The epithelial barriers of the skin, gastrointestinal system, and respiratory tract exhibit both similarities and differences in terms of structure, function, and biochemical properties. For instance, the skin provides a robust physical barrier, while the epithelial ciliary movement in the airways continuously clears particulate matter, facilitating gas exchange. In the gastrointestinal system, the epithelium facilitates a broad range of nutrient and water exchange while concurrently offering protection against microbes, toxins, and environmental exposures (15). Consequently, epithelial tissues serve multifaceted roles encompassing physical, chemical, and immune barrier functions. Notably, the epithelial cells at each site collaboratively form a cohesive epithelial barrier through cellular connections ( Figure 1 ). These connections are established by tight junctions (TJs), adherens junctions (AJs), and desmosome (16). AJs consist of diverse components such as E-cadherin, actinin, vinculin, α-catenin, and β-catenin, while TJs form a complex involving claudins, occludins, and junctional adhesion molecules (17). TJs create a barrier by sealing the apical boundary, preventing the unhindered entry of microorganisms, toxins, and pollutants, and regulating the paracellular transport of ions and certain small molecules (18). AJs play a crucial role in initiating and maintaining intercellular adhesion, contributing to the establishment and regulation of the apicobasolateral membrane structure (18). Desmosomes, characterized by a symmetrical structure comprising two adjacent plasma membranes separated by a 30-nanometer cellular gap, possess a central dense layer or midline flanked by mirrored triple-electron dense plaques (19). Desmosomes play a pivotal role in establishing and maintaining stable cell junctions.

Disruption of the epithelial barrier emerges as a common pathway contributing to the initiation and exacerbation of allergic diseases (20, 21). Research has unequivocally established the involvement of the epithelial barrier in the pathological progression of allergic diseases (5). Dysfunction in the epithelial barrier across various human tissues is characterized by cell differentiation, compromised junction integrity, and impaired innate defenses. Genetic predisposition, environmental influences, and aberrant inflammation collectively promote the dysfunction and breakdown of the epithelial barrier, thereby precipitating the onset and progression of allergic diseases (22). Studies indicate that compromised epithelial barriers activate epithelial cells, leading to the release of alarm factors such as interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP). This, in turn, promotes cytokine release by type 2 innate immune cells, triggering and exacerbating type 2 immune responses (23, 24). Epithelial cells play a pivotal role in the initiation and exacerbation of allergic diseases. Key cytokines, including IL-4, IL-13, IL-5, IL-9, TSLP, and IL-33, feature prominently in allergic diseases, as they stimulate the development of inflammatory responses and tissue repair (25–27). However, inflammatory cytokines such as IL-4, IL-3, IFN-γ, and TNF-α have been demonstrated to disrupt epithelial barrier function through various mechanisms. In primary bronchial epithelial cells (PBEC) cultured at the gas-liquid interface, IFN-γ and TNF-α collaboratively impair barrier function, leading to decreased expression of ZO-1 and JAM (28). IL-4 and IL-13 induce epithelial barrier dysfunction by inhibiting the expression of ZO-1, occludin, E-cadherin, and β-catenin ( Figure 2 ) (29).

Asthma, characterized as a chronic inflammatory disease of the airways, heavily relies on the integrity of respiratory epithelial cells, which collectively establish a physical, functional, and immune barrier. This barrier is crucial in safeguarding the host from potential hazards associated with inhaled environmental risk factors, thereby maintaining the overall health of the host. Prolonged exposure to external stimuli, however, can lead to the manifestation of epithelial barrier dysfunction within the asthma phenotype (30). The human airway epithelium is composed of predominant ciliated epithelial cells, mucous-secreting goblet cells, club cells, and airway basal cells (6). In a healthy airway, TJs and AJs establish connections between epithelial cells, forming a closed barrier that effectively prevents the invasion of risk factors. This cell barrier is naturally coated with mucus containing antimicrobial agents, peptides, and antibodies, serving as a protective measure against the intrusion of pathogenic bacteria and allergens (17, 31). However, patients with asthma often exhibit airway epithelial barrier disorders characterized by an increase in basal and goblet cells and a decrease in terminally differentiated ciliated cell (32), This is frequently accompanied by basement membrane thickening and epithelial exfoliation, resulting in the formation of Creola bodies composed of exfoliated epithelial clusters (4). Research indicates that during the course of asthma pathology, the number of MUC5B decreases, while the expression of MUC5AC increases, leading to mucus overproduction, airway obstruction, and the accumulation of mucus materials, ultimately inducing chronic inflammation (33). In addition, studies highlight the disruption of tight junctions and adherent junctions in the epithelial barrier as typical features of asthma. Similarly, deficiencies and dysfunction of E-cadherin, α-catenin, ZO-1, and occludin have been identified in patients with asthma (34), resulting in impaired barrier function. Moreover, a damaged airway epithelial barrier activates cytokines (IL-4, IL-5, and IL-13) released by ILC2s, further exacerbating the damage to the epithelial barrier (20, 35). Beyond the damage to epithelial barrier function caused by inflammation in asthma, several recent studies indicate the potential existence of barrier function abnormalities in airway epithelial cells in asthma patients (36). Further in-depth research is still needed to elucidate the mechanism of action of the epithelial barrier during asthma pathogenesis.

In summary, sustained exposure to risk factors such as allergens, pathogenic bacteria, and viruses, coupled with immune inflammatory responses, can lead to severe damage to epithelial barrier components. This damage results in the disruption of epithelial barrier function and structure, ultimately increasing barrier permeability and contributing to the onset and exacerbation of asthma.

AR, characterized as an inflammatory condition affecting the nasal mucosa and mediated by allergens, exhibits an escalating incidence, particularly in industrialized and modernized regions, influenced by diverse factors. Recent investigations have brought attention to the role of nasal mucosal epithelium in the pathogenesis of AR (6). The nasal epithelium, acting as the primary interface for allergens, pollutants, and pathogens, anatomically comprises two segments: the initial third of the nasal cavity features stratified squamous epithelium, while the remaining two-thirds possess a pseudostratified columnar ciliary epithelium with goblet cells covering the basement membrane (17). In a healthy state, coordinated ciliary movement and mucus secretion constitute the primary defense mechanism, preventing compromise of the nasal mucosal barrier by various risk or irritant factors. However, in the pathological context of allergic rhinitis, the central role played by the dysfunction and disruption of TJs becomes evident, compromising the integrity of the nasal epithelial barrier and subsequently hindering ciliary motility and mucus secretion (37, 38). Under normal conditions, nasal epithelial cells are bound together by TJs, forming a complex known as an occlusion zone (ZO), inclusive of claudin, occludin, and junction adhesion molecules (37). Notably, studies have revealed diminished expression and immunoreactivity of E-cadherin and ZO-1 in the nasal epithelium of individuals with allergic rhinitis (39). Furthermore, Protease-activated receptor-2 (PAR-2) has been implicated in diminishing the expression of ZO-1 and claudin-1, with the latter involved in epithelial barrier dysfunction in AR (40). Subsequent in vitro assessments of barrier function using primary epithelial cells from AR patients demonstrated diminished barrier function and reduced expression of tight junction proteins occludin and ZO-1 in comparison to healthy controls (41). Additionally, type 2 cytokines (IL-4, IL-5, IL-13, TNF-α, etc.) produced during immune-inflammatory responses can directly impact the nasal epithelial barrier, resulting in decreased expression of ZO-1 and E-cadherin (28, 39). Furthermore, proteases from certain allergens have been demonstrated to disrupt epithelial TJs and induce AR disease (4).

In summary, current studies suggest a pervasive disruption of epithelial barrier function and increased permeability in AR patients. This accelerates the penetration of allergens through the nasal epithelial barrier, contributing to the onset and development of AR. Multiple pathways in the pathogenic process of AR lead to damage to the epithelial barrier, necessitating further in-depth research to comprehensively understand the underlying mechanisms.

AD stands as the most prevalent chronic inflammatory skin disease influenced by a combination of genetic and environmental factors (42, 43). Current insights into AD pathogenesis encompass skin barrier dysfunction, epigenetic alterations, immune factors, skin, and intestinal dysbiosis, alongside interactions with external risk factors (2, 44, 45). The pathology of AD is distinguished by a disruption of skin barrier function. The human epidermis comprises the stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC) (43). The SC, situated as the outermost layer above keratinocytes and Langerhans cells (LC), plays a pivotal role in skin barrier function (46). Studies reveal that the SC consists of proteins such as filaggrin, involucrin, loricin, and an outer lipid layer. Particularly, filaggrin, encoded by the FLG gene, serves as the primary source of natural moisturizing factor (NMF) in SC (47). Mutations in FLG can significantly reduce NMF in AD patients, closely correlating with disease severity and emphasizing NMF reduction as a common feature in AD (47, 48). Currently, FLG gene mutations resulting in epithelial dysfunction stand as the most prevalent and severe genetic risk factor for AD (49). Notably, epithelial injury can trigger innate immune responses, activating the release of pro-inflammatory cytokines and chemokines by keratinocytes, and enhancing antigen presentation by Langerhans cells and dermal dendritic cells. Even in subjects with FLG null-mutation, type 2 immune inflammation can lead to decreased FLG expression in AD-afflicted skin (50–52). Additionally, FLG mutations elevate skin pH and activate skin proteases, inducing skin barrier dysfunction (53). Additionally, FLG mutations elevate skin pH and activate skin proteases, inducing skin barrier dysfunction (54). Jungersted et al. have indicated that the pathogenesis of AD extends beyond FLG mutations (55). During epidermal differentiation, keratinocytes sequentially alter gene expression programs, culminating in terminal differentiation and the formation of a mature corneal layer. In AD-afflicted skin, the loss of corneodesmosin disrupts barrier lipids, impairing skin barrier and antimicrobial function (56). Furthermore, AD alters other proteins in the corneal layer, including corneal adhesion, loricrin (LOR), and involucrin (IVL), resulting in compromised skin barrier function and type 2 immune response (56–59). Additionally, lipids such as ceramides are reduced, and the release of inflammatory cytokines during allergic reactions can further decrease the lipid content of SC, exacerbating barrier dysfunction in AD patients (60–62). Various environmental factors contribute to the disruption of skin barrier function, including detergents, microplastics, particulate matter (PM), etc., confirmed to alter the integrity of the skin barrier (51). Specifically, SC tight junctions can be disrupted by anionic surfactants in commercial detergents, while other components can release inflammatory cytokines that aggravate impairment of barrier function (1, 63). Furthermore, dysregulation of the skin microbiome exacerbates damage to the skin’s barrier function (51, 64, 65). Analyses of bacterial communities in AD states reveal that Staphylococcus aureus colonization contributes to the pathogenesis and aggravation of AD, with intestinal microbiota dysbiosis also considered a significant factor in AD pathogenesis (1, 66). According to existing research, AD can progress from skin diseases to food allergies, allergic rhinitis, and later asthma, a phenomenon commonly referred to as the atopic march (43, 67, 68).

In summary, the skin structure is compromised by a range of environmental and genetic factors, including FLG mutations, skin microbiota colonization, intestinal microbial dysbiosis, and environmental pollution hazards. Skin barrier dysfunction allows exposure to allergens, bacteria, and fungi, triggering immune responses and leading to the onset of AD. Moreover, the progression of AD can further induce the development of allergic diseases such as allergic rhinitis and food allergy.

FA represents an immune-inflammatory-mediated adverse reaction to specific foods (69, 70). The underlying mechanism across various food allergies involves immune activation and the disruption of tolerance to the intake of specific foods. Dysfunctions of the gastrointestinal tract and skin barriers can contribute to food sensitivities (71). Notably, CD103⁺ DCs mediate immune tolerance in the gastrointestinal tract, while CD11b⁺ dermal DCs and Langerhans cells (LCs) mediate cutaneous tolerance (72, 73). In the pathogenic process of food allergy, impaired development of regulatory T (Treg) cells is observed, being replaced by the production of helper T2 (Th2) cells. These Th2 cells drive IgE conversion and the expansion of allergic effector cells, thereby exacerbating the immune response associated with food allergy (72). The intestinal epithelial barrier is not a static physical barrier but maintains a dynamic balance with the intestinal microbiome and immune cells (74). Comprising a single layer of columnar epithelium interspersed with goblet cells, encased by a layer of mucus, the intestinal barrier protects the host from penetration by digestive enzymes and microorganisms (67). Intestinal epithelial cells selectively allow the absorption of nutrients, electrolytes, and water while defending against the invasion of harmful microorganisms and toxins (75). The mucus layer, the outermost part of the intestinal epithelium, effectively blocks harmful substances and tissues (74). It consists of an outermost mucus rich in antimicrobial peptides and immunoglobulin A, and an inner layer of mucus adhering directly to neighboring epithelial cells (74, 76). The inner layer of mucus, primarily composed of glycocalyx produced by goblet cells, prevents antigens from invading the lamina propria of the intestinal mucosa (74, 77). Moreover, studies have highlighted the role of TJs as a key component in controlling intestinal barrier permeability in epithelial cell junctions (76). In the context of FA, impaired function of the intestinal epithelial intercellular junctions leads to barrier dysfunction and loss of osmotic function. This results in increased permeability, allowing allergens to penetrate the intestinal barrier and stimulate the submucosal immune system. Damaged epithelial cells release inflammatory cytokines, such as TSLP, IL-25, and IL-33, inducing cutaneous DCs and other cell types to shift the immune response from tolerance to hypersensitivity. This process is involved in allergic sensitization and triggering reactions by activating innate lymphoid cells type 2 (ILC2) and producing IL-4 and IL-13 (69).

In summary, when stimulated by allergens, epithelial cells release alarmins, activating immune cells and antigen-presenting cells. This promotes the occurrence of immune responses and the release of cytokines and inflammatory mediators, further exacerbating the destruction of the epithelial barrier. This, in turn, increases the permeability of the intestinal barrier, forming a vicious circle and aggravating the degree of food allergy disease (78).

With the advancement of industrialization, modernization, and urbanization, various factors such as environmental pollution, increased consumption of processed foods, reduced contact with animals, and excessive hygiene practices have contributed to a rising incidence of allergic diseases. Changes in the environment, health, and lifestyles have significantly impacted microbial diversity and homeostasis. Recent research indicates that alterations in the gut, oral, and skin microbiota may trigger immune-mediated diseases, including autoimmunity, allergies, and chronic inflammatory conditions (79). Host-microbiota interactions play a fundamental role in immune system development (79). The local immune system not only adapts to the presence of host-beneficial microbiota, maintaining internal homeostasis, but also responds appropriately to pathogenic microorganisms (79). Microbial dysbiosis, a key focus in the field of epithelial barrier dysfunction (5, 80). refers to the phenomenon where changes and loss of biodiversity result in an unstable microbial ecosystem dominated by one or several microorganisms. This alteration disrupts the immune balance maintained by the gut, skin, and respiratory microbiota, leading to disease development (81, 82). Beneficial microbiota on mucosal surfaces regulating various aspects of barrier homeostasis, including barrier permeability, TJ expression, angiogenesis, local microinflammation, and mucosal tolerance (2). However, microbial dysregulation and epithelial barrier leakage can disturb immune homeostasis. When the epithelial barrier is compromised, the microbiota within the epithelium (beneficial flora, viruses, conditionally pathogenic bacteria, etc.) can migrate between affected epithelial cells or transfer to other sites (11, 83, 84). The occurrence and development of allergic diseases are closely linked to the imbalance of microbial flora in the epithelium. For instance, studies have demonstrated an association between microbiota dysbiosis and asthma (85). Multiple risk factors contribute to asthma development, with dysregulation of external microorganisms and host microbiota playing a significant role (86). Host microorganisms participate in asthma pathogenesis through the metabolites of gut microbes, such as Lachnospira, Veillonella, Faecalibacterium, and Rothia ( 87). The “gut-lung axis” proposes that metabolites produced by gut-derived microbiota reach the lungs, shifting the Th2-Treg balance to Treg, protecting against asthma development (79). Similarly, the composition and function of upper respiratory tract microbiota influence asthma pathogenesis, with variations observed at different ages (88). Microbial flora dysbiosis is also implicated in allergic rhinitis (AR). Studies have noted changes in nasal mucosal microbiota associated with AR, including increased abundance of Staphylococcus aureus, Propionibacterium, Corynebacterium, and Bacteroidetes, and decreased abundance of Prevotella and Streptococcus ( 89). Environmental microbiota exposure in early life may be biologically linked to allergic manifestations, emphasizing the importance of microbial interactions in AR pathogenesis (90). The skin, as the body’s largest organ, is in constant contact with the external environment and harbors a variety of microorganisms between epithelial cells. Disruption of skin function increases skin leakage, allowing resident bacteria and opportunistic pathogens to enter epithelial tissue, inducing inflammatory responses or exerting protective effects. Studies suggest that decreased microbiome diversity in AD patients is associated with increased disease severity and colonization of pathogenic bacteria such as Staphylococcus aureus. Topical application of commensal organisms can potentially reduce AD severity (51, 91). The gastrointestinal tract, closely interacting with environmental microorganisms through food ingestion and excretion, is rich in microbiota crucial for maintaining body microenvironment homeostasis. However, damage to the intestinal epithelial barrier increases mucosal permeability, allowing the invasion of pathogenic bacteria and causing diseases (92). Dynamic changes in gut microbiota are implicated in the development of FA (93), with age and diet influencing intestinal flora abundance and FA occurrence (94).

In summary, the interaction between dysbiosis of the microbiota and epithelial barrier dysfunction can contribute to the occurrence and progression of allergic diseases. Microbial dysbiosis alters the microenvironment balance maintained by microorganisms in respiratory tract, skin, and intestinal tissues, leading to increased epithelial barrier permeability, heightened sensitivity to allergens, and the onset and exacerbation of various allergic diseases.

Particulate matter (PM), also known as dust, is a variety of solid or liquid particles that are uniformly dispersed in an aerosol system. PM can be divided into primary particulate matter and secondary particulate matter. Primary particulate matter is particulate matter that is released into the atmosphere from a direct source of pollution, such as combustion soot, automobile exhaust, etc. Secondary particles are formed by some polluting gas components in the atmosphere, or these components are formed by photochemical oxidation reactions with normal components in the atmosphere. According to its aerodynamic diameter, it can be mainly divided into three types (PM0.1, with a diameter of < 0.1μm; PM 2.5, diameter< 2.5 μm; PM10 has a diameter of <10 μm) and due to its small size and toxicity, it is easy to cause diseases, especially respiratory diseases (147, 148). PM can significantly alter epithelial barrier structure. Studies have shown that PM may disrupt the integrity of the airway epithelial barrier by degrading TJ proteins such as occludin, claudin-1, and ZO-1 (96–99). In addition, in mouse models, exposure to PM2.5 inhibits E-cadherin levels in lung tissue, increasing IFN-γ, IL-2, IL-4, IL-6, and IL-10 in bronchoalveolar lavage fluid (100). Likewise, at lower combustion temperatures, aromatic compounds chemically adhere to the surface of metal oxide-containing PMs, resulting in the formation of surface-stable environmentally persistent free radicals (EPFRs). The reactive oxygen species (ROS) are produced by the EPFR redox cycle containing PM, and the antioxidant and inflammatory responses triggered by ROS after inhalation are closely related to the degradation of claudin-1 and occludin proteins in the airway epithelium and mouse lung tissues induced by PM (97, 101). Likewise, at lower combustion temperatures, aromatic compounds chemically adhere to the surface of metal oxide-containing PMs, resulting in the formation of surface-stable environmentally persistent free radicals (EPFRs). The ROS are produced by the EPFR redox cycle containing PM, and the antioxidant and inflammatory responses triggered by ROS after inhalation are closely related to the degradation of claudin-1 and occludin proteins in the airway epithelium and mouse lung tissues induced by PM (102). Furthermore, PM2.5 and PM0.1 can cause increased lysosomal membrane permeability, oxidative stress and lipid peroxidation at low doses, and epithelial cell necrosis at high doses (103). Recent studies have shown that PM can lead to DNA damage, protein carbonation, and loss of cytokeratin and filaggrin in epidermal structural proteins (104–106).

Nanoparticles (NPs), also known as ultrafine particles, typically range in size between 1 and 100 nm. Over the past few decades, the prevalence of nanoparticles in environmental pollution has been steadily increasing, contributing significantly to air pollution. Common nanoparticles include titanium dioxide (TiO2) and silicon dioxide (SiO2), frequently utilized as additives in various products such as food, cosmetics, paints, and catalysts. Research has demonstrated that nanoparticles exhibit a high affinity for lipids, leading to the encapsulation and disruption of phospholipid membranes. This disruptive action extends to various lipid-rich environments, including pulmonary surfactants and endothelial cell junctions in lung blood vessels. Additionally, nanoparticles have been shown to compromise the stability of lysosomal membranes, triggering cell death (107). Specifically, TiO2-NP has been implicated in enhancing the synthesis of interleukin-1a (IL-1a) by inducing an unbalanced overexpression of immature neurotrophic factors. This process, mediated through p75NTR signaling, is associated with apoptosis of epithelial cells (108). Needle-like TiO2-NP has also been found to stimulate the release of pro-inflammatory cytokines such as IL-1a, IL-1b, IL-6, TNF-a, and IL-8, disrupting cellular connections and compromising the skin barrier (109). Moreover, nanoparticles tend to accumulate on the surface of intestinal epithelial cells, M cells, and Peyer patches. Through endocytosis by M cells or increased cell membrane integrity, nanoparticles can disrupt the epithelial barrier, leading to cell leakage and increased intestinal epithelial permeability (110). Similarly, NPs have been observed to raise human intestinal epithelial paracellular permeability (111).

Ozone, an oxygen allotrope (O₃), exhibits robust oxidizing properties and finds applications as a bleach, air purifier, and disinfectant. It serves as an alternative to catalytic oxidants in chemical production and is utilized as a rocket fuel oxidizer in its liquid form. Despite its beneficial uses, ozone poses a threat to human health as a harmful air pollutant. Recent studies have revealed that prolonged ozone exposure can lead to various respiratory issues, including bronchial hyperresponsiveness, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and, in severe cases, death (112). Acute exposure to ozone is known to impair epithelial barrier function, inducing airway inflammation, peribronchial collagen deposition, and airway hyperreactivity (AHR) (113). This acute exposure manifests as asthma symptoms, reduced lung function, increased inflammatory cell infiltration, and heightened AHR (114). Notably, ozone exposure detrimentally affects key molecules involved in epithelial barrier function (149). The inflammatory response induced by ozone in human lungs is reliant on the production of ROS (115), leading to acute epithelial barrier injury and subsequent disruption (116). Upon acute ozone stimulation, cell stress, desquamation, and death occur through reactive ROS. This process is followed by sustained injury and death of bronchiolar epithelial cells, resulting in protein leakage, infiltration of neutrophils and macrophages, and the production of IL-1a and IL-33 by epithelial and myeloid cells (117). Emerging data indicate that, under the control of the IL-33/ST2 axis, ozone directly instigates barrier damage prior to the inflammatory damage mediated by myeloid cells (117).

Tobacco stands out as one of the most prevalent toxic substances in the environment, containing approximately 5,000 chemicals notorious for their toxicity to the respiratory system. Research conducted by Burns et al. has elucidated that exposure to cigarette smoke induces an elevation in the permeability of the alveolar epithelial barrier (118). Furthermore, the enduring exposure to tobacco not only leads to diminished gene and protein expression levels of various TJs and AJs proteins but also culminates in the disruption of intercellular junctions (119, 120). In recent years, e-cigarettes have gained prominence, initially marketed as aids for smoking cessation. Despite their advertised potential for assisting in quitting smoking, there is insufficient evidence supporting this claim. E-cigarettes release evaporated nicotine and flavoring, both of which harbor numerous known toxicities capable of causing damage to the epithelial barrier (121).

Enzymes present in allergens serve as enhancers of allergic reactions (122). Numerous studies have provided further validation to the notion that the protease activity inherent in allergens, including molds, pollen, cockroaches, house dust mites (HDMs), and certain foods, plays a crucial role in disrupting epithelial integrity and triggering innate immune responses (150). For instance, investigations have demonstrated that mite allergens contribute to the breakdown of TJs by cleaving occludin, leading to intracellular ZO-1 proteolysis and the consequent disruption of the epithelial barrier (123, 124). Matsumura et al. propose that allergen-derived proteases induce TJs disruption among airway epithelial cells, activate protease-activated receptor-2, and generate TSLP, thereby activating the immune response (122). Additionally, Vinhas et al. identified high-molecular-weight proteases with serine and/or aminopeptidase activity in various sensitized pollens, such as Olea europaea, Dactylis glomerata, Cupressus sempervirens, and Pinus sylvestris. These proteases were found to increase Calu-3 transepithelial permeability by disrupting transmembrane adhesion proteins, including occludin, claudin-1, and E-cadherin (125). Aspergillus, known for its abundant production of proteases, induces the release of cytokines like IL-6, IL-8, and MCP-1 in airway epithelial cells. These enzymes also disrupt tight epithelial junctions and prompt cell desquamation (126). Furthermore, Grozdanovic et al. posit that cysteine proteases in food may contribute to the sensitization process of food allergies by disrupting tight junctions (127). In summary, the enzymes present in various active allergens play a pivotal role in disrupting epithelial barrier function, resulting in heightened epithelial barrier permeability. This, in turn, facilitates the invasion of allergens, triggers immune responses, and contributes to the development of allergic diseases.

Microplastics (MPs) are water-insoluble polymer particles with a size of less than 5 mm, while nanoplastic particles have a diameter ranging from 1 nm to 1 μm. Recognized as emerging international pollutants due to their small particle size, microplastics are derived from petroleum and are extensively utilized in various aspects of daily life, presenting potential risks to human health (151). The minute dimensions of micro and nanoplastics facilitate their penetration into tissues, allowing interactions with cells and cellular structural molecules (151). Prolonged exposure to these particles has been associated with various degrees of damage to human health (152). Research by Hollóczki et al. has demonstrated the propensity of nanoplastics to interact with proteins, fundamentally altering the secondary structure of these biological macromolecules critical to their function (128). Molecular dynamics simulations have revealed that polyethylene nanoparticles dissolve into an incoherent single polymer chain network within the hydrophobic core of the lipid bilayer, inducing structural and dynamic changes that impact the cell membrane (129). Recent studies evaluating the effects of polystyrene nanoparticles, with diameters of 25 nm and 70 nm, on human alveolar epithelial A549 cell lines indicated that the toxicological effects of PS-NPs on alveolar epithelial cells were dependent on exposure time, diameter, and concentration (130). Jin et al. further observed that polystyrene MPs could induce dysbiosis in intestinal microbiota, leading to intestinal barrier dysfunction and metabolic disorders in mice (131). Additionally, compared with spherical fluorescent polystyrene (PS) particles of different sizes, particles with a diameter of less than 1.5 nm could directly penetrate the gastrointestinal barrier, causing impaired intestinal function (132). Similarly, nanomaterials have been linked to oxidative stress, inducing autophagy in human lung epithelial cells (133). Amidst rapid development, the escalating use of microplastics and nanoplastics raises serious concerns regarding environmental pollution, with concomitant hidden health hazards for human beings.

The rise of modernization and industrialization has reinforced people’s emphasis on hygiene, particularly highlighted during the outbreak of the new coronavirus pneumonia epidemic. This attention to hygiene has led to widespread use of detergents and sanitizing products. However, excessive contact and utilization of these cleaning agents can contribute to various diseases, especially skin and respiratory conditions. Research indicates that detergents can play a role in triggering the development of allergic diseases by influencing epithelial barrier disorders (20, 153). Even at minimal concentrations, anionic surfactants and detergents have been shown to directly compromise the integrity of cutaneous keratinocytes and bronchial epithelial barriers by disrupting TJs and associated molecules (63, 134). Long-term use of cleansers, as demonstrated by Douwes et al., can elevate transepidermal water loss (TEWL) in the stratum corneum of the skin, subsequently increasing the risk of contact dermatitis (135). The heightened risk of airway inflammation is linked to the interaction of airway epithelium with environmental air pollutants. Residues of detergents on recently cleaned clothing and floor surfaces can be easily inhaled into the airways, impairing airway barrier function and bronchial epithelial cells. Studies have revealed that emulsifiers can thicken mucosal surface fluid, entrap commensal bacteria, disrupt healthy interactions between epithelial cells and commensal bacteria, alter the microbiota, and interfere with mucosa-bacterial interactions, thereby inducing intestinal inflammation (136). Current research is ongoing to determine whether detergent residues from cleaned dishes can damage the esophageal or gastrointestinal epithelial barrier. Identification of such effects would necessitate the implementation of appropriate avoidance measures (20).

In the pathological mechanisms of epithelial barrier dysfunction, dysbiosis of the microbiota has been reported (5, 154). Among them, bacteria were significantly associated with epithelial barrier dysfunction. Bacterium infections mainly rely on its ability to disrupt the epithelial barrier by affecting cell-cell junctions and altering the expression of TJ and AJ proteins. For example, Staphylococcus aureus colonization and release of enterotoxin B (SEB) can reduce epithelial cell integrity and increase mucosal permeability by decreasing the expression of occlusin and the expression of ZO-1 protein during ALI culture of polyp epithelial cells (137). Similarly, the addition of purified Staphylococcus aureus V8 protease to ALI-cultured human nasal epithelial cells (HNECs) also found the same barrier integrity impairment and discontinuous expression of ZO-1 (155). Studies also have shown that Staphylococcus aureus secreted α-hemolysin interacts with the metalloproteinase domain-containing protein 10 (ADAM10), which can lead to the cleavage of AJ protein E-cadherin and disrupt the lung epithelial barrier in mice (138). Furthermore, Peter et al., when studying human lung tissue with Streptococcus pneumoniae infection, found that pneumococcal infection reduced the levels of alveolar occludin, ZO-1, claudin-5, and VE-cadherin (139). In dextran sulfate sodium (DSS)-induced mouse models of colitis and Caco-2 cell lines, Fusobacterium nucleatum was found to disrupt epithelial integrity and increase permeability by regulating the expression and distribution of tight junction proteins ZO-1 and occulin, causing an aberrant inflammatory response and aggravating colonic inflammation (140). Besides, bacteria can also cause dysfunction of the epithelial barrier through other pathways. Studies have shown that Pseudomonas aeruginosa mediates the disruption of the epithelial barrier by using four effectors: protein exosomes (Exo) S, ExoT, ExoU and ExoY (141). For example, ExoS and ExoT disrupt the host actin cytoskeleton and induce barrier disruption by impairing cell-to-cell adhesion, where ExoY disrupts barrier integrity without cytotoxicity, while another effector protein, ExoU, produces rapid necrotic cytotoxicity (141). In the human body, beneficial commensal bacteria are able to protect and maintain the homeostatic balance of the microenvironment in the body, and the destruction of the epithelial barrier function by pathogenic bacteria leads to an increase in its permeability, which not only enables pathogenic bacteria to reach the subepithelial tissue, but also promotes the secondary invasion of other allergens and pathogens.

Viruses are a non-cellular organism that is tiny, simple in structure, contains only one nucleic acid (DNA or RNA), and must parasitize and replicate in living cells. Some studies have found that epithelial dysfunction has a certain correlation with the invasion of viruses. Sajjan et al. found the loss of ZO-1 in the tight junction complex of rhinovirus (RV)-infected cells in a mouse model, and pointed out that RV promotes bacterial binding and translocation by disrupting airway epithelial barrier function, leading to disease occurrence (142). It is worth noting that RV can stimulate the production of ROS and destroy the epithelial barrier, and can also disrupt the epithelial barrier function through dsRNA produced during RV replication (143). In addition, The E protein of SARS coronaviruses and novel coronaviruses interacts with PALS1, a tight junction-related protein, and alter tight junction formation and epithelial morphology, which is manifested by the loss of PALS1 leading to the destruction of TJs and AJs (144, 145). Similarly, Smallcombe et al. found that the molecular composition of TJs in the Respiratory syncytial virus (RSV)-infected airways was altered, as evidenced by significant upregulation of claudin-2 expression and downregulation of ZO-1, occludin, and claudin-1 protein expression, suggesting that increased claudin-2 expression contributes to airway epithelial barrier leakage (146). Different viruses have different mechanisms of epithelial barrier damage, but all of them can increase epithelial barrier permeability and lead to disease infection. Therefore, strategies to maintain barrier function have great potential in the development of antiviral drugs.