarmins (IL‐33, TSLP) and pro‐inflammatory cytokines (IL‐6, IL‐8, IL‐1β), induction of type 2 immune responses	[17, 18, 62, 83, 96, 110, 114, 130, 152, 244]
Artificial sweeteners	Sucralose, aspartame	Diet foods and beverages, sugar substitutes.	Potential direct interaction with protein structures (sucralose); promotion of amyloid‐like aggregation (aspartame)	ER stress and UPR (impaired protein folding), ferroptosis	[97, 104, 112, 113]

Synthetic detergents were first mass‐produced in the early 20th century, and the steep rise in asthma and AD paralleled the household uptake of sulfated anionic surfactants during the 1960s [49]. Patch testing with SLS causes a reproducible increase in transepidermal water loss and a fall in stratum corneum hydration, confirming direct cutaneous barrier compromise [50, 51]. Professional cleaners chronically exposed to detergents show higher transepithelial water loss and a greater risk of work‐related hand dermatitis, which links occupational contact to sustained barrier injury [52]. Even diluted laundry detergent aerosolized from treated fabrics upregulates IL25, IL33, and thymic stromal lymphopoietin (TSLP) in airway epithelium, illustrating how trace residues can initiate epithelitis and prime type 2 immune pathways [16].

The widespread use of emulsifiers in the food industry is increasingly scrutinized as a potential contributor to gut barrier‐related diseases. Processed food emulsifiers have been shown to increase intestinal permeability, potentially via mechanisms involving surface tension changes and direct cellular toxicity, similar in some ways to detergents. Emulsifiers, such as polysorbates, lecithin, carboxymethylcellulose, and sorbitolmonostearate, thicken the mucosal surface fluid, trap commensal bacteria, disrupt mucus–bacterial interactions, and drive colitis‐like inflammation in mice [53, 54]. Even low concentrations can lead to mucosal damage, as observed in animal models [55]. Emulsifier exposure may also trigger epithelial cell activation and facilitate bacterial translocation across the compromised barrier [21, 54, 56]. A recent study showed that exposure to food emulsifiers polysorbate 20 and 80, even at concentrations 20 times more diluted than the allowed amount, led to cellular stress and pro‐inflammatory responses in gut epithelial cells [21]. Residual rinse aid and dishwasher detergent left on ‘clean’ crockery are being investigated as a previously overlooked source of esophageal and intestinal barrier injury [20, 57].

Micro‐ and nanoplastics represent an emerging skin and mucosal barrier toxin class: polystyrene microplastics reduced intestinal mucus secretion and damaged gut barrier function in mice, while 1 μm particles penetrated the epithelium more readily than larger fragments [19, 58]. At the nanoscale, plastic particles bind proteins, distort secondary structure, destabilize lipid bilayers, and activate pro‐inflammatory transcription programs, culminating in oxidative stress‐driven epithelial cell death [59, 60].

As Paracelsus said 500 years ago, ‘Sola dosis facit venenum’, ‘Only the dose makes the poison’. Studies have shown that the dose and time of exposure to these substances are critical in determining their cellular and molecular toxicity [20, 21, 22]. The molecular mechanisms of how environmental toxic substances cause cellular damage, the discovery of which is key to being able to mitigate their toxic effects, have been started to be elucidated; they include multiple intertwined pathways, explained below, that lead to dysregulation in cellular metabolism, cellular stress, and cell death [18, 22, 57, 61, 62]. Although environmental toxic substances may initiate the cascade of cellular stress from different points, as most intracellular stress mechanisms converge, they tend to lead to similar toxic effects in epithelial cells (Fig. 2A). Many of the subsequent mechanistic details are based on in vitro studies; while these are essential for understanding cellular processes, their extrapolation to in vivo physiology should be approached with due consideration.

Fig. 2.

(A) Mechanisms by which environmental toxicants induce cellular damage. Undigested particles (micro‐ and nanoplastics) trigger endoplasmic reticulum (ER) stress and oxidative stress, leading to NF‐κB activation. Alcohol and cigarette smoke cause mitochondrial dysfunction, resulting in reactive oxygen species (ROS) generation and caspase‐mediated apoptosis. Surfactants (detergents and emulsifiers) primarily disrupt cellular membranes, causing electrolyte leakage, mitochondrial impairment, tight‐junction disruption, and additional ROS production. Excess ROS leads to DNA strand breaks, the release of damage‐associated molecular patterns (DAMPs) and NF‐κΒ signaling. If these insults are not resolved, they culminate in multiple forms of cell death—including apoptosis, pyroptosis, ferroptosis, and necrosis. (B) Schematic view of the principal tight‐junction architecture showing barrier‐forming and pore‐forming claudins, tight junction‐associated MARVEL proteins (TAMPs), junctional adhesion molecules (JAMs), the coxsackie and adenovirus receptor (CAR), zonula occludens‐1 (ZO‐1), and their linkage to the Actin‐myosin cytoskeleton.

Intracellular pathways of epithelial cell toxicity

ROS as a central mediator in toxic substance‐induced cellular stress

Environmental toxic substances trigger a cascade of interconnected intracellular stress events, with reactive oxygen species (ROS) often emerging as a common and pivotal mediator. While the initial points of impact may vary depending on the toxicant's chemical structure, the resulting oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress are frequently interlinked, culminating in cellular damage and epithelial barrier compromise.

Mitochondrial damage and the dysregulation of the electron transport chain represent a central process leading to both ROS generation and the disruption of key metabolic processes, such as oxidative phosphorylation (OXPHOS) [63, 64, 65]. How environmental toxic substances cause mitochondrial damage and loss of mitochondrial membrane potential depends on the substance's chemical structure. For example, SDS or SLS, a surfactant, disrupts cellular membranes, including mitochondrial membranes [66]. Damage to the inner mitochondrial membrane may also cause leakage of electrons into the matrix, generating ${\mathrm{O}}_2^{-}$ radicals and initiating a cascade of ROS generation [63, 67]. Another example is the food emulsifier polysorbate 80 (P80), which structurally contains an oleic acid molecule bound to a sugar moiety [68]. P80 can lead to mitochondrial membrane damage and ROS generation, as well as activate peroxisome‐proliferator‐activated receptor and cause an increase in β‐oxidation, resulting in excess ROS formation [21, 69]. Mitochondrial damage not only leads to ROS generation but also results in dysregulation of cellular metabolism, depleting the OXPHOS capacity and diminishing the ATP generation capacity of the cell [64, 70, 71]. This is followed by downstream effects, including disrupted protein folding [72], and decreased capacity of the cell to mitigate various stress factors, such as further oxidative stress [64, 73], ER stress [72], genotoxic stress [74, 75], and calcium imbalance [76, 77, 78]. Furthermore, severe damage to the mitochondrial membrane can lead to the leakage of cytochrome c into the cytosol, potentially initiating apoptosis [79, 80].

The surge in ROS from dysfunctional mitochondria or from other cellular compartments, such as the plasma membrane/endosome/lysosomes (via NADPH oxidase, particularly activated by phagocytosed, nondegradable particles like particulate matter and micro‐nanoplastics that resist lysosomal degradation [81, 82, 83]), peroxisomes, or the ER itself during stress responses [81, 84, 85], becomes a common pathogenic hub [18, 20, 69, 86, 87, 88]. This ROS can directly attack cellular macromolecules and trigger specific damage pathways. A critical consequence is extensive membrane lipid peroxidation. This process, involving enzymatic lipid peroxidation through lipoxygenases and nonenzymatic lipid peroxidation via Fenton reactions with iron, can be initiated by environmental toxic substances containing lipid‐like structures with double bonds (e.g., most food emulsifiers like P80 and soy lecithin) [89, 90, 91], and can overwhelm cellular antioxidant capacities, leading to ferroptosis—a form of cell death dependent on iron and characterized by excessive lipid peroxidation [92, 93, 94]. Substances that trigger excessive ROS generation, such as micro‐nanoplastics, particulate matter, and non‐nutritional sweeteners like sucralose and aspartame, have been shown to induce ferroptosis [95, 96, 97]. While food emulsifiers and SDS have not been shown to induce ferroptosis directly, it is probable that they also trigger this pathway through ROS‐mediated lipid peroxidation [20, 57]. These events cause changes in membrane stiffness, fluidity, and permeability, ultimately resulting in plasmalemma rupture and cell death [98].

In addition to direct oxidative damage to lipids, ROS profoundly impacts protein homeostasis and ER function. The controlled formation of disulfide bonds is critical for the proper folding of proteins in the ER lumen [99, 100]. Excess ROS in the ER lumen, whether originating from damaged mitochondria or other sources, may lead to the premature and incorrect formation of these bonds, preventing proteins from achieving their intended tertiary structure [101, 102]. This accumulation of misfolded proteins triggers the unfolded protein response (UPR), a physiological mechanism designed to restore ER homeostasis [99, 100]. However, if the toxic stimulus is overwhelming or persistent, the UPR becomes maladaptive, initially promoting autophagy and, if still unresolved, ultimately leading to inflammatory signaling and cell death, primarily through apoptosis [103]. Some environmental toxic substances, such as aspartame, may initially cause protein folding defects that lead to an excess UPR, which in turn causes increased ROS inside the ER lumen; if this exceeds the ER's antioxidant capacity, it can disrupt membranes and leak out [104, 105, 106, 107]. Besides ROS‐induced misfolding, other environmental toxicants can directly compromise the ER: surfactants like SDS can disrupt the ER membrane, similar to other cellular membranes, causing dysfunction of membrane‐associated proteins and disturbing Ca⁺⁺ and ROS homeostasis in the ER lumen [66, 76, 108, 109]. Particulate matter has been shown to disrupt Ca⁺⁺ homeostasis within the ER lumen by interacting with membrane proteins, resulting in ER stress and apoptosis [110]. Microplastics have also been documented to accumulate within the ER lumen, impairing protein folding and causing ER stress in human syncytiotrophoblasts [111]. Artificial sweeteners, such as sucralose and aspartame, also induce ER stress; sucralose may interact with hydrophobic protein surfaces [112], and aspartame can lead to the self‐assembly of amyloid‐like structures [113], suggesting that protein aggregation may also hinder proper folding. While the precise initiating mechanisms through which many environmental toxic substances cause a sustained UPR remain to be fully elucidated, their ROS‐generating capabilities and direct interactions with membranes and proteins represent plausible links [21, 104, 114, 115].

Ultimately, whether originating from mitochondrial dysfunction, direct membrane damage, or ER stress, supraphysiologic levels of ROS can act as signaling molecules. Two transcription factors commonly activated are NF‐κB and AP‐1, which orchestrate the release of pro‐inflammatory cytokines and mediators, propagating stress signals to surrounding cells and contributing to tissue inflammation [116, 117, 118, 119]. The direct attack by ROS on major cellular building blocks—amino acids, lipids (which also causes Ca⁺⁺ leakage into the cell [120], disrupting intracellular signaling pathways and activating Ca⁺⁺‐dependent proteases), and nucleic acids—further compounds the damage, leading to dysfunctional cells and, consequently, a dysfunctional epithelial barrier [85, 90, 91, 121, 122].

Inflammasome & pyroptosis

Pyroptosis is a form of regulated cell death that is canonically caused by inflammasome activation, leading to the release of IL‐1β and IL‐18, as well as the cleavage of Gasdermin D. This process results in water influx, cellular swelling, and cell death [123, 124, 125]. Unlike apoptotic cell death, pyroptosis leads to the release of cytokines and cellular contents, which act as damage‐associated molecular patterns (DAMP)s to trigger and perpetuate inflammation [123, 126]. Numerous triggers exist for NLRP3 inflammasome activation, including K⁺ efflux, lysosomal damage, ROS generation, and bacterial cell wall components [127, 128]. Other inflammasomes, such as NLRC4, AIM2, NLRP1, and Pyrin, are primarily activated by microbial products, including cell wall components, dsDNA, or toxins [127, 128]. AIM2 can be activated through the binding of dsDNA, regardless of its source, whether derived from bacterial, host‐nuclear, or host‐mitochondrial origins [129].

The initial insult from various environmental toxic substances can lead to inflammasome activation in epithelia through multiple mechanisms. Micro‐nanoplastics and particulate matter result in lysosomal damage and ROS generation, resulting in inflammasome activation and pyroptotic cell death [95, 96, 130, 131]. Membrane‐disrupting substances, such as SLS disrupt the fluidity and permeability of cellular membranes and cause disturbances in ion homeostasis, which may result in K⁺ leakage and inflammasome activation. Substances, such as p80 or SLS, may also cause inflammasome activation through ROS generation and mitochondrial damage [21, 132, 133].

Environmental toxic substances not only damage the epithelia directly but also cause microbial dysbiosis [54, 134, 135, 136]. The presence of dysbiotic bacteria causes further damage to the epithelia and can lead to increased inflammasome activation through engulfment by epithelia and intracellular release of components or toxin production [137, 138]. As the integrity of the epithelial barrier is compromised, both commensal and pathogenic bacteria start dislocating to the lamina propria [1]. This results in excess activation of macrophages encountering these bacteria and further inflammasome activation. Environmental toxic substance‐induced epithelial injury and microbial dysbiosis synergistically undermine barrier integrity, promoting bacterial translocation and a self‐amplifying cycle of inflammasome‐driven inflammation [139].

Environmental toxins provoke epithelial inflammasome activation and pyroptosis through mechanisms like lysosomal damage, ROS, and ion flux, while external stresses drive microbial dysbiosis that further compromises barrier integrity. This dual assault facilitates bacterial translocation and perpetuates a vicious cycle of inflammasome‐driven inflammation and epithelial barrier injury.

DNA damage/p53 axis and apoptosis

We have mentioned above multiple mechanisms of cellular stress leading to cellular dysfunction when cells encounter environmental toxic substances. If these stressors persist, they can overwhelm cellular defense mechanisms, leading to cell death. There are several mechanisms of cell death, including programmed cell death, such as apoptosis [20, 21, 140], ferroptosis [90], and pyroptosis [132, 141, 142], as well as nonprogrammed cell death, that is, necrosis, which can occur when the cell's defense mechanisms are overcome due to constant or high‐dose exposure to ETS.

Apoptosis is a tightly regulated mechanism of cell death triggered by intrinsic and extrinsic factors [80]. Intrinsic triggers include nutrient and growth factor deprivation, DNA damage, ER stress, oxidative stress, mitochondrial membrane damage, and Ca⁺⁺ overload [143, 144, 145]. As mentioned previously, nearly every trigger of the intrinsic apoptotic pathway can be initiated by environmental toxic substance exposure.

DNA damage is sensed by p53 by activation of ATM/ATR kinases [146], which induces cell cycle arrest via the induction of p21, an inhibitor of the Cdk2/Cyclin E complex, enforcing a G₁/S checkpoint arrest [147]. This provides an opportunity for DNA repair. If the damage is too extensive or the repair mechanisms are overwhelmed, p53 triggers the production of pro‐apoptotic proteins, namely Noxa, BID, and Puma, leading to the initiation of apoptosis [148]. Increased DNA breaks from excess ROS generation due to persistent or high‐dose environmental toxic substance exposure can be a major contributor to apoptotic cell death.

Unresolved ER stress causes sustained UPR activation, which can lead to pro‐apoptotic signals through multiple pathways of ER stress. PERK–eIF2α signaling drives ATF4‐mediated CHOP induction, which downregulates Bcl‐2 and upregulates BH3‐only proteins (e.g., Bim), tipping the mitochondrial permeabilization balance [100, 149]. Additionally, ER Ca²⁺ leakage activates calpains and ER‐resident caspase‐12, linking ER stress to the intrinsic caspase cascade [149]. As most environmental toxic substances result in chronic ER stress, the downstream signals of the UPR signaling pathway can be another contributor to environmental toxic substance‐induced apoptotic cell death.

Mitochondrial damage that leads to dysfunction and dysregulation is a central aspect of environmental toxic substance‐induced damage in cells. As mentioned, this can occur through direct damage to the mitochondrial membrane by surfactants like SDS [66] or through indirect membrane damage caused by excess ROS generation and lipid peroxidation from multiple substances, such as micro‐nanoplastics [150, 151], particulate matter [152], and SDS. Damage to the mitochondrial membrane can lead to apoptosis via the leakage of cytochrome c and the second mitochondria‐derived activator of caspases (SMAC) into the cytoplasm [153]. Cytochrome c associates with APAF‐1/Casp9, while SMAC prevents its inactivation, thus triggering the apoptotic cascade, providing another route through which environmental toxic substances can induce apoptosis.

It is well known that excess ROS is a major cause of increased double‐strand (ds) DNA breaks [154, 155, 156]. Excess ROS caused by exposure to environmental toxic substances leads to dsDNA breaks. Although DNA break repair is a robust process in epithelial cells, chronic exposure to these substances at low doses may result in ongoing dsDNA break‐repair cycles, ultimately leading to mutations, as seen in chronic inflammation, which is a well‐established risk factor for the development of malignancies [157, 158].

Environmental pollutants may drive cells toward demise through DNA damage, protein‐folding machinery overload, oxidative stress provocation, and mitochondrial integrity compromise. Chronic exposure, therefore, leads to excessive cell loss as well as tissue injury [1]. This underscores the importance of reducing pollutants and improving cellular defenses.

Cytoskeletal contraction and early junctional opening

All major barrier epithelia—from the gut and airway to the skin and esophagus—can undergo a rapid increase in paracellular permeability due to cytoskeletal contractions. Under homeostasis, TJ and adherens junction (AJ) complexes seal the space between epithelial cells and are tethered to the peri‐junctional actin‐myosin ring (Fig. 2B, Table 3). The inherent resilience and baseline integrity of these barriers are crucial; they are established and maintained through cellular differentiation processes that progressively mature intercellular junctions and enhance overall barrier strength, involving specific molecular regulators and changes in junctional protein composition (Fig. 3A). Early in inflammation or injury, various triggers (pro‐inflammatory cytokines like TNF‐α or IL‐13, ROS from oxidative stress, surges in intracellular Ca⁺⁺ levels, and environmental toxicants) initiate signaling events that target this actomyosin apparatus [159]. These stimuli cause the circumferential actomyosin belt to contract, exerting tension on cell–cell contacts and pulling junctions slightly apart. The result is an ‘early junctional opening’, where small gaps form between cells, and transepithelial resistance drops before any widespread cell death or gross tissue damage occurs. Notably, this early, transient barrier defect is often reversible if the cytoskeletal tension is released or counteracted, but it can also progress to larger junctional disassembly if the stimuli persist.

Table 3.

Key tight‐junction proteins and their predominant expression/role in various epithelial tissues.

Protein family	Specific protein(s)	General function(s) in tight junctions	Predominant epithelial tissue expression/key roles
Claudins	Claudin‐1	Barrier‐forming; seals paracellular space; maintains cell polarity; epidermal barrier integrity	Skin (epidermis): Essential for water barrier function Intestine: Contributes to barrier properties Lung: Present in airway epithelium Kidney: Expressed in various nephron segments
	Claudin‐2	Pore‐forming (cation‐selective, primarily Na+, Ca2+); increases paracellular water flux	Intestine (small & large): Contributes to Na+ and water reabsorption; upregulated in IBD (e.g., UC by IL‐13) Kidney (proximal tubule): Involved in Na+ reabsorption Liver (bile ducts): Regulates bile composition
	Claudin‐3, Claudin‐4	Barrier‐forming; contribute to epithelial tightness. Claudin‐4 can act as a receptor for CPE	Various epithelia: Widely expressed, including intestine, lung, kidney, pancreas, breast Claudin‐4 in intestine: Contributes to barrier; target for Clostridium perfringens enterotoxin (CPE) Skin: Present
	Claudin‐5	Barrier‐forming; predominantly in endothelial tight junctions, but also some epithelia	Endothelium (blood–brain barrier, blood‐retinal barrier): Critical for vascular integrity Lung epithelium (alveoli): Contributes to alveolar barrier Kidney (glomerulus): Expressed in podocytes
	Claudin‐7	Barrier‐forming; ion transport regulation; cell adhesion	Intestine (colon): Important for barrier function; mislocalization in IBD Kidney (collecting duct): Regulates paracellular Cl− transport Skin: Present
	Claudin‐10 (a & b)	Pore‐forming (Claudin‐10a: anion‐selective; Claudin‐10b: cation‐selective)	Kidney: Different isoforms in distinct nephron segments regulating ion transport Skin (sweat glands): CLDN10B crucial for sweat ion composition (mutations cause HELIX syndrome) Intestine: Expressed
	Claudin‐15	Pore‐forming (cation‐selective, Na+); contributes to fluid and nutrient absorption	Intestine (small intestine): Forms Na+ pores, crucial for nutrient and water absorption
	Claudin‐16 (Paracellin‐1)	Pore‐forming (Mg++ and Ca++ selective channel in complex with Claudin‐19)	Kidney (thick ascending limb): Essential for paracellular reabsorption of Mg++ and Ca++. Mutations cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)
Occludin	Occludin	Barrier‐forming; regulates paracellular permeability; scaffolding & signaling roles; cell polarity	Most Epithelia & endothelia: A key component of TJs (intestine, lung, kidney, skin, BBB). Target for disruption by pathogens/cytokines (e.g., Der p1, TNF‐α)
Tricellular TJ proteins	Tricellulin (MARVELD2)	Seals tricellular contacts; prevents macromolecule leakage at three‐cell junctions	Various epithelia: Concentrated at tricellular TJs (intestine, kidney, inner ear). Reduced expression in UC
	Angulins (ILDR1/2, LSR)	Recruit tricellulin to tricellular TJs; essential for tricellular barrier function	Various epithelia: Co‐localize with tricellulin at tricellular TJs
JAMs (junctional adhesion molecules)	JAM‐A (F11R), JAM‐B, JAM‐C	Cell–cell adhesion; leukocyte transmigration; scaffolding; TJ assembly & maintenance	Epithelia & endothelia: Widely expressed (intestine, lung, kidney). JAM‐A is involved in barrier regulation and immune cell interactions
CAR (coxsackie and adenovirus receptor)	CAR	Viral receptor; cell adhesion; TJ localization and barrier function	Various Epithelia: Brain, heart, pancreas, intestine, airway. Contributes to TJ's integrity
ZO (zonula occludens) proteins	ZO‐1, ZO‐2, ZO‐3	Scaffolding proteins (MAGUK family); link TJ transmembrane proteins (claudins, occludin, JAMs) to the actin cytoskeleton; signaling roles; regulate TJ assembly and function	All TJ‐forming cells: Ubiquitous plaque proteins essential for TJ structure and function. ZO‐1 is a key marker for TJs. Disrupted/mislocalized in many barrier diseases (e.g., IBD, asthma, and AD)

Fig. 3.

(A) Wnt‐2b and R‐spondin‐3 sustain stem‐cell proliferation, whereas Dkk‐3 and BMP‐5 drive maturation; weak claudin‐2‐rich junctions in transit‐amplifying cells are gradually replaced by sealing claudins and reinforced ZO‐1 strands, increasing epithelial barrier strength. (B) TGF‐β (via TGFBR) or IL‐4/IL‐13 (via IL4R) initiate the epithelial‐to‐mesenchymal transition, downregulating ZO‐1, tricellulin, angulin‐1, and occludin, while inducing SNAIL, TWIST, and ZEB transcription factors and erasing apicobasal polarity. (C) Vesicular transcytosis ferries luminal macromolecules across enterocytes, providing a tight‐junction–independent, size‐flexible transport route. (D) Paracellular permeability is shaped by three TNF‐responsive conduits: a claudin‐2 pore pathway (< 8 Å) amplified by IL‐22 or IL‐13; a leaky pathway (~ 100 Å) created by loss of occludin, tricellulin, and angulin‐1; and an unrestricted pathway that arises when TNF‐induced epithelial cell death leaves transient gaps between neighboring cells.

Mechanistically, cytoskeletal contraction at the apical junction is driven by classical Rho GTPase and Ca⁺⁺‐dependent pathways. RhoA activation and its effector Rho‐associated kinase (ROCK) stimulate myosin II activity by phosphorylating the myosin light chains (either directly or via intermediate kinases), while Ca⁺⁺‐calmodulin signaling activates myosin light‐chain kinase (MLCK) with a similar outcome [159]. Phosphorylation of myosin II regulatory light chains triggers contraction of the peri‐junctional actin ring, which increases tension on TJs and AJs and can force open the TJ strands. In epithelial cells exposed to inflammatory cytokines like TNF‐α or IL‐1β, for example, MLCK is activated and contributes to barrier loss [159]. This causes modest tightening of the junctional belt and a reversible increase in permeability, often without immediate disruption of the junction structure. By contrast, strong activation of RhoA–ROCK (for instance, via Rho GEF‐H1 released from microtubules during stress) induces more pronounced actomyosin contraction and can drive actual junctional disassembly [159]. Consistently, experimental models show that sustained MLCK activity alone causes only a minor (~ 20%) drop in epithelial resistance with intact TJs, whereas excessive RhoA signaling leads to dramatic AJ/TJ disruption [159]. In parallel with force generation, contractile signaling can also provoke remodeling of junction proteins—for instance, endocytosis of TJ components like occludin is triggered by MLCK‐dependent actomyosin pulls during TNF‐α exposure, weakening the seal [159]. Thus, the early phase of barrier opening involves a concerted mechanism: phosphorylation‐driven myosin contraction that physically enlarges the paracellular space, accompanied by dynamic changes in junctional protein localization.

Beyond these canonical pathways, a variety of cytoskeletal‐ and junction‐associated regulators fine‐tune actomyosin contraction and junctional opening. The actin‐binding scaffold cortactin is one such regulator; it co‐localizes with ZO‐1 at TJs and appears to restrain excessive contractility, as cortactin deficiency leads to heightened RhoA–ROCK activity and barrier leakage in intestinal epithelia (with loss of ZO‐1 and E‐cadherin at contacts) [160]. On the other hand, the mechanosensitive protein vinculin (recruited by α‐catenin at AJs) is required to stabilize junctions under stress. Upon increased tension, vinculin is rapidly recruited to junctional sites—especially tricellular junctions—where it anchors cortical actin and myosin II to the membrane; without vinculin, actin disengages from the junction, and TJ proteins like ZO‐1 show breakage, resulting in local leaks [161]. Tight‐junction plaque proteins, such as cingulin (and its paralog paracingulin), also link the contractile apparatus to junctions and modulate Rho GTPase signaling, effectively tethering myosin II filaments to the TJ complex [159]. Similarly, the submembrane spectrin–adducin network has emerged as a structural support that connects cortical actin to junctional complexes, acting as a mechanical transducer to maintain adhesion during active remodeling [162]. Additional cytoskeletal linkers like the ERM family (ezrin, radixin, and moesin) contribute by anchoring actin to apical membrane proteins, thereby organizing microvilli and the apical cortex in ways that support junction stability [163]. Signaling molecules also play nuanced roles in early junctional regulation: for example, Ca⁺⁺/calmodulin‐dependent protein kinase II (CaMKII) has been identified as a negative regulator of TJ assembly (its inhibition actually strengthens the barrier) [164], and LIM domain kinases (downstream of Rho) phosphorylate cofilin to stabilize F‐actin—a change that can increase junctional tension and permeability [159]. Through their structural and signaling interactions with the actin cytoskeleton, these regulators (cortactin, vinculin, cingulin, spectrin/ERM networks, CaMKII, LIMK, and others) integrate with the classic Rho–myosin pathways to determine the extent and reversibility of junction opening.

These early cytoskeletal and junctional changes have important disease ramifications across different organs. In the gut, excessive cytokine‐induced contraction of the peri‐junctional actin ring underlies the ‘leaky gut’ phenomenon in IBD. For instance, during Crohn's disease or ulcerative colitis (UC), immune‐derived TNF‐α and interferon‐γ drive MLCK‐mediated myosin phosphorylation and occludin removal from TJs, compromising intestinal barrier function [159]. This permits antigen and microbe translocation that can exacerbate mucosal inflammation. In the airway epithelium of asthmatic patients, Th2 cytokines, such as IL‐4 and IL‐13, similarly induce early junctional opening. Experiments show that IL‐13 exposure causes a significant drop in transepithelial electrical resistance (TEER) and increases macromolecular flux across bronchial cell layers, accompanied by redistribution or loss of junction proteins like ZO‐1 and E‐cadherin [165]. Environmental pollutants (e.g. ozone and particulate matter) and allergens can amplify this by causing oxidative stress and Ca⁺⁺ influx in airway epithelia, further activating Rho/MLCK pathways and contributing to the barrier dysfunction in asthma. In AD (eczema), the skin's barrier defect is partly due to cytoskeletal‐junctional alterations: chronic Th2 inflammation (high IL‐4/IL‐13) downregulates key junction proteins (like claudin‐1) and loosens TJs, while repeated scratching triggers Ca⁺⁺‐dependent actomyosin contraction in epidermal cells. The result is increased epidermal permeability (reflected by lower electrical resistance in lesional skin) and greater entry of allergens and microbes, feeding a vicious cycle of inflammation [9]. Likewise, in EoE, an allergic inflammatory condition of the esophagus, elevated IL‐13 levels lead to an early breakdown of the epithelial barrier. IL‐13 not only alters junctional protein expression but also induces an epithelial protease (calpain‐14) that cleaves cytoskeletal or junctional components, thereby weakening cell–cell adhesion [166]. This makes the esophageal epithelium leaky to dietary antigens and irritants, provoking chronic eosinophilic inflammation. Across these disorders, the common theme is that diverse stimuli initiate actomyosin‐driven junctional opening as an early event in pathogenesis. Therefore, targeting the regulatory nodes of cytoskeletal contraction (e.g., using ROCK inhibitors or cytokine blockers) is being explored as a strategy to reinforce epithelial barriers and mitigate disease severity [160, 165].

Epithelial–mesenchymal transition and peri‐epithelial fibrosis

Epithelial‐to‐mesenchymal transition (EMT) is a process whereby epithelial cells lose polarity and adhesion, becoming mesenchymal‐like and motile (Fig. 3B). Across barrier tissues (gut, skin, airways, esophagus), chronic insults can trigger EMT, driving an early ‘leaky’ epithelium toward long‐term structural remodeling [167, 168]. Under persistent inflammation, epithelial TJs and AJs are disrupted, compromising the barrier and allowing pathogens and antigens to penetrate. Simultaneously, epithelial cells begin to assume mesenchymal characteristics, contributing to tissue fibrosis and architectural changes. This phenomenon has been observed in disorders ranging from IBD to asthma, in which the epithelium orchestrates fibrotic remodeling via EMT in response to sustained injury [167, 168]. Overall, EMT serves as the bridge between epithelial barrier dysfunction and the permanent remodeling that underlies chronic inflammatory diseases [167, 168].

Fibrosis results from the mesenchymal phenotype obtained by cells after undergoing EMT at damaged epithelial barriers. A good example of this is lamina reticularis thickening beneath the basal lamina in asthmatic bronchi, which is readily observed at the time of first diagnosis, as shown in biopsies taken on the day of initial diagnosis of asthma in children [5]. We presume that this second layer of barrier develops in epithelial barrier leaky individuals to protect the deeper tissues from environmental pollutants, the microbiome, allergens, and toxins.

Persistent inflammation in barrier tissues provides a rich milieu of cytokines and growth factors that induce EMT. Transforming growth factor‐β1 (TGF‐β1) is the prototypical EMT driver, and it is often elevated in chronic inflammation. In addition, type 2 helper T‐cell (Th2) cytokines like IL‐4 and IL‐13, as well as Th17 cytokines like IL‐17A, synergize with TGF‐β1 to downregulate epithelial junctional proteins and upregulate mesenchymal genes [168, 169]. For example, AD lesions (a Th2‐dominated inflammation) show increased Snail1 and Twist transcription factors in keratinocytes, along with co‐expression of epithelial keratins and mesenchymal vimentin—evidence of partial EMT in the skin [169]. Similarly, in severe asthma, IL‐13 and IL‐17 levels are high; these cytokines induce airway epithelial cells to lose E‐cadherin and gain α‐smooth muscle actin (α‐SMA), indicating an EMT program [168]. The classic pro‐inflammatory cytokines tumor necrosis factor‐α (TNF‐α) and IL‐1β also contribute by activating NF‐κB and other pathways that promote EMT. Indeed, long‐term exposure to TNF‐α and IL‐1β can drive otherwise normal epithelial cells to acquire mesenchymal traits (e.g., vimentin and fibroblast‐specific protein) in culture and in wounds [170, 171]. In summary, chronic exposure to cytokines, such as TGF‐β1, IL‐13/IL‐4, IL‐17, TNF‐α, and IL‐1β, creates a pro‐EMT microenvironment that makes epithelial barriers leaky and primes and stimulates them for structural change to develop a secondary barrier.

Beyond cytokines, a variety of environmental toxicants and irritants can directly injure epithelial barriers and initiate EMT. In the gut, ingested environmental microparticles are significant EMT triggers. Microplastics—tiny plastic particles now ubiquitous in food and water—have been shown to disrupt the intestinal barrier, causing a ‘leaky gut’. Chronic oral microplastic exposure leads to microbiome dysbiosis, epithelial TJ loss, and mucosal immune activation. As a result, pro‐inflammatory cytokines and bacterial toxins translocate across the gut wall, fueling further inflammation and tissue injury. Processed food additives like emulsifiers (e.g., polysorbate 80) similarly act as detergents in the gut lumen. At sub‐toxic concentrations, these emulsifiers can strip away mucus and disturb epithelial TJs, lowering transepithelial resistance and provoking a pro‐inflammatory transcriptomic response in intestinal cells [21]. Airborne pollutants are another EMT trigger: particulate matter (such as diesel exhaust, smoke, or carbon nanoparticles) chronically inhaled into airways injures the respiratory epithelium and triggers repair responses. Studies show that exposure to cigarette smoke or fine particulates can induce EMT in bronchial epithelial cells—especially in combination with inflammatory cytokines like IL‐17—leading to loss of E‐cadherin and gain of mesenchymal markers in the airway lining [168]. Thus, environmental toxins (from microplastics to air pollution) can initiate epithelial stress and inflammation that set off EMT programs, compounding barrier dysfunction [1, 168].

At the cellular level, inflammation‐ or toxin‐induced EMT is driven by well‐characterized molecular mechanisms. Key EMT‐activating transcription factors—including SNAIL1/2 (Snail and Slug), TWIST1/2, and ZEB1/2—are upregulated in epithelial cells under EMT‐inducing conditions [168]. These transcription factors repress epithelial genes (such as CDH1 encoding E‐cadherin) and activate mesenchymal genes, effectuating a ‘cadherin switch’ (downregulating E‐cadherin and upregulating N‐cadherin) and intermediate filament shift (increasing vimentin) [168]. The loss of E‐cadherin, along with downregulation of TJ proteins like claudins and occludin, leads to the dissolution of AJs, TJs, and desmosomes between cells [168]. Consequently, epithelial cells lose their polarity and cell–cell contacts, becoming spindle‐shaped and migratory. Cytoskeletal remodeling is a hallmark of this transition: EMT stimulates actin stress fiber formation and focal adhesions, often through Rho GTPase signaling, which enhances cell contractility and motility. EMT also endows epithelial‐derived cells with invasive capabilities by inducing matrix‐degrading enzymes. Notably, EMT‐activated cells begin secreting matrix metalloproteinases (MMPs), such as MMP‐2 and MMP‐9, that degrade the basement membrane and local extracellular matrix [168]. Degradation of the underlying basement membrane is a crucial step in allowing epithelial cells to detach and migrate into the tissue as mesenchymal (fibroblast‐like) cells. In parallel, EMT cells upregulate extracellular matrix components (fibronectin, collagen I, etc.) and α‐SMA, adopting a myofibroblast‐like phenotype [168]. This myofibroblastic transformation enables formerly epithelial cells to contribute to fibrosis by depositing collagen and contracting the matrix. In summary, EMT involves coordinated reprogramming: master transcription factors silence epithelial adhesion molecules (like E‐cadherin) and induce mesenchymal genes (vimentin, N‐cadherin, and α‐SMA), causing junctional disassembly, cytoskeletal reorganization, MMP activation, and basement membrane breakdown [168]. These molecular events convert a stable barrier epithelium into a migratory, matrix‐remodeling cell population at the core of tissue structural changes.

EMT has significant pathological consequences for barrier tissues, linking chronic inflammation to disease progression. As epithelial cells undergo EMT and lose their cohesive barrier function, the tissue becomes more permeable—essentially a barrier ‘failure’. A leaky barrier permits increased infiltration of antigens, microbes, and environmental particles into the tissue, which in turn recruits immune cells and amplifies local inflammation in a vicious cycle. In IBD, for example, long‐standing intestinal inflammation triggers epithelial EMT, and these EMT‐derived mesenchymal cells directly contribute to fibrosis (excessive ECM deposition) in the gut wall [167]. EMT of intestinal epithelial cells yields a population of mesenchymal cells that activate resident fibroblasts and differentiate into myofibroblasts, promoting fibrotic strictures in Crohn's disease and UC. In the airways, repeated epithelial injury in chronic asthma or CRS similarly leads to EMT‐driven remodeling. The airway epithelium in asthma, usually a tight barrier, becomes disrupted; some epithelial cells transition into fibroblast‐like cells that migrate beneath the basement membrane. This contributes to subepithelial fibrosis and smooth muscle hyperplasia, thickening the airway wall [168]. A good example of this is lamina reticularis thickening beneath the basal lamina in asthmatic bronchi, which is readily observed at the time of first diagnosis as shown in biopsies taken on the day of initial diagnosis of asthma in children [5]. The result is airway narrowing and loss of elasticity, manifesting as irreversible airflow limitation in severe asthma. In allergic diseases, EMT is increasingly recognized as a feature of chronic tissue changes. Atopic dermatitis (chronic eczema) skin shows areas of EMT indicated by keratinocytes expressing mesenchymal markers, which correlates with barrier breakdown and lichenified (thickened) skin lesions [169]. Eosinophilic esophagitis (EoE), an allergic inflammation of the esophagus, provides a striking example: IL‐13–driven inflammation in EoE causes esophageal epithelial cells to downregulate E‐cadherin and acquire mesenchymal markers, contributing to tissue stiffening and dysmotility. Notably, a clinical trial in EoE found that an anti–IL–13 antibody could restore epithelial E‐cadherin and reduce vimentin‐positive cells, effectively reversing EMT biomarkers in the esophageal lining [172]. This demonstrates that EMT is not only present in these diseases but is functionally important in barrier dysfunction and can be therapeutically targeted. Across these conditions—from IBD in the gut to asthma/CRS in the airways to AD and EoE—EMT under chronic inflammatory conditions leads to compromised barriers, infiltration of immune cells, and progressive fibrosis. We presume that this second layer of fibrotic barrier develops in epithelial barrier leaky individuals to protect the deeper tissues from environmental pollutants, the microbiome, allergens, and toxins, which become pathologic in the presence of chronic damage to the epithelial barriers. These changes often perpetuate inflammation and can cause organ dysfunction (such as strictures, bronchial hyperresponsiveness, or impaired peristalsis), thereby driving the chronic nature of the disease.

Phenotypes and mechanisms of epithelial barrier leakage

More than 2000 years ago, Hippocrates said, ‘What diseases the medicines cannot heal, iron heals; what iron cannot heal, fire heals; and what fire cannot heal, these must be considered incurable’, which means if the medicine is not sufficient, particularly for surgical wounds and abscesses, surgical drainage, full cleaning of the wound with further drainage by heated oils will be needed as a further step after surgical drainage. What he suggested was that surgical drainage takes place in the epithelium. If there is epithelial damage and a breach in the barrier with ongoing subepithelial inflammation, the response of the tissue is to expel, drain, or wash away the insulting substance, inflammatory cells, and cytokines to decrease the inflammatory burden [5, 13].

Epithelial cells, including enterocytes, actively ferry luminal macromolecules across the barrier via vesicular transcytosis (Fig. 3C), a crucial transport route that is both TJ‐independent and size‐flexible. In response to epithelial damage and subsequent subepithelial inflammation, an adaptive tissue mechanism involving increased epithelial permeability may be triggered to facilitate the clearance or ‘washing away’ of noxious substances and inflammatory mediators into the lumen, potentially reducing the local inflammatory burden [5]. Studies investigating type 2 inflammation, relevant to conditions like asthma, have demonstrated that type 2 innate lymphoid cells (ILC2s), primarily through the action of interleukin‐13 (IL‐13), can directly induce bronchial barrier disruption by downregulating crucial TJ proteins, such as Occludin and ZO‐1 [13]. This leads to functionally compromised barrier integrity, evidenced by reduced TEER, increased paracellular flux, and the in vivo leakage of tissue proteins like α2‐macroglobulin and transferrin into the airway lumen [13]. Although this IL‐13‐driven leakiness is often implicated in asthma pathogenesis by potentially increasing allergen penetration and contributing to chronicity, the resulting outward flux of endogenous molecules physically aligns with the conceptual possibility of draining inflammatory components from the tissue across the compromised epithelial barrier [5, 13].

The pore pathway

The pore pathway refers to paracellular leaks of small ions and solutes through size‐ and charge‐selective channels in TJs (Fig. 3D). These channels are formed by claudin proteins; for example, claudin‐2 forms cation‐selective pores that increase conductance for small molecules. In inflammatory conditions, pore‐forming claudins can be upregulated, enhancing this pathway. A striking example is in UC, in which the Th2 cytokine IL‐13 is overproduced and drives a ~ 10‐fold increase in claudin‐2 expression, significantly reducing TEER [173]. This IL‐13‐induced pore‐type leak allows excess Na⁺ and water efflux into the gut lumen, contributing to diarrhea. Although this contributes to chronic leakiness, in principle, it functions to drain the inflammation in the deeper colon tissues and decreases the inflammatory burden [5]. Parallel changes are seen in UC patient biopsies (claudin‐2 up nearly 956% over normal) [173], underscoring the pore pathway's role in disease. Other epithelial barriers have analogous mechanisms—for instance, claudin shifts in airway or skin epithelium can alter ion permeability—but the pore pathway is most clearly implicated in intestinal disorders like UC. Importantly, pore‐size leaks predominantly allow small nutrient molecules or electrolytes to cross, so while they disturb fluid balance, larger antigenic molecules and microbes remain mostly restricted. Thus, pore pathway dysfunction often leads to symptoms like fluid loss (as in UC) without immediately provoking massive immune activation.

The leak pathway

The leak pathway involves a nonspecific loosening of TJs that permits larger molecules (up to tens of kDa) to permeate between cells. This can occur via cytokine‐driven junctional changes or direct injury to junction proteins. Pro‐inflammatory cytokines are a common cause: for example, TNF‐α and IFN‐γ synergistically disrupt intestinal TJs by activating myosin light‐chain kinase (MLCK), which pulls the peri‐junctional actin ring and opens the junctional seal [174]. In vitro, TNF on IFN‐γ–primed intestinal monolayers caused a steep drop in TEER and ‘unzipping’ of TJ strands—effects that were prevented by MLCK inhibition [174]. Notably, this form of barrier dysfunction does not require cell death; junctional proteins (occludin, ZO‐1, etc.) are redistributed or internalized, creating large pores between still‐viable cells [174]. Such cytokine‐induced leakiness is prominent in Crohn's disease, where elevated TNF levels lead to high paracellular permeability and allow antigens/bacterial products to cross the gut lining, correlating with systemic immune activation [174]. Environmental factors can also trigger the leak pathway. A classic example is the house dust mite allergen Der p1 in airways, a protease that cleaves epithelial TJ proteins. Der p1 rapidly cuts occludin (and claudin‐1) in bronchial epithelium, causing TJ breakdown and a surge in macromolecular permeability [175]. This enables allergens to traverse the airway barrier and access submucosal immune cells, facilitating allergic sensitization in asthma. Likewise, in AD skin, the Th2 cytokines IL‐4 and IL‐13 downregulate key TJ components, such as claudin‐1, weakening the junctional seal [176]. Skin models exposed to IL‐4/IL‐13 show reduced claudin‐1 and consequent barrier impairment, allowing ingress of environmental antigens and irritants. These leak‐pathway defects in AD are linked to flare‐ups, as more allergens and microbes penetrate the loose junctions to activate cutaneous immune responses. In summary, the leak pathway—detectable by increased flux of larger tracers (e.g., 4 kDa dextran)—is a common consequence of inflammation and toxins. It underlies conditions from IBD (where it can presage relapses) to asthma and eczema, by permitting abnormal antigen passage and immune triggering.

Tricellular junction disruption (macromolecule leak at three‐cell contacts)

At points where three epithelial cells meet (tricellular junctions), a specialized structure seals the tiny central gap. Tricellulin is a critical protein concentrating at tricellular contacts to prevent leakage. If tricellulin or associated proteins (e.g., angulin) are compromised, a distinct leak pathway opens preferentially for large solutes. In cell experiments, lowering tricellulin levels dramatically increases paracellular permeability to macromolecules while only mildly affecting small ion flow [177]. This is because the ‘central tube’ at tricellular contacts—normally too narrow to contribute to ion conductance—can widen enough to pass molecules > 4 kDa when not sealed by tricellulin [177]. In contrast, abundant tricellulin closes this route. Such a mechanism has been implicated in diseases like UC. Active UC mucosa exhibits significantly reduced tricellulin expression, which is reversible upon remission. A 2018 study found that IL‐13 signaling (via IL‐13Rα2) downregulates tricellulin in the intestinal epithelium, increasing the flux of macromolecular tracers across the barrier [178]. In UC patients, this tricellular leak may allow large antigens or bacterial products to permeate the gut lining, fueling mucosal immune responses. Interestingly, Crohn's disease (a Th1/Th17‐dominant IBD) did not show tricellulin loss in that study, highlighting that tricellular defects might be more relevant to Th2‐associated inflammation (as seen in UC's atypical Th2 profile). Although less studied in skin and airway, tricellular TJs exist in those tissues and could be targeted by similar mechanisms—for example, IL‐13 in allergic asthma or AD might hypothetically loosen tricellular contacts as well. Overall, tricellular junction disruption creates a pathway for large molecules (e.g., dietary antigens and pathogens' products) that are normally too big to cross. When this occurs in the gut or other organs, it can lead to heightened immune surveillance and inflammation due to the abnormal influx of luminal macromolecules.

Apoptotic or mechanical cell extrusion

Epithelial barriers undergo continuous cell turnover—old or damaged cells are extruded and replaced by neighbors. Apoptotic or mechanical cell extrusion can transiently disrupt the barrier if the expelling cell leaves behind a gap. In healthy epithelia, an intricate remodeling of TJs accompanies extrusion to preserve barrier integrity. Live imaging in mice has shown that when tumor necrosis factor induces extensive intestinal epithelial shedding, surviving neighbors mobilize their TJ proteins to form a ‘funnel’‐shaped structure beneath the extruding cell [179]. ZO‐1 and occludin relocate along lateral membranes, and together with actomyosin contraction, they seal the opening as the apoptotic cell exits [179]. Thanks to this dynamic TJ expansion, the gut can withstand a certain rate of cell loss without gross leakage. However, even in these adaptive events, there are momentary leaks—for instance, local conductance mapping reveals a spike in ion permeability directly under shedding cells [179]. If cell extrusion is excessive or dysregulated, the compensatory mechanisms fail. In inflammatory conditions like graft‐versus‐host disease or severe Crohn's flares, epithelial apoptosis is greatly increased, leading to multiple synchronous extrusions. Under such strain, small gaps (‘microerosions’) can remain unsealed, forming localized ‘unrestricted pathways’ for paracellular passage that permit paracellular leakage of solutes and even microbes (Fig. 3D). Experimentally, high‐dose TNF in mice caused rapid epithelial shedding that, despite active junctional remodeling, resulted in measurable drops in barrier function [179]. Likewise, mechanical stresses can induce extrusion‐based leaks: in asthma, for example, chronic coughing or allergen exposure can damage airway epithelial cells, causing them to slough off. The shed cells (seen as Creola bodies in sputum) reflect epithelial gaps that can let inhaled particles or pathogens penetrate more deeply. In summary, accelerated cell extrusion due to apoptosis or mechanical injury produces transient leak phenotypes. These are often patchy and short‐lived, but can cumulatively compromise the barrier if cell loss outpaces repair, thereby exposing underlying tissues to antigens.

Erosive barrier loss (full‐thickness breaches)

The most severe phenotype is erosive barrier loss, where regions of epithelium are denuded entirely, leaving the basement membrane or submucosa directly exposed. In this scenario, there is essentially no cellular barrier—a ‘leak’ in the form of an outright wound or ulcer. All epithelial organs can suffer erosions under extreme conditions. In the gut, erosive lesions are hallmark features of severe IBD. For instance, during a fulminant UC flare and in severe cases of Crohn's disease, widespread epithelial necrosis leads to ulceration of the colonic mucosa. These ulcerated areas permit unrestrained exchange of material: luminal bacteria and antigens flood into tissue, while fluids and proteins leak out. The result is often acute immune activation with intense inflammation (and systemically, fever and elevated C‐reactive protein). Even in Crohn's disease, microscopic erosions can precede visible ulcers—one study noted that increased intestinal permeability can precede clinical disease and predicts relapse [174]. Erosive loss of barrier is also seen in EoE and chronic reflux esophagitis, where chronic inflammation plus mechanical stress (e.g., swallowing food boluses against a stiff and inflamed esophagus) can strip away patches of the stratified epithelium. EoE patients often exhibit dilated intercellular spaces and weakened epithelial adhesion due to IL–13–mediated loss of structural proteins (filaggrin and desmoglein‐1). In a 2014 study, knockdown of DSG1 (desmoglein‐1) in esophageal epithelial cultures caused cells to separate and barrier function to drop, even when viability was maintained [180]. This suggests that in EoE, chronic Th2 inflammation can disrupt cohesion so that sheets of epithelium detach (erosion), manifesting endoscopically as friable ‘crepe‐paper’ mucosa. Skin barrier erosions are common in severe AD: repeated scratching and Staphylococcus infection can create open sores where the epidermis is breached. Bullous skin diseases, characterized by sloughing of the epidermal layer, are prototypical examples of erosive barrier loss. Pemphigus vulgaris is an autoimmune disease in which autoantibodies against desmoglein lead to disruption of desmosomes, formation of vesicles, and erosion of the epithelium [181]. These sites allow allergens and microbes to penetrate unabated, often leading to localized infection or even systemic effects (e.g., eczema herpeticum when viral entry occurs through broken skin). Notably, an erosive barrier loss creates an entry portal for organisms—bacterial translocation from gut to blood can occur through intestinal ulcers, and in chronic liver disease patients, leaky gut ulcers are a known source of sepsis. Clinically, sealing erosions (with medications or physical barriers) is crucial, as even small ulcers can perpetuate inflammation by providing a route for continuous antigen influx. Thus, erosive barrier defects represent an extreme leak pattern underlying the most acute and dangerous phases of barrier‐related diseases, from IBD with profuse bleeding to refractory EoE and infected eczematous dermatitis. In all cases, restoring epithelial coverage is necessary to re‐establish homeostasis.

Peri‐epithelial inflammatory pathways

Innate immune response

Epithelial barrier integrity is not only threatened by external toxic substances but is also compromised by underlying subepithelial inflammation [182]. Activated epithelial cells release cytokines, including alarmins like IL‐25, IL‐33, and TSLP, which are potent drivers and amplifiers of allergic inflammation [182]. Open TJs, while potentially serving to drain inflammatory mediators from below, simultaneously permit easier access of foreign substances into deeper tissue layers [182]. Both type 1 and type 2 inflammatory responses impact epithelial barriers. Type 1 inflammation can directly injure epithelial cells through apoptosis induction, while type 2 inflammation, mainly driven by T‐helper 2 (Th2) and innate lymphoid type 2 (ILC2) cells releasing IL‐4 and IL‐13, is known to disrupt bronchial, sinus, and skin epithelial barriers [8, 12, 13]. It is crucial to consider that exposure to different barrier‐disrupting substances might exert synergistic, rather than merely additive, effects due to shared toxicity mechanisms. Moreover, individuals with pre‐existing epithelial inflammation may be susceptible to barrier damage at lower concentrations of these substances.

A proposed cascade of events linked to the epithelial barrier hypothesis begins with barrier damage, often induced by environmental exposures [1]. This initial insult can lead to microbial dysbiosis, favoring opportunistic pathogens over commensals and facilitating the transepithelial translocation of these microbes and potentially commensals into the subepithelium [1, 183]. This translocation stimulates immune responses, leading to subepithelial or submucosal inflammation [1]. Persistent inflammation and immune responses against both pathogens and potential commensals can further drive dysbiosis and decrease microbial biodiversity [1, 184]. For instance, the association between Staphylococcus aureus colonization and anti‐S. aureus IgE with the severity of asthma, AD, and CRS appears more prominent now than decades ago [185, 186, 187, 188, 189]. This chronic inflammatory state promotes dysregulated tissue repair, remodeling (such as epithelial basement membrane thickening, potentially as a secondary barrier attempt), and fibrosis [1]. Systemic consequences may arise from the migration of inflammatory cells from leaky barrier sites or through sustained low‐level systemic inflammation and immune activation, potentially contributing to the development or exacerbation of various chronic diseases [1].

Acute epithelial injury launches a peri‐epithelial ‘Type 0’ circuit initiated by DAMPs. Necrotic or stressed epithelial cells release nuclear alarmins like IL‐33 and IL‐1α, as well as ATP and HMGB1, which activate sentinel immune cells (resident macrophages, dendritic cells, and mast cells) via pattern‐recognition receptors [190, 191]. These innate sensors assemble inflammasomes that activate caspase‐1, leading to pyroptotic cell death and release of IL‐1β and IL‐18 [191, 192]. The result is an early burst of IL‐1 family cytokines that recruit neutrophils and amplify inflammation. IL‐1β itself increases local endothelial and epithelial permeability, and epithelial pyroptosis creates physical gaps in the barrier [191]. Meanwhile, epithelial‐derived IL‐33 and TSLP directly alert group 2 innate lymphoid cells (ILC2s), mast cells, and basophils, skewing local immunity toward Type 2 responses [190]. This Type 0 circuit compromises barrier integrity through rapid TJ disruption and cell loss—a priming event that sets the stage for downstream adaptive immunity. Notably, in diseases like AD, mechanical epithelial damage (scratching) leads to repetitive DAMP release (IL‐33 and TSLP), fueling an innate cycle of barrier destruction and inflammation [190].

Type 1 inflammation and epithelial barriers

Following an initial DAMP‐driven phase, an immune response can polarize toward a Type 1 circuit if antigen‐presenting cells provide IL‐12 and IFN‐α/β signals. Type 1 peri‐epithelial inflammation is classically triggered by intracellular pathogens (viruses and certain bacteria) and characterized by IFN‐γ and TNF‐α production from Th1 cells, ILC1s, and NK cells. IFN‐γ‐activated dendritic cells and macrophages amplify this circuit by secreting IL‐12 and IL‐18, creating a positive feedback that sustains IFN‐γ release [193]. These Type 1 cytokines act on epithelial barriers to potentiate leakiness: IFN‐γ signaling in epithelial cells induces endocytosis of TJ proteins (occludin, claudin, and JAM‐A), leading to increased paracellular permeability [194]. In parallel, TNF‐α released by activated macrophages and Th1 cells triggers epithelial cell apoptosis and initiates a ‘leak’ pathway in TJs [139]. Indeed, TNF‐α not only induces programmed cell death in barrier epithelial cells, but also opens paracellular junctional channels via cytoskeletal contraction [139]. The combined assault of IFN‐γ and TNF causes focal epithelial loss and loosened TJs, as seen in Crohn's disease, in which Th1 cytokines drive mucosal ulceration. Cell death mechanisms like apoptosis and pyroptosis are prominent: IFN‐γ and TNF synergistically activate caspases and inflammasomes in the epithelium, causing shed cells and exposing the lamina propria [139, 195]. A downstream loop is established as a barrier breach that allows microbial products to penetrate, stimulating more IL‐1β and IL‐12 release from sentinel cells and perpetuating chronic Type 1 inflammation. For example, in IBD of the Crohn's type, granulomas rich in IFN‐γ and IL‐12 form alongside deep epithelial fissures, and blockade of TNF‐α can rescue TJ integrity [139]. Thus, Type 1 circuits compromise barriers via cytokine‐driven junctional disassembly and cell death, linking infections and autoimmunity to epithelial dysfunction.

Type 2 inflammation and epithelial barriers

In contrast, Type 2 peri‐epithelial circuits are launched by epithelial encounters with allergens, parasites, and environmental irritants. Damaged or exposed barrier cells release alarmins (IL‐33, IL‐25, and TSLP) that activate local dendritic cells, mast cells, and ILC2s, skewing the response toward a Th2 phenotype [190]. These sentinel cells produce IL‐4, IL‐5, IL‐13, and other Type 2 cytokines, which orchestrate eosinophilic inflammation and mucus hypersecretion. Crucially, IL‐4 and IL‐13 from Th2 cells and ILC2s directly impair epithelial TJs and differentiation. IL‐4/IL‐13 signaling in keratinocytes and mucosal epithelium downregulates key barrier proteins like filaggrin, loricrin, claudins, and E‐cadherin [190]. In the airway and sinus epithelium, IL‐4/IL‐13 reduce transepithelial resistance and junctional adhesion molecules, effectively opening paracellular ‘pore‐pathways’ that increase permeability [139, 190]. Likewise in skin, IL‐4/IL‐13 suppress filaggrin and lipid production, raising pH and permitting Staphylococcus aureus colonization [190]. Recruited eosinophils further damage the barrier by releasing cytotoxic granule proteins (major basic protein and eosinophil peroxidase) and proteases. These eosinophil mediators directly disrupt TJ function and stratum corneum integrity, creating microscopic breaches [190]. The result is a self‐amplifying loop: barrier defects allow deeper allergen and microbe penetration, which sustains epithelial alarmin release and chronic Type 2 inflammation [139, 190]. This circuit underlies diseases like asthma, AD, and EoE. In asthma, epithelial exposure to allergens (dust mite proteases and pollen) induces IL‐33/TSLP, driving ILC2‐mediated IL‐13 production that increases airway epithelial permeability and goblet cell metaplasia [190]. In AD, an IL‐4/IL‐13‐rich milieu causes epidermal junctional weakening and loss of the moisture barrier, while IL‐31 from Th2 cells provokes itching that leads to further barrier trauma (the itch‐scratch cycle) [190]. In EoE, Th2 cytokines (notably IL‐13) induce an esophageal epitheliopathy: IL‐13 downregulates desmoglein‐1 in the esophageal epithelium, loosening cell–cell adhesion and contributing to epithelial barrier leak [196]. Thus, Type 2 circuits center on a cytokine‐driven barrier defect—via junctional dilatation, impaired differentiation, and cell loss—that is characteristic of allergic diseases.

Type 17 inflammation and epithelial barriers

A third peri‐epithelial circuit, Type 17, emerges in response to extracellular bacteria and fungi breaching barrier defenses. This circuit is mediated by IL‐17‐producing cells (Th17 CD4⁺ T cells, γδ T cells, and ILC3s) activated under the influence of IL‐23, IL‐1β and IL‐6 from antigen‐presenting cells [193]. Signature cytokines IL‐17A, IL‐17F, IL‐22, and GM‐CSF define the Type 17 milieu [193]. IL‐17 profoundly reshapes the epithelial microenvironment: it induces chemokines (CXCL1 and CXCL8/IL‐8) and G‐CSF from epithelial and stromal cells, driving massive neutrophil recruitment to the barrier [193]. Neutrophils in turn release ROS and proteases (elastase, cathepsin G, and MMPs) that cause collateral tissue damage—cleaving extracellular matrix and junctional proteins and even activating more inflammatory cytokines (pro‐TNF and pro‐IL‐36) in the tissue [191]. Indeed, neutrophil‐derived IL‐1β and IL‐36α act on local cells to amplify Th17 responses, creating a feed‐forward loop [191]. Barrier integrity is compromised as IL‐17 and associated cytokines alter epithelial biology: IL‐17 and IL‐1β together downregulate epithelial adhesion molecules and TJ components, leading to junctional disorganization [191]. For example, in psoriatic skin, IL‐17 and IL‐1 signals together reduce the expression of claudins and E‐cadherin, and TJ dysregulation is detectable even in early lesions [191]. IL‐22 from Th17/Th22 cells further contributes by inducing keratinocyte hyperproliferation while inhibiting their differentiation, resulting in a thick but functionally leaky epithelium [197]. At mucosal sites, IL‐17 can paradoxically strengthen acute defenses (promoting mucus and antimicrobial peptides), but in chronic Type 17 inflammation, these protective effects are offset by excessive neutrophil‐driven damage and impaired barrier repair [193]. In the intestine, for instance, persistent IL‐23/Th17 activation disrupts the epithelial TJ seal and goblet cell function, allowing microbial translocation that perpetuates colitis [193]. This is evident in Crohn's disease and some cases of UC, where IL‐17/IL‐22 and TNF form an inflammatory axis causing deep crypt damage and erosions. In psoriasis, a prototypical Type 17 disease, IL‐17 and IL‐22 lead to epidermal hyperplasia and neutrophil microabscess formation, with measurable loss of barrier function (increased transepidermal water loss and penetrance of antigens) [191]. Thus, the Type 17 circuit compromises epithelial barriers through cytokine‐mediated junctional disruption and neutrophil‐induced tissue injury, tying mucocutaneous infection control to autoimmune pathology.

Notably, these peri‐epithelial inflammatory circuits interconnect, and chronic barrier diseases often involve multiple overlapping types [1, 139]. An initial Type 0 DAMP response can bias the immune milieu toward Type 1, 2, or 17 depending on context—for example, epithelial IL‐33 release (Type 0) favors a Type 2 cascade, whereas IL‐1β release favors neutrophils and Th17 differentiation [190, 191]. Once established, each circuit creates a pro‐inflammatory microenvironment that can recruit elements of the others. In AD, a primarily Type 2 disorder, barrier disruption and microbial dysbiosis (e.g., S. aureus colonization) can provide PAMP signals that induce local IL‐1β and IL‐17, layering a Type 17 component onto chronic eczema [190, 191]. Conversely, in psoriasis or Crohn's disease (Type 17/Type 1 conditions), periods of tissue damage can release IL‐33 and TSLP, acutely activating Type 2‐like wound‐healing responses that coexist with the Th17/Tc17 milieu. Thus, real‐world inflammatory lesions are a mosaic: Type 1 and Type 2 circuits often coactivate (both IFN‐γ and IL‐13 are elevated in inflamed atopic skin and gut) [139, 173], and Type 17 may emerge when Type 1 or 2 responses fail to clear pathogens (as in steroid‐resistant neutrophilic asthma). These interactions create vicious cycles in the peri‐epithelial niche. Barrier breach leads to microbe ingress and antigen exposure, which triggers further immune activation and cytokine release, in turn causing more barrier damage [139]. A persistent loop of ‘injury–inflammation–injury’ develops, with each circuit's mediators aggravating the others. For instance, IL‐4/IL‐13 can recruit neutrophils via IL‐8 from epithelial cells, IL‐17 can stimulate macrophages to produce IL‐1β and TNF, and IFN‐γ can induce epithelial cells to secrete the alarmin IL‐33 under stress. Without counter‐regulation, these feedback loops lock the system in a state of chronic inflammation and defective barrier repair [139]. In summary, while Type 0, 1, 2, and 17 responses are described separately, in chronic disease, they form an integrated network of cytokine loops that continually erode epithelial integrity.

Acute and chronic epithelitis in the initiation and maintenance of chronic peri‐epithelial inflammation

The concept of ‘chronic epithelitis’, characterized by sustained pro‐inflammatory cytokine release and barrier damage, emerges from exposure to compounds like food emulsifiers and detergents. Environmental toxic insults to epithelium can induce significant expression of alarmins, IL‐33 and TSLP, together with inflammasome activation, expression of pro‐inflammatory cytokines and multiple chemokines, and eosinophilic inflammation in tissues like the airways, gut, and esophagus, and skin [16, 20, 21, 57, 86, 198, 199]. Mouse studies demonstrated that even brief intranasal exposure to common detergents or surfactants induced eosinophilic airway inflammation involving IL‐33 and ILC2 activation, an effect mitigated in mice lacking adaptive lymphocytes and ILCs or IL‐33 [86]. Similarly, low‐dose SDS exposure in models relevant to EoE decreased esophageal barrier integrity, increased IL‐33, and promoted esophageal eosinophilia and inflammation [57], suggesting detergents in products like toothpaste could be triggers.

Genetic and epigenetic changes linked to epithelial barriers

Individual susceptibility is significantly modulated by genetic factors. Mutations in genes encoding crucial epithelial barrier proteins are linked to asthma, AD, and food allergies [200, 201, 202, 203]. For instance, rare variants impairing desmosome structures (desmoplakin and periplakin) contribute to EoE [204], mutations in AP1S1 cause congenital diarrhea via intestinal barrier defects [205], and mutations in CLDN10B affect sweat gland barriers [206]. Congenital tufting enteropathy, typically resulting from mutations in the EPCAM gene encoding an epithelial cell adhesion molecule, involves disrupted enterocyte adhesion and differentiation, leading to pathognomonic ‘tufts’, a profoundly compromised intestinal barrier and severe, intractable lifelong diarrhea [207]. Polymorphisms in genes for alarmins (TSLP and IL‐33) and type 2 cytokines (IL‐4 and IL‐13) influence asthma risk and severity [202], although many genetic contributors remain unidentified [208]. Filaggrin deficiency, known in AD, may also promote Th2 inflammation in airways by affecting E‐cadherin expression and enhancing IL‐33/TSLP release, potentially contributing to asthma [209].

Epigenetic modifications add another layer of regulation. Studies show altered histone acetylation/deacetylation patterns in asthmatic bronchial epithelial cells, with increased levels of HDACs 1 and 9, and SIRTs 6 and 7 [12, 210]. IL‐4 and IL‐13 can drive these changes, and inhibiting HDACs can improve barrier integrity in asthmatic cells by restoring TJ molecule synthesis [12]. Altered DNA methylation patterns affecting pro‐inflammatory and regulatory cytokine gene expression have also been observed [210]. These epigenetic changes can impact the healing capacity of epithelial stem cells and contribute to the chronicity of barrier defects and associated inflammation [12, 210]. Epigenetic and metabolic reprogramming in epithelial and immune cells locks in disease‐driving pathways—evident in enduring psoriasis and IBD lesions, where an entrenched inflammatory ‘memory’ resists healing [211, 212].

Role of the microbiome

Microbial dysbiosis is a central element of the epithelial barrier theory. Barrier damage facilitates colonization by opportunistic pathogens like S. aureus in AD [213], or facultative pathogens like Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in respiratory conditions [15, 214, 215], loss of beneficial commensals, and subsequent bacterial translocation [1, 56]. This translocation is implicated in driving autoimmune and chronic inflammatory conditions [216, 217, 218, 219, 220, 221, 222, 223, 224]. The altered host‐microbiota interactions lead to abnormal mucosal immune responses, potentially skewing toward Th17, Th1, or Th2 responses, downregulating regulatory T cells, and dysregulating humoral immunity [184, 225]. Persistent exposure to harmful factors might also impair epithelial cell metabolism and regenerative capacity [226].

The immune system's interaction with microbes is complex. Normally, host defenses prevent opportunistic infections. However, in chronic inflammatory settings, bacteria can manipulate immune responses, sometimes evading detection (e.g., by inactivating Toll‐like receptors) [227, 228]. S. aureus, for example, employs numerous strategies to evade neutrophil defenses, including inhibiting chemotaxis, resisting phagocytosis, killing neutrophils, and neutralizing antimicrobial peptides and proteases using factors like Eap proteins [229, 230].

Diet significantly influences the interplay between the epithelium and the immune system and the microbiome. Fiber deprivation in mice led to an increase in Akkermansia muciniphila, which, in the absence of fiber, exacerbated food allergy symptoms, possibly through anti‐commensal IgE and innate type 2 responses [231]. Commensal protozoa like Trichomonas musculis can stimulate tuft cells via succinate to release IL‐25, activating ILC2s to produce IL‐13, thereby altering Paneth cell function and microbial composition [232]. Specific microbial strains can also drive pathology; high virulence Candida albicans strains that dominate the gut in IBD patients aggravate inflammation via IL‐1β, potentially involving toxins like candidalysin.

Barrier dysfunction directly impacts microbial niches. In AD‐like skin, structural and metabolic changes facilitate the overgrowth of the commensal fungus Malassezia [231, 233]. There are also systemic consequences mediated through gut‐axis communication. Intestinal Candida dysbiosis in mice enhanced Th2 responses to airway allergens (HDM), associated with increased lung ILC2s, demonstrating a gut–lung connection [234]. Conversely, skin damage can alter gut microbial composition and function, potentially exacerbating intestinal inflammation via a skin–gut axis [235]. Pathogens can also actively remodel their niche; Pseudomonas aeruginosa uses its toxin LasB to induce epithelial amphiregulin and type 2 inflammation, promoting mucin production, which serves as its energy source, thereby facilitating colonization and allergic sensitization [236].

Loss of microbial diversity is a common feature of dysbiosis linked to Western lifestyles and numerous diseases, including dermatological conditions [237, 238, 239]. Host factors are crucial for maintaining diversity; for example, neutrophil recruitment via CXCR2 is essential for controlling the periodontal microbiome and preventing inflammatory bone loss [240]. Similarly, epithelial TLR4 signaling helps maintain gut homeostasis during pancreatitis, possibly involving interactions with beneficial bacteria like Lactobacillus reuteri [241]. Therapeutic modulation is also possible; a protease inhibitor from Trichinella spiralis (rTsSPI) showed potential to reduce gut inflammation, shift macrophage polarization, increase IL‐10, and enhance gut microbial diversity in mice [242].

Persistent epithelial barrier defects and the resulting chronic inflammation drive tissue‐specific pathology [1]. In EoE, overexpression of IL‐33 alone can induce EoE‐like inflammation and remodeling, likely via the IL‐13 pathway [243]. As mentioned, common household detergents and dishwashing agents disrupt airway, skin, and esophageal barriers, inducing inflammatory responses and cell death pathways [16, 20, 22, 57]. Air pollutants contribute by activating type 2 pathways, promoting epithelial cytokine release (IL‐33 and TSLP), oxidative stress, and pro‐inflammatory mediators (IL‐6, IL‐8, and IL‐1β) relevant to asthma [244]. In CRS with nasal polyps, type 2 cytokines orchestrate inflammation, immune cell recruitment, tissue remodeling, and chronic barrier dysfunction [245]. Aeroallergen exposure can trigger ATP/ADP release, activating purinergic receptors (like P2Y1) on epithelial cells to induce IL‐33 and HMGB1 release, contributing to asthma pathogenesis [246]. This highlights a recurring theme: barrier disruption, often environmentally triggered, leads to alarmin/cytokine release, driving inflammation and disease‐specific pathology. The ongoing interplay between barrier leakiness and peri‐epithelial inflammation creates a vicious cycle that perpetuates tissue damage and dysfunction [1].

Measuring epithelial barrier status

Accurate evaluation of epithelial barrier function now spans quantitative biophysics, functional permeability testing, and molecular readouts (Table 4, Fig. 4). In vitro and ex vivo, TEER remains the reference standard: a high‐throughput, nondestructive readout of TJ integrity that is easily integrated into organ‐on‐chip platforms. The usage of primary cells obtained from tissues of affected individuals and induced pluripotent stem cells has brought a new perspective to the area. A sustained fall in TEER is usually paralleled by increased paracellular tracer flux, and both parameters tightly correlate with morphological junctional disruption across gut, airway, renal, and blood–brain barrier models [247]. In patients, the functional leak is best captured by differential sugar absorption, the lactulose–mannitol ratio. Meta‐analysis of over 30 studies confirmed that this simple 5‐h urine test discriminates healthy subjects from active coeliac or Crohn's disease with large effect sizes, supporting its value as a bedside surrogate of intestinal ‘leakiness’ [248].

Table 4.

Assays for quantifying epithelial barrier integrity. BAL, bronchoalveolar lavage; CLE, confocal laser endomicroscopy; EIS, electrical impedance spectroscopy; OoC, organonchip; TJ, tight junction.

Modality	Principle	Prep/scale	Readout (units)	Applications a	References
TEER	Ion conductance across TJs	Monolayers, OoCs	Ω·cm2 (real time)	S, T	[247]
Tracer flux (FITCdextran, 51CrEDTA)	Fickian diffusion through paracellular pores	Monolayers, excised mucosa	μg·cm−2·h−1	S, Q
Sugar test (Lactulose/Mannitol)	Differential trans vs. paracellular uptake	Human intestine in vivo	L : M ratio	D, M	[248]
CLE	Real‐time fluorescein leakage imaging	GI mucosa	Pixel leak index	D	[249]
EIS	Complex impedance of stratum corneum or mucosa	Skin probe, esophageal catheter	(kΩ)	D, T	[250]
Baseline mucosal impedance	Baseline ion permeability	Esophageal lumen	Ω profile	D	[253]
Biomarkers	Shedding or alarmin release	Serum, stool, BAL	ng·mL−1	P, E	[1, 22]

^a Key codes—S: safety/toxicology screening; T: tight‐junction gene manipulation studies; Q: quantitative permeability kinetics; D: diagnostic use in humans; M: therapy monitoring; P: population biomarker; E: endpoint in interventional trials.

Fig. 4.

Representative assays for quantifying epithelial barrier integrity and their underlying mechanisms: transepithelial electrical resistance (TEER) measurements in Transwell cultures or organs‐on‐chips determine ionic conductance across tight junctions by applying a low‐amplitude alternating current; mucosal and skin bioelectrical impedance spectroscopy injects frequency‐swept currents through the epithelium and subepithelium to record complex impedance changes; confocal laser endomicroscopy, together with dual‐sugar or polyethylene glycol (PEG) oligomer permeability tests, monitors paracellular passage of fluorescent or labeled macromolecules to detect junctional disruption.

Imaging and biomarker technologies add spatial and mechanistic resolution. Confocal laser endomicroscopy (CLE) allows real‐time, in vivo visualization of fluorescein leakage through epithelial gaps; in a prospective study, it identified barrier dysfunction in 96% of adults with proven food allergy and outperformed routine histology for diagnostic sensitivity [249]. Complementary immunostaining or electron microscopy of biopsies localizes loss or misdistribution of ZO1, occludin, or claudins and is routinely used to validate TEER/permeability findings, while circulating or luminal biomarkers, such as zonulin, IFABP, IL33, and TSLP reflect epithelial stress or loss and increasingly guide clinical trials that aim to restore barrier integrity.

Electrical impedance–based approaches are now translating these concepts directly to the clinic. On the skin, portable electrical impedance spectroscopy (EIS) probes quantify frequency‐dependent impedance [250, 251]; a 2024 controlled study showed EIS detects subclinical barrier impairment in AD and is less affected by ambient factors than transepidermal water loss, positioning it for therapy monitoring in dermatology clinics [252]. Within the esophagus, catheter or endoscope‐mounted mucosal impedance sensors provide an instantaneous readout of ionic permeability: baseline values fall two to three‐fold in reflux disease and EoE, predict response to proton pump inhibitors, and help differentiate functional heartburn from nonerosive reflux when pHmetry is equivocal [253]. Together, TEER/tracer assays, CLE‐guided imaging, molecular biomarkers, and emerging EIS‐based tools form a complementary toolkit that can interrogate epithelial barrier status across organs, from bench to bedside.

Challenges and future directions

The epithelial barrier theory offers a valuable framework to understand and explain the rapid increase in the prevalence of chronic NCDs during the last six decades. Research in this area has been focused on the potential role of environmental factors interacting with host susceptibility, immune response, and the microbiome. However, establishing definitive causality and understanding the precise contribution of barrier dysfunction across the diverse spectrum of NCDs remain challenging. Rigorous research is needed to move beyond association and demonstrate causation in humans, particularly through longitudinal studies. Accurately assessing real‐world human exposure levels to potentially harmful substances (like detergents, emulsifiers, micro‐nanoplastics, and pollutants) and defining clear dose–response relationships are critical.

Furthermore, NCDs are inherently multifactorial; epithelial barrier dysfunction and microbiome changes must be considered alongside genetics, broader dietary patterns, lifestyle, and socioeconomic factors, stress, physical activity levels, and other environmental influences. Future research should focus on developing reliable biomarkers for epithelial barrier integrity, microbiome changes, immune system activation, and relevant environmental exposures, refining experimental models to better reflect human physiology and exposure scenarios, and exploring the complex feedback loops between the three main pillars: the epithelial barrier, the microbiome, and the immune system. Intervention studies targeting barrier protection or restoration (through lifestyle changes, specific dietary components, or novel therapeutics) and microbiome modulation are warranted.

In conclusion, there is substantial evidence from epidemiological, clinical, and experimental studies suggesting that compromised epithelial barriers are associated with a wide range of chronic inflammatory diseases. Substances common in modern environments appear capable of damaging these barriers, potentially initiating or exacerbating pathological processes involving microbial dysbiosis, immune dysregulation, and chronic inflammation. While the hypothesis requires further validation and refinement, particularly regarding direct causality and the relative importance of barrier dysfunction across different NCDs, it highlights the critical role of epithelial integrity in health maintenance. This perspective encourages greater scrutiny of the chemicals used in daily life, may stimulate the development of safer alternatives, and supports investigation of preventive and therapeutic strategies focused on preserving or restoring epithelial barrier function through lifestyle, diet, and potentially microbiome‐targeted interventions.

Conflict of interest

R.D. is a cofounder and CEO of Seed Health. K.C.N. reports grants from the National Institute of Allergy and Infectious Diseases (NIAID), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Environmental Health Sciences (NIEHS), the Immune Tolerance Network (ITN), and the National Institutes of Health (NIH) clinical research centers during the course of the study; in addition, other grants were received from IgGenix, Seed Health, ClostraBio, Cour, Alladapt, Excellergy, Red Tree Ventures, Regeneron, and Latitude outside the submitted work. In addition, K.C.N. has the following patents: ‘Mixed allergen composition and methods for using the same’, ‘Granulocyte‐based methods for detecting and monitoring immune system disorders’, and ‘Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders’. M.A. has received research grants from the Swiss National Science Foundation, Bern; research grants from Stanford University; Leading House for the Latin American Region; and Seed Money Grants. She is a Scientific Advisory Board member of Stanford University Sean Parker Asthma Allergy Center, CA; an Advisory Board member of the LEO Foundation Skin Immunology Research Center, Copenhagen; and a Scientific Co‐Chair of the World Allergy Congress (WAC) Istanbul, 2022, Scientific Programme Committee Chair, EAACI. 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, California), 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. He 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. C.Z., H.B., I.O., S.A., Y.P., D.Y., B.Z., L.C., X.L., P.D., M.L., C.B., F.H.K.B., and M.‐C.B. declare no relevant conflicts of interest.

Author contributions

C.Z., H.B., I.O., S.A., Y.P., D.Y., B.Z., L.C., X.L., P.D., M.L., C.B., F.H.K.B., R.D., K.C.N., M.‐C.B., M.A., and C.A.A. contributed to the conception, structure, development, writing, and review of this manuscript.