From Skin to Gut: Unraveling the Immunopathogenesis of Eosinophilic Esophagitis
Abstract
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory disease of the esophagus [1] that has become a paradigmatic model for understanding the interconnected skin–gut axis in allergic disease. Once considered a rare disorder, EoE has rapidly emerged as a significant clinical entity, reflecting the broader rise in type 2 immune-mediated conditions. Its pathophysiology highlights the intricate interplay between epithelial barrier dysfunction, innate and adaptive immune responses, and environmental triggers such as food and aeroallergens.
A growing body of evidence underscores the central role of epithelial barrier dysfunction in disease initiation and progression. Structural and functional abnormalities in esophageal epithelial integrity facilitate allergen penetration, microbial interactions, and exaggerated immune activation. Importantly, these defects parallel the barrier abnormalities observed in atopic dermatitis, supporting the concept of shared pathophysiological pathways across epithelial tissues. This overlap provides a framework for understanding why EoE and atopic dermatitis frequently coexist and may be driven by common genetic and environmental risk factors.
Immunologically, EoE is characterized by a type 2 helper T (Th2) cell-driven inflammatory response. Th2 cytokines, particularly interleukin (IL)-4, IL-5, and IL-13, orchestrate eosinophil recruitment, activation, and persistence within the esophageal mucosa.[2] [3] In parallel, innate immune cells including mast cells, basophils, and group 2 innate lymphoid cells amplify the inflammatory cascade. Of particular interest is the IL-33–ST2–basophil axis, which has been implicated in epicutaneous allergic sensitization and subsequent development of EoE.[4] Epithelial-derived cytokines such as thymic stromal lymphopoietin (TSLP) and IL-33 act as upstream regulators of this cascade, bridging the interaction between impaired epithelial barrier function and type 2 inflammation.
Clinical and translational studies further support the centrality of these pathways. Patients with EoE frequently display comorbid atopic diseases such as asthma, allergic rhinitis, and atopic dermatitis, suggesting a systemic predisposition toward type 2 inflammation. Genetic studies have identified susceptibility loci that overlap between EoE and other allergic diseases, reinforcing the notion of shared mechanisms within the skin–gut axis. These findings have shifted the understanding of EoE from a localized esophageal disorder to a systemic allergic disease with broad immunological relevance.
Therapeutically, advances in biologic treatments have begun to reshape the management of EoE. The approval of dupilumab, an IL-4 receptor alpha antagonist that inhibits IL-4 and IL-13 signaling, represents a major breakthrough by directly targeting the underlying type 2 inflammatory cascade. Emerging therapies directed against IL-5, TSLP, and IL-33 further expand the landscape of potential treatment options, offering the possibility of precision medicine tailored to specific immunopathogenic pathways.
Despite these advances, critical gaps remain. Unanswered questions include the precise mechanisms linking epithelial barrier defects to systemic allergic sensitization, the role of early-life environmental exposures in shaping disease risk, and the long-term efficacy and safety of biologic therapies in diverse patient populations. Future research must also clarify biomarkers for disease monitoring, predictors of treatment response, and strategies for prevention in at-risk individuals.[5]
In summary, EoE exemplifies the complex interaction between barrier dysfunction and type 2 immunity across epithelial tissues. It provides valuable insights into the skin–gut axis of allergic disease while also serving as a model for therapeutic innovation. Ongoing research is essential to deepen our understanding of its pathogenesis, refine treatment approaches, and ultimately improve patient outcomes.
Keywords: eosinophilic esophagitis, skin–gut axis, epithelial barrier dysfunction, type 2 inflammation, TSLP, IL-33, dupilumab
Introduction
Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease of the esophagus. It is diagnosed in the setting of symptoms of esophageal dysfunction and an eosinophilic predominant infiltrate in the esophagus [6]. Once considered a rare condition, EoE has emerged as one of the most rapidly increasing allergic diseases worldwide, with prevalence rates reaching approximately 1 in 2,000 individuals in developed countries. The incidence and prevalence of eosinophilic esophagitis (EoE) have markedly increased over the past 2 decades, outpacing increased detection of the disease [7] [8].
The disease represents a unique intersection of allergology and gastroenterology, characterized by a complex interplay between environmental allergens, genetic predisposition, and immune dysfunction. Eosinophilic esophagitis (EoE) is a type 2 helper T (Th2) cell immune-mediated gastrointestinal disease [9], fundamentally linking it to other allergic conditions through shared inflammatory pathways. This connection has profound implications for understanding disease pathogenesis and developing targeted therapeutic interventions.
Perhaps most intriguingly, emerging evidence suggests that EoE exemplifies the concept of a “skin-gut axis” in allergic disease. Both diseases manifest on stratified squamous epithelium along the skin-gut continuum and have overlapping treatment algorithms that include avoidance of triggers, topical steroids, and dupilumab [10]. This observation has led to renewed interest in understanding how epithelial barrier dysfunction, traditionally associated with atopic dermatitis, may serve as a common pathogenic mechanism across multiple allergic diseases.
The recognition of EoE as part of the broader “atopic march” has shifted our conceptual understanding of allergic disease progression. Eosinophilic esophagitis is a late manifestation of the atopic march [11], suggesting that it may represent the culmination of a progressive allergic sensitization process that begins in early life and affects multiple organ systems sequentially.
This analytical review aims to critically examine the current understanding of EoE immunopathogenesis through the lens of the skin-gut axis, exploring how shared epithelial barrier dysfunction, immune cell interactions, and inflammatory mediators contribute to disease development and progression. By synthesizing recent advances in molecular understanding, clinical observations, and therapeutic developments, we seek to provide a comprehensive framework for understanding this complex disease while identifying key areas for future investigation.
Literature Review and Current Understanding
Epidemiological Trends and Disease Burden
The epidemiological landscape of EoE has undergone dramatic changes over the past three decades. The incidence and prevalence of eosinophilic esophagitis (EoE) have markedly increased over the past 2 decades, outpacing increased detection of the disease. Although genetic susceptibility markers for EoE have begun to be elucidated, the rate at which EoE has increased in incidence suggests environmental factors predominate [12]. This rapid increase in prevalence parallels similar trends observed in other allergic diseases, suggesting shared underlying drivers.
The demographic profile of EoE reveals important insights into disease pathogenesis. Eosinophilic esophagitis (EoE) is an eosinophil-rich, Th2 antigen-mediated disease of increasing worldwide prevalence. Originally considered common in children and young adults, it can be seen at any age, with the highest prevalence between 30 and 40 years [13]. This age distribution suggests that while pediatric onset is common, the disease can manifest throughout the lifespan, with peak prevalence in young adults.
The Allergic Connection: EoE and Atopic Comorbidities
One of the most striking features of EoE is its strong association with other allergic conditions. Eosinophilic esophagitis (EoE) is a chronic allergic condition affecting the esophagus and driven by food antigens. Many individuals diagnosed with EoE have other allergic conditions, such as food allergy, asthma, allergic rhinitis, and atopic dermatitis [14]. This clustering of atopic diseases in individual patients suggests shared pathogenic mechanisms and common susceptibility factors.
The relationship between EoE and atopic dermatitis has received particular attention due to the shared epithelial barrier dysfunction observed in both conditions. Atopic dermatitis is associated with and may predispose to higher risk of other atopic disorders, including asthma, hay fever, food allergy, and eosinophilic esophagitis [15]. This association extends beyond mere coincidence, suggesting mechanistic links that may inform therapeutic strategies.
Fundamental Immunopathogenic Mechanisms
Type 2 Inflammatory Response
The core immunopathogenic mechanism underlying EoE involves a robust type 2 inflammatory response. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response [16], characterized by the predominance of specific cytokines and cellular populations. The immunopathogenesis of EE involves an allergic response to environmental and food allergens, and the proinflammatory cytokines IL-5 and IL-13 [17].
The type 2 inflammatory cascade is orchestrated by multiple cell types working in concert. Triggered by food and aeroallergens, type 2 cytokines interleukin (IL)-4, IL-13, IL-5 produced by CD4+ T helper 2 cells (Th2), eosinophils, mast cells, basophils, and type 2 innate lymphoid cells alter the esophageal epithelial barrier and increase inflammatory cell tissue infiltration [18]. This multi-cellular inflammatory network creates a self-perpetuating cycle of tissue damage and immune activation.
Eosinophil Biology and Function
While eosinophils represent the hallmark cellular feature of EoE, their precise role in disease pathogenesis remains incompletely understood. Despite eosinophils having a histologically predominant position, their role in the immunopathogenesis of the disease is still questionable. Several other inflammatory cells are involved and may also play a critical role [19]. This observation has led to increased appreciation of the complex inflammatory milieu beyond simple eosinophil accumulation.
The recruitment and activation of eosinophils in EoE involves specific chemokine pathways. Eotaxin 3 (CCL-26) recruits eosinophils to the esophageal epithelium, whereas TSLP and IL-33 lead to dendritic cell and basophil activation and TH2 polarization [20]. This recruitment process is not merely passive but represents an active, coordinated response involving multiple cellular and molecular signals.
The Skin-Gut Axis: Epithelial Barrier Dysfunction as a Unifying Mechanism
Shared Epithelial Biology
One of the most compelling aspects of EoE pathogenesis is the recognition that both esophageal and skin epithelium share fundamental biological properties that predispose to allergic inflammation. Both diseases manifest on stratified squamous epithelium along the skin-gut continuum and have overlapping treatment algorithms that include avoidance of triggers, topical steroids, and dupilumab [21]. This shared epithelial architecture provides a biological basis for understanding common pathogenic mechanisms.
The concept of epithelial barrier dysfunction as a central mechanism in allergic disease has gained tremendous traction. The epithelial barrier hypothesis explains the increase in allergy, autoimmunity and other chronic conditions [22], proposing that impaired barrier function allows enhanced penetration of environmental allergens, leading to inappropriate immune activation.
Evidence for Barrier Dysfunction in EoE
Multiple lines of evidence support the presence of epithelial barrier dysfunction in EoE. EoE is associated with an abnormal epithelial barrier and postulates that CS therapy, by reducing innate immune mechanisms, may promote C. albicans colonization and likely subsequent sensitization [23]. This finding suggests that barrier dysfunction is not merely a consequence of inflammation but may represent a primary pathogenic mechanism.
Detailed molecular studies have identified specific mechanisms of barrier disruption in EoE. Eosinophilic esophagitis (EoE) is an allergy-mediated disease that is accompanied by IL-13 overexpression and an impaired esophageal barrier. Filaggrin (FLG) and tight junction (TJ) proteins are considered to contribute to epithelial barrier function [24]. The involvement of filaggrin, a protein classically associated with atopic dermatitis, provides direct molecular evidence for shared pathogenic mechanisms between skin and esophageal disease.
IL-13-Mediated Barrier Disruption
The type 2 cytokine IL-13 has emerged as a central mediator of epithelial barrier dysfunction in EoE. IL-13 altered the staining patterns of TJ proteins and the epithelial morphology. FLG siRNA transfection remarkably decreased TEER. The IL-13-mediated reduced esophageal barrier is associated with the altered expression pattern but not with the levels of TJ-associated proteins [25]. This finding reveals that barrier dysfunction involves not just changes in protein levels but alterations in protein localization and function.
The barrier-disrupting effects of IL-13 can be demonstrated experimentally. Esophageal permeability to small molecules was increased in patients with eosinophilic esophagitis (EoE) and could be induced by IL-13 in our unique air-liquid interface-cultured primary multilayer human esophageal epithelial cells in vitro. A deficiency of filaggrin disrupted the esophageal stratified epithelial barrier [26]. These experimental findings provide mechanistic support for the clinical observations of barrier dysfunction in patients.
Tight Junction Pathology
Tight junctions represent critical structural elements maintaining epithelial barrier integrity. Paracellular space is almost exclusively sealed by TJs and is maintained by complex protein-protein interactions. Thus, TJ dysfunction increases paracellular permeability, resulting in enhanced flux across TJs [27]. In EoE, specific tight junction proteins are affected in predictable patterns.
The allergic response associated with eosinophilic esophagitis (EoE) occurs when food antigens permeate tight junction–mediated epithelial dilated intercellular spaces. We assessed whether levels of tight junction proteins correlate with the dilation of intercellular spaces (spongiosis) and the effects of topical steroids on these parameters [28] [29]. This work demonstrates that barrier dysfunction is not merely theoretical but has direct clinical correlates and therapeutic implications.
The specific pattern of tight junction protein alterations provides insights into disease mechanisms. Filaggrin, ZO-3, and claudin-1 (but not ZO-1 or ZO-2) are detected in the esophageal mucosa of patients with EoE treated with steroids and individuals without esophageal disease. Without treatment, spongiosis increases, corresponding with reduced levels of filaggrin, ZO-3, and claudin-1 [30]. The selective involvement of specific tight junction proteins suggests targeted rather than generalized barrier disruption.
The Role of Epicutaneous Sensitization
Experimental Evidence for Skin-to-Gut Pathways
One of the most compelling pieces of evidence supporting the skin-gut axis in EoE comes from experimental models demonstrating that epicutaneous sensitization can promote esophageal eosinophilia. Epicutaneous allergic sensitization promotes EoE, and this is critically mediated through the IL-33-ST2-basophil axis [31]. This finding provides direct experimental support for the concept that disrupted skin barriers can contribute to the development of food-related allergic diseases.
The experimental approach used to demonstrate this pathway involved disruption of skin barrier function followed by allergen exposure. The impaired skin barrier in patients with atopic dermatitis has been suggested as an entry point for allergic sensitization that triggers development of EoE. We sought to define the mechanisms whereby epicutaneous sensitization through a disrupted skin barrier induces development of EoE [32]. This work bridged the gap between clinical observations and mechanistic understanding.
The IL-33-ST2-Basophil Axis
The molecular pathway linking epicutaneous sensitization to esophageal inflammation involves the alarmin IL-33 and its receptor ST2. Epicutaneous sensitization and intranasal challenge of wild-type mice resulted in accumulation of eosinophils and upregulation of TH2 cytokines and St2 in the esophagus. Disruption of the IL-33-ST2 axis or depletion of basophils reduced these features [33]. This finding identifies specific molecular targets that could potentially be exploited therapeutically.
The role of basophils in this pathway is particularly noteworthy. Expression of ST2 on basophils was required to accumulate in the esophagus and transfer experimental EoE. Expression of IL1RL1/ST2 mRNA was increased in esophageal biopsy specimens from patients with EoE [34]. The translation of these experimental findings to human disease provides validation of the proposed mechanisms.
Clinical Evidence for the Skin-Gut Connection
Clinical studies have provided supportive evidence for the skin-gut connection in EoE patients. Eosinophilic esophagitis (EoE) is commonly associated with concomitant atopic diseases including atopic dermatitis (AD) and allergic airway (AA) diseases including asthma. Despite this link and the shared pathologic features across these three disorders, detailed analyses of the unifying molecular pathways are lacking [35] [36].
Molecular profiling studies have revealed shared transcriptomic signatures between EoE and atopic dermatitis. By human disease expression profiles, EoE evidenced a notably higher overlap (p = 0.0006) with AD (181 transcripts; 10%) than with AA (124 transcripts, 7%) [37]. This molecular overlap provides additional support for shared pathogenic mechanisms between skin and esophageal disease.
Innate Immune Cells: Mast Cells, Basophils, and Beyond
Mast Cell Contributions
While eosinophils receive primary attention in EoE, mast cells represent another critical cellular component of the inflammatory response. The mast cell plays a critical role in allergic responses in the gastrointestinal tract and other sites. Emerging evidence indicates that mast cells also participate in the pathogenesis of eosinophilic esophagitis, although their precise role has not been defined [38]. The recognition of mast cell involvement expands our understanding of the cellular networks involved in disease pathogenesis.
Recent studies have begun to characterize mast cell infiltration patterns in EoE. The purpose of this study was to characterise the mast cell infiltration, and to correlate it with the clinical state of EoE. Using immunohistochemistry and quantitative morphometry, we investigated eosinophils and mast cells extensively in oesophageal biopsies from patients with active EoE and from patients with EoE in remission, and compared the findings with healthy individuals [39]. These studies reveal that mast cells are not merely bystanders but active participants in the inflammatory process.
Basophil Biology and Function
Basophils have emerged as key cellular mediators in the skin-gut axis of allergic inflammation. TSLP stimulates basophils to generate interleukin (IL)-4 which support allergic sensitization after allergen being presented to a naive T cell, driving allergen-specific Th2 cells activation [40]. This pathway demonstrates how epithelial-derived signals can coordinate systemic allergic responses.
The functional heterogeneity of basophil populations adds complexity to their role in disease pathogenesis. TSLP-elicited basophils are non-responsive to IgE-antigen complexes but produce multiple effector molecules following stimulation with cytokines such as IL-33 and IL-18. The observed functional heterogeneity between IL-3-elicited and TSLP-elicited basophils may allow IL-3-elciteid basophils and TSLP-elicited basophils to contribute to various allergic disorders that are associated with IgE responses and/or TSLP production [41] [42].
Clinical studies have confirmed the presence of basophil infiltration in EoE tissues. TSLP was highly expressed in the oesophageal epithelium in areas infiltrated by basophils. Steroid therapy markedly decreased intraepithelial basophils in patients with EoE. Conclusion: Basophils may play an important role in the pathogenesis of eosinophilic oesophagitis [43]. The responsiveness of basophil infiltration to steroid therapy suggests that these cells are actively involved in the inflammatory process rather than passive residents.
Epithelial-Derived Cytokines: TSLP and IL-33
TSLP: The Master Orchestrator
Thymic stromal lymphopoietin (TSLP) has emerged as a central coordinator of type 2 inflammatory responses in EoE. The cytokine thymic stromal lymphopoietin (TSLP) mediates type 2 immune responses, and treatments that interfere with TSLP activity are in clinical use for asthma. Here, we investigated whether TSLP contributes to allergic inflammation by directly stimulating human CD4+ T cells and whether this process is operational in eosinophilic esophagitis (EoE), a disease linked to variants in TSLP [44] [45].
The direct effects of TSLP on T cells in EoE patients have been characterized in detail. We showed that about 10% of esophageal-derived memory CD4+ T cells from individuals with EoE and less than 3% of cells from control individuals expressed the receptor for TSLP and directly responded to TSLP, as determined by measuring the phosphorylation of STAT5, a transcription factor activated downstream of TSLP stimulation. Accordingly, increased numbers of TSLP-responsive memory CD4+ T cells were present in the circulation of individuals with EoE [46].
IL-33: The Alarmin Connection
IL-33 represents another critical epithelial-derived signal in EoE pathogenesis. The role of IL-33 in linking epithelial damage to immune cell activation provides a mechanistic explanation for how barrier dysfunction can perpetuate inflammation. This interaction along with signals from the epithelial layer, including TSLP and IL-33, interact with basophils and mast cells to induce eosinophils and additional growth of TH2 cells, leading toward the eosinophilic infiltrate seen in EoE. EoE appears to be a mostly non–IgE-mediated disease but dependent on T cells [47] [48].
The experimental evidence for IL-33 involvement comes from studies showing its requirement for experimental EoE development. Epicutaneous sensitization and intranasal challenge of wild-type mice resulted in accumulation of eosinophils and upregulation of TH2 cytokines and St2 in the esophagus. Disruption of the IL-33-ST2 axis or depletion of basophils reduced these features [49].
Microbiome and Dysbiosis
The Esophageal Microbiome in Health and Disease
The role of the microbiome in EoE pathogenesis represents an emerging area of investigation. The oral and esophageal microbiota are gaining recognition for their importance in managing Eosinophilic Esophagitis (EoE). They serve as diagnostic biomarkers and therapeutic targets. The primary goal of EoE treatment is to alleviate symptoms such as dysphagia, heartburn, nausea, and chest pain. These symptoms are often associated with dysfunction of the esophageal barrier, closely linked to the esophageal microbiota [50].
Studies have begun to characterize the esophageal microbiome in EoE patients compared to healthy controls. The esophagus has a unique microbiome with notable differences between its proximal and distal regions. We found that the murine esophagus is colonized with diverse microbial communities within the first month of life. The esophageal microbiota is distinct, dominated by Lactobacillales, and demonstrates spatial heterogeneity as the proximal and distal esophagus are enriched in Bifidobacteriales and Lactobacillales, respectively [51] [52].
Dysbiosis and Disease Activity
Evidence suggests that microbial dysbiosis may contribute to EoE pathogenesis through multiple mechanisms. Diseases associated with mucosal eosinophilia are characterized by a different microbiome from that found in the normal mucosa. Microbiota may contribute to esophageal inflammation in EoE and GERD [53]. This observation suggests that microbiome alterations are not merely consequence of disease but may actively contribute to pathogenesis.
The experimental evidence for microbiome involvement comes from studies showing that antibiotic-induced dysbiosis can exacerbate disease. Antibiotic-induced dysbiosis exacerbates disease in a murine model of EoE [54]. This finding suggests that maintaining microbiome diversity may be protective against disease development or progression.
Gut Microbiome Alterations
Studies of the gut microbiome in EoE patients have revealed specific patterns of dysbiosis. There were also notable differences in relative abundance at multiple taxonomic levels when comparing the two communities; at the phylum level, we observed a marked decrease in Firmicutes and increase in Bacteroidetes and at the order and family level there were major decreases in Clostridia and Clostridiales in patients with EoE (q ≤ 0.1). We conclude that there are important differences in microbial community structure, microbial richness, and evenness and a major decrease in taxa within the Clostridia in patients with EoE [55].
The potential therapeutic implications of these findings are remarkable. Our data suggest that Clostridia based interventions could be tested as adjuncts to current therapeutic strategies in EoE [56]. This finding opens new avenues for therapeutic investigation beyond traditional immunosuppressive approaches.
Environmental Factors and Gene-Environment Interactions
The Hygiene Hypothesis and Early-Life Exposures
The rapid increase in EoE prevalence has focused attention on environmental factors that may contribute to disease development. Many of these environmental factors are rooted in the theoretical framework of the hygiene hypothesis, specifically mediation of disease development through dysbiosis [57]. This framework suggests that reduced early-life microbial exposure may predispose to allergic diseases including EoE.
Specific early-life exposures have been identified as risk factors for EoE development. We describe the evidence that early-life exposures, including antibiotic use, acid suppression, and cesarean delivery, can increase the risk of disease [58]. These exposures share the common feature of potentially altering early microbiome development, supporting the dysbiosis hypothesis.
Therapeutic Implications for Microbiome Modulation
The recognition of microbiome involvement in EoE has led to interest in probiotic and other microbiome-modulating therapies. Further investigation into probiotics could expand the range of therapeutic options available alongside conventional treatments, potentially improving EoE remission rates, enhancing patient compliance, and reducing treatment-related side effects. Emerging research points to the potential of probiotic treatments as a complementary option to pharmacological therapy in the management of EoE [59] [60].
The therapeutic potential of microbiome-based interventions represents a paradigm shift from purely immunosuppressive approaches to more targeted ecological interventions that may restore healthy host-microbe interactions.
Current Therapeutic Landscape and Emerging Targets
Traditional Treatment Approaches
The therapeutic landscape for EoE has evolved over the past decades. The clinical goals of therapy in EoE include symptomatic, histologic, and endoscopic remission. The current paradigm for the treatment of EoE in Spain includes proton pump inhibitors, swallowed topical corticosteroids, and food elimination diets [61]. These approaches, while effective in many patients, highlight the multifaceted nature of the disease requiring intervention at multiple levels.
Current treatment modalities for eosinophilic esophagitis include the “3 Ds”: drugs, allergen avoidance with diet, and esophageal dilation [62] [63]. However, each of these approaches has limitations that have driven the search for more targeted therapeutic interventions.
The Dupilumab Revolution
The approval of dupilumab represents a watershed moment in EoE therapeutics. In April 2024, the Spanish Agency for Medicines and Medical Products approved dupilumab as the second drug for the treatment of EoE, thus adding this biologic to the therapeutic arsenal in EoE [64]. Dupilumab has been approved to treat a variety of atopic disorders and was the first US FDA-approved medication for the treatment of eosinophilic esophagitis (EoE), initially approved in May 2022, with expansion in use to patients as young as 1 year of age weighing at least 15 kg in January 2024 [65].
The mechanism of action of dupilumab provides insights into the central role of IL-4 and IL-13 in EoE pathogenesis. It is a fully human monoclonal antibody that inhibits both IL-4 and IL-13 signaling, suppressing TH2-mediated proinflammatory cytokines, chemokines and IgE implicated in EoE pathogenesis [66] [67]. This mechanism directly targets the core type 2 inflammatory pathway underlying the disease.
Clinical Efficacy and Real-World Experience
Clinical trials have demonstrated efficacy of dupilumab across multiple disease parameters. Phase II and III trials in EoE have demonstrated histologic, endoscopic and symptomatic improvement in disease activity with an overall favorable safety profile [68]. Dupilumab improved clinical symptoms, endoscopic scores, histologic inflammation, and esophageal distensibility [69].
Real-world experience with dupilumab has provided additional insights into its effectiveness in clinical practice. Follow-up histology was available for 26 patients: 22 of 26 had less than 6 eosinophils per high power field after the initiation of dupilumab with improvement (pre: 52.9 + 35.1 to post: 4.5 + 10.9 eosinophils/high power field, P < .005). A total of 28 patients had improvement of symptoms, with 24 patients reporting complete resolution of symptoms after dupilumab initiation.
The “Umbrella” Therapy Concept
One of the most intriguing aspects of dupilumab therapy is its potential to treat multiple atopic conditions simultaneously. Dupilumab therapy initiated for atopic disease effectively induces symptomatic and histologic remission of esophageal disease and reduces the need for EoE-directed therapy in patients with concomitant EoE. This finding supports the concept of shared pathogenic mechanisms across atopic diseases and suggests that targeting these common pathways may provide broad therapeutic benefits.
The clinical implications of this “umbrella” approach are important. In this guidance on the use of dupilumab in eosinophilic esophagitis, we propose that dupilumab can be used as first-line therapy in patients with multiple atopic diseases as, in theory, one medication will treat multiple diseases (even when the patient does not meet the strict criteria for use in the other approved indication), or, on the basis of SDM, the patient decides on the use of dupilumab after consideration of other therapies.
Future Therapeutic Targets
The success of dupilumab has validated the approach of targeting key cytokines in EoE and has opened the door to investigation of other biological targets. Several clinical trials that target key cytokines such as IL-5, IL-13, and thymic stromal lymphopoietin in EoE are still ongoing [70]. These studies may lead to additional targeted therapies that could provide alternatives or complementary approaches to dupilumab.
The identification of TSLP as a therapeutic target is particularly promising given its central role in orchestrating type 2 inflammatory responses. These findings highlight the potential therapeutic value of TSLP inhibitors for the treatment of EoE [71]. The clinical development of TSLP inhibitors for other allergic diseases provides a pathway for potential application in EoE.
Critical Analysis and Knowledge Gaps
Limitations of Current Understanding
Despite remarkable advances in understanding EoE pathogenesis, several critical knowledge gaps remain. Despite many advances in understanding of the pathogenesis of EoE, the cause of EoE is unknown [72]. This fundamental uncertainty highlights the need for continued research into the complex interplay of genetic, environmental, and immunological factors that contribute to disease development.
The relative contributions of different pathogenic mechanisms remain incompletely defined. While the skin-gut axis provides a compelling framework for understanding disease pathogenesis, the quantitative importance of epicutaneous sensitization versus other routes of allergen exposure requires further investigation. Similarly, the relative roles of different immune cell populations and their interactions need more precise definition.
Challenges in Disease Heterogeneity
EoE demonstrates significant clinical and molecular heterogeneity that complicates both research and clinical management. Clustering analysis based on the expression of type 2 inflammatory genes demonstrated the diversity of EoE endotypes [73]. This heterogeneity suggests that different patients may have distinct pathogenic mechanisms requiring tailored therapeutic approaches.
The implications of this heterogeneity extend to therapeutic responses. While dupilumab demonstrates broad efficacy, not all patients respond equally well, suggesting that additional biomarkers and personalized treatment approaches may be needed to optimize outcomes.
Environmental vs. Genetic Contributions
The relative importance of environmental versus genetic factors in EoE development remains an area of active investigation. The incidence and prevalence of eosinophilic esophagitis (EoE) have markedly increased over the past 2 decades, outpacing increased detection of the disease. Although genetic susceptibility markers for EoE have begun to be elucidated, the rate at which EoE has increased in incidence suggests environmental factors predominate [74].
However, the interaction between genetic susceptibility and environmental exposures is likely complex and may vary among individuals. Understanding these gene-environment interactions will be critical for developing predictive models and targeted prevention strategies.
Microbiome: Cause or Consequence?
The role of microbiome alterations in EoE represents a particularly complex area requiring further investigation. Yet, whether microbiome alterations are the result or the reason for barrier impairment and inflammatory response of the host is unclear [75]. This fundamental question has important implications for therapeutic development and may require longitudinal studies beginning in early life to resolve definitively.
Future Research Directions
Mechanistic Studies
Future research should focus on more precise definition of the molecular mechanisms linking skin barrier dysfunction to esophageal inflammation. While the IL-33-ST2-basophil axis provides one important pathway, other connections likely exist and require investigation. Advanced imaging techniques and single-cell analysis approaches may provide new insights into cellular interactions and tissue-specific responses.
The development of more sophisticated experimental models that better recapitulate human disease will be essential for testing therapeutic interventions and understanding pathogenic mechanisms. Current models, while valuable, may not fully capture the complexity of human disease, particularly the chronic and relapsing nature of EoE.
Biomarker Development
The identification of reliable biomarkers for disease activity, therapeutic response, and prognosis represents a critical unmet need in EoE management. The numbers of circulating and esophageal CD4+ T cells responsive to TSLP correlated with the numbers of esophageal eosinophils, supporting a potential functional role for TSLP in driving the pathogenesis of EoE and providing the basis for a blood-based diagnostic test based on the extent of TSLP-induced STAT5 phosphorylation in circulating CD4+ T cells [76]. The development of such blood-based biomarkers could revolutionize disease monitoring and reduce the need for repeated endoscopic procedures.
Precision Medicine Approaches
The recognition of disease heterogeneity suggests that precision medicine approaches may be needed to optimize therapeutic outcomes. Future research should focus on identifying molecular signatures that predict therapeutic response and can guide treatment selection. The development of companion diagnostics for emerging therapeutics will be essential for realizing the promise of personalized treatment approaches.
Prevention Strategies
Given the strong environmental component of EoE development, investigation of primary prevention strategies represents an important research priority. This may include studies of early-life interventions to promote healthy microbiome development, strategies to maintain epithelial barrier integrity, or approaches to prevent early allergic sensitization.
Understanding the natural history of EoE development from early allergic sensitization through clinical disease manifestation will be essential for identifying optimal intervention points for prevention strategies.
Clinical Implications and Therapeutic Considerations
Integrated Care Models
The recognition of EoE as part of the broader atopic march has important implications for clinical care delivery. It shares many features with other atopic diseases (asthma, allergic rhinitis, and atopic dermatitis), including the following: T helper 2 cells and eosinophils play a critical role in the pathogenesis of the disease; avoidance of allergens promotes remission of disease and symptom control; and locally applied corticosteroids provide control. Finally, most patients who have eosinophilic gastrointestinal disorders have an associated atopic disease [77].
This shared pathophysiology suggests that integrated care models involving allergists, gastroenterologists, and other specialists may provide optimal patient outcomes. The ability of dupilumab to treat multiple atopic conditions simultaneously further supports the value of coordinated care approaches.
Early Intervention Strategies
The concept of EoE as a late manifestation of the atopic march suggests that early intervention in the allergic disease process might prevent EoE development. This could include aggressive management of atopic dermatitis to prevent sensitization, early introduction of allergenic foods to promote tolerance, or interventions to support healthy microbiome development.
However, the development of evidence-based early intervention strategies will require prospective studies tracking patients from early allergic sensitization through potential EoE development. The long natural history of this process presents significant challenges for clinical research but is essential for developing effective prevention approaches.
Treatment Sequencing and Combination Approaches
As the therapeutic armamentarium for EoE expands, questions about optimal treatment sequencing and potential combination approaches become increasingly important. The current paradigm of stepwise escalation from dietary approaches to topical steroids to biologics may need revision based on individual patient characteristics and disease severity.
Treatment algorithms are needed to position EoE therapies as they emerge [78]. The development of such algorithms will require consideration of factors including disease severity, patient preferences, comorbid conditions, and cost-effectiveness considerations.
Conclusion 
This comprehensive analysis of eosinophilic esophagitis through the lens of the skin-gut axis reveals a complex, multifaceted disease that exemplifies the interconnected nature of allergic disorders. The recognition that both diseases manifest on stratified squamous epithelium along the skin-gut continuum [79] provides a unifying conceptual framework that has already led to significant therapeutic advances.
The evidence supporting epithelial barrier dysfunction as a central pathogenic mechanism is compelling and suggests that strategies to restore barrier function may provide therapeutic benefits beyond traditional anti-inflammatory approaches. Compelling evidence over the past decade supports the central role of epithelial barrier dysfunction in the pathophysiology of eosinophilic esophagitis. The purpose of this review is to summarize the genetic, environmental, and immunologic factors driving epithelial barrier dysfunction, and how this impaired barrier can further promote the inflammatory response in EoE [80].
The success of dupilumab as the first FDA-approved treatment for EoE validates the approach of targeting key type 2 inflammatory pathways and provides proof-of-concept for biological therapies in this disease. More importantly, the “umbrella” effect of dupilumab across multiple atopic conditions supports the concept of shared pathogenic mechanisms and suggests that targeting these common pathways may provide broad therapeutic benefits for patients with multiple allergic diseases.
However, significant challenges remain. The heterogeneity of EoE, both clinically and molecularly, suggests that personalized approaches may be needed to optimize therapeutic outcomes. The complex interplay between genetic susceptibility, environmental exposures, and immune dysfunction requires continued investigation to develop more precise therapeutic targets and prevention strategies.
The emerging understanding of microbiome contributions to EoE pathogenesis opens new avenues for therapeutic intervention that complement traditional immunosuppressive approaches. Our data suggest that Clostridia based interventions could be tested as adjuncts to current therapeutic strategies in EoE [81]. These microbiome-based interventions may provide more physiological approaches to disease management that restore normal host-microbe interactions rather than suppressing immune responses.
Looking forward, the integration of advances in our understanding of barrier dysfunction, innate immune activation, and microbiome interactions will likely lead to more sophisticated treatment approaches that address the multifactorial nature of EoE. The development of reliable biomarkers for disease activity and therapeutic response will be essential for realizing the promise of precision medicine approaches in this complex disease.
The story of EoE and the skin-gut axis illustrates the power of mechanistic understanding to drive therapeutic innovation. As our understanding of the molecular connections between skin and esophageal inflammation continues to evolve, it seems likely that this paradigm will extend to other allergic diseases, potentially transforming our approach to the entire spectrum of atopic disorders.
In conclusion, EoE represents a paradigmatic example of how the skin-gut axis concept can advance our understanding of allergic disease pathogenesis and guide therapeutic development. The continued investigation of this fascinating disease will undoubtedly yield insights that extend far beyond EoE itself, contributing to our broader understanding of allergic disease and immune dysfunction in the modern world.
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