Etiology Of Eosinophilic Esophagitis Research Articles

Epithelial overexpression of IL-33 induces eosinophilic esophagitis dependent on IL-13

BackgroundEosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsies from EoE subjects. ObjectiveWe hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. MethodsWe evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 (saIL-33) in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. ResultsEoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and Th2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathological changes in vivo. EoE33 mice were steroid responsive. ConclusionIL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.

The microbiota in eosinophilic esophagitis: A systematic review.

Eosinophilic esophagitis (EoE) is an atopic disease of the esophagus that has shown a significant increase in incidence and prevalence in the last 20 years. The etiology of EoE is unclear, and few studies explore the esophageal microbiota in EoE. The local microbiome has been implicated in the pathogenesis of several allergic and inflammatory diseases, such as asthma and eczema. In this study, we performed a systematic review to evaluate differences in the microbiota profile of patients with EoE compared with controls. MEDLINE, Embase, Cochrane Library, Scopus, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases were searched to identify studies investigating the microbiota composition in EoE. Three reviewers screened the articles for eligibility and quality. Seven articles underwent full‐text review, and a narrative synthesis was undertaken. The microbiota of the mouth and esophagus are correlated. Patients with active EoE present increased esophageal microbial load and increased abundance in particular species, such as Haemophilus and Aggregatibacter. On the other hand, EoE patients present a decrease in Firmicutes. High microbial load and abundance of Haemophilus are observed in EoE patients, but little evidence exists to demonstrate their influence on inflammation and disease. Understanding microbial signatures in EoE might contribute to the development of novel therapeutic strategies.

Association between Schatzki ring and eosinophilic esophagitis: a systematic review and meta-analysis.

The involvement of hydrochloric acid in the etiology of eosinophilic esophagitis and numerous reports on its coexistence and interaction with reflux disease, as well as the rings of the esophageal mucosa formed with the advancement of the disease, suggest a potential association of eosinophilic esophagitis with another disorder of esophageal morphology potentially caused by exposure to acid reflux-Schatzki ring. Therefore, it seems reasonable to check the relationship of eosinophilic esophagitis with the coexistence of the Schatzki ring as a potential effect of advanced esophageal trachealization, which is the subject of this systematic review with a meta-analysis. The protocol of this meta-analysis was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. A systematic search of the indexed literature in the MEDLINE and Scopus databases from early to December 2019 was performed to identify all original research articles on the association between the occurrence of the Schatzki ring and eosinophilic esophagitis in adults. Out of 68 searched studies, after the analysis and evaluation of the works, only 4 met the criteria set according to the protocol and were included in the meta-analysis. Based on the performed meta-analysis, no relationship was found between the occurrence of Schatzki ring and eosinophilic esophagitis. The present study did not show a significant relationship between the occurrence of the Schatzki ring and eosinophilic esophagitis in the adult population, which suggests that these are two independent causes of dysphagia in this patient population.

Signals from the various immune cells in promoting food allergy-induced eosinophilic esophagitis like disease.

Eosinophilic esophagitis (EoE) is a recently recognized esophageal inflammatory disease with clinical manifestations arising from esophageal dysfunction. The etiology of EoE is currently being clarified and food allergy is evolving as the central cornerstone of EoE disease pathogenesis. Given the large number of eosinophils in the esophagus of people with EoE verified by data from murine models EoE is widely considered as the hallmark T-helper type 2 (Th2) disease of the esophagus. It is also known that some eosinophilic inflammation is controlled by other subsets of T cells such as Th9 or Th17 and control is also exerted by type 2 innate lymphoid cells acting together with basophils. In this paper we review results from molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and present in-depth molecular understanding of EoE.

IL-33 is induced in undifferentiated, non-dividing esophageal epithelial cells in eosinophilic esophagitis

The molecular and cellular etiology of eosinophilic esophagitis (EoE), an emerging tissue-specific allergic disease, involves dysregulated gene expression in esophageal epithelial cells. Herein, we assessed the esophageal expression of IL-33, an epithelium-derived alarmin cytokine, in patients with EoE. IL-33 protein was markedly overexpressed within the nuclei of a subpopulation of basal layer esophageal epithelial cells in patients with active EoE compared to control individuals. IL-33 exhibited dynamic expression as levels normalized upon EoE remission. IL-33–positive basal epithelial cells expressed E-cadherin and the undifferentiated epithelial cell markers keratin 5 and 14 but not the differentiation marker keratin 4. Moreover, the IL-33–positive epithelial cells expressed the epithelial progenitor markers p75 and p63 and lacked the proliferation markers Ki67 and phospho-histone H3. Additionally, the IL-33–positive cells had low expression of PCNA. IL-33 expression was detected in ex vivo–cultured primary esophageal epithelial cells in a subpopulation of cells lacking expression of proliferation markers. Collectively, we report that IL-33 expression is induced in an undifferentiated, non-dividing esophageal epithelial cell population in patients with active EoE.

Mechanisms of Disease of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disease of the esophagus with clinical symptoms derived from esophageal dysfunction. The etiology of EoE is now being elucidated, and food hypersensitivity is emerging as the central cornerstone of disease pathogenesis. Herein, we present a thorough picture of the current clinical, pathologic, and molecular understanding of the disease with a focus on disease mechanisms.

The Role of Environmental Exposures in the Etiology of Eosinophilic Esophagitis A Systematic Review

The Role of Environmental Exposures in the Etiology of Eosinophilic Esophagitis A Systematic Review

Re: Might the Use of Acid-Suppressive Medications Predispose to the Development of Eosinophilic Esophagitis?

To the Editor: In a recent issue of the American Journal of Gastroenterology, we read with immense interest the article by Merwat and Spechler (1) about the possible role of acid-suppressive medications in the pathogenesis of eosinophilic esophagitis. At present, the etiology of eosinophilic esophagitis is still questionable. What is already known is that eosinophilic esophagitis is a manifestation of food allergy and that personal or family history of atopy represents a predisposing factor. The authors discuss the possible role of acid-suppressive therapy in the pathogenesis of eosinophilic esophagitis by two probable mechanisms: insufficient protein degradation due to proteinase inactivity in diminished gastric acidity, which can elicit an immune response, and increased mucosal permeability as a consequence of therapy with proton pump inhibitors, which can contribute to the development of food allergy (2,3,4).

Seasonal Distribution in Newly Diagnosed Cases of Eosinophilic Esophagitis in Adults

The etiology of eosinophilic esophagitis (EoE) is not well understood. It has been proposed that eosinophils migrate to the esophagus in response to various ingested and inhaled allergens. Recent reports in children found an increased proportion of cases of EoE during months with higher outdoor aeroallergens. To our knowledge, this has not been evaluated in adults. We aimed to determine whether there is a seasonal distribution in the number of newly diagnosed cases of EoE in an adult population. We conducted a retrospective review of consecutive adult cases newly diagnosed with EoE in 1 year. Cases were grouped based on the index month when the diagnosis was made at endoscopy. To test the consistency of the observations, a second cohort of consecutive cases of similar sample size diagnosed at a different period in time was also analyzed. In total, 41 patients were diagnosed with EoE at our center during the study period, providing an annual prevalence of 0.98%. More cases were diagnosed with EoE during the months of April and May than any other month (P<0.001). When patients were grouped seasonally, there was a significant increase of EoE cases in spring and summer months (n=28) when compared with the fall and winter months (n=13) (P=0.019). Analysis of the second cohort of cases (n=37) from 2002 to 2006 confirmed a similar seasonal diagnostic pattern for EoE during the outdoor seasons. Our data demonstrate that EoE has a seasonal prevalence in adults. The seasonal variation pattern found in newly diagnosed EoE cases in adults supports the potential role of aeroallergens in the pathogenesis of EoE.

Is the etiology of eosinophilic esophagitis in adults a response to allergy or reflux injury? Study of cellular proliferation markers

Recent research suggests that allergy may be the key factor in the etiology of eosinophilic esophagitis (EE); however, historically, the condition was hypothesized as related to reflux injury to the esophageal mucosa. We studied this hypothesis by comparing markers of inflammation and cellular proliferation in EE and reflux esophagitis. Lower esophageal biopsies of adult patients with EE (n = 10), reflux esophagitis (n = 8), and normal controls (n = 13) were assessed quantitatively for the expression of the cyclooxygenase-2 (COX-2) enzyme, cellular proliferation, and oncogenic resistance to apoptosis using monoclonal antibodies for COX-2, Ki-67, and Bcl-2, respectively. Normal esophageal epithelium demonstrated weak diffuse uptake of COX-2 stain in the basal layer. No COX-2 expression was demonstrated in the EE group, significantly less than the control and reflux groups (P < 0.01 and P < 0.001, respectively). Cellular proliferation measured by Ki-67 expression was higher in EE and reflux compared with control (P < 0.001 and P < 0.01). Ki-67 expression, and thus degree of hyperplasia, appeared greater in EE than reflux, but was not statistically significant (P = 0.228). The degree of apoptosis was similar in all study groups. EE and reflux esophagitis are proliferative conditions expressing Ki-67 in higher concentrations than control. Mucosal proliferation in reflux esophagitis is COX-2 dependent. This novel research in EE has demonstrated downregulation of COX-2 expression compared with reflux esophagitis and control. We hypothesize that the allergy-related cytokine IL-13 known to inhibit COX-2 expression and found in high concentrations in EE as responsible for this. The pathogenesis of EE is likely dependent on allergy rather than reflux injury to the esophagus.

Seasonal Variation in the Diagnosis of Eosinophilic Esophagitis

Purpose: The etiology of eosinophilic esophagitis (EoE) is unknown, though allergens may play a pathogenic role. The purpose of this study was to examine seasonal variation in diagnosis of EoE as compared to gastroesophageal reflux disease (GERD). We hypothesized that EoE would be more frequently diagnosed at times of high allergen burden (spring/summer) and there would be no seasonal variation in GERD diagnosis. Methods: We performed a retrospective study of the University of North Carolina EoE clinicopathologic database which contains information on patients with esophageal eosinophilia from 2000–2007. Cases of EoE were defined as having ≥15 eosinophils per high-powered field (0.23 mm2; eos/hpf) with at least one typical symptom (eg dysphagia, heartburn, or feeding intolerance) and with other causes of esophageal eosinophilia excluded. Incident cases were categorized by their esophageal biopsy date. Controls were patients with GERD who also underwent endoscopy and biopsy over this time course. Cases of EoE and GERD were stratified by season and month of diagnosis and compared with chi-square. Results: 149 cases of EoE were identified (mean age 24.5 yrs; range: 8 mos-77 yrs); 72 were 18 years or older (48%), 105 (70%) were male, and 119 (80%) Caucasian. 684 GERD controls were identified (mean age 44.1 yrs; range: 4 mos–87 yrs); 49% were male and 81% Caucasian. 19% of EoE cases were diagnosed in the winter (Dec–Feb), 19% in the spring (Mar–May), 34% in the summer (June-Aug), and 28% in the fall (Sept-Nov; see Figure) compared with 23%, 29%, 23%, and 25% of the GERD cases, respectively (P= 0.01). The highest proportion of EoE cases was diagnosed in August (14%) compared with 7% of GERD cases (P= 0.04). Tissue eosinophil counts were also highest during the summer (77 eos/hpf) compared with winter (57 eos/hpf), with a peak level in August (95 eos/hpf). There was no difference in EoE diagnosis based on age, atopic disease, food allergy, or asthma.FigureConclusion: There is evidence of seasonal variation in the diagnosis of EoE at our center, but not in the diagnosis of GERD. The highest percentage of cases of EoE are diagnosed over the summer, which was also the time of highest tissue eosinophil counts. These findings may help generate hypotheses about environmental etiologies of EoE.

Epidemiology and Etiology of Eosinophilic Esophagitis

Eosinophilic esophagitis (EE) is an inflammatory disease of the esophagus characterized by eosinophilic infiltration of the esophageal mucosa. Symptoms of EE are variable, and include gastroesophageal reflux symptoms, abdominal pain, growth failure, and dysphagia. Dysphagia is a more common presentation in adults and older children. Serious complications of EE consisting of esophageal food impactions necessitating urgent endoscopic removal of the food and esophageal strictures requiring endoscopic balloon dilatations are also seen. The potential severity of these symptoms points to the importance of proper recognition and management of the disease, especially given that EE has become more prevalent over the past decade. In this article, available evidence on the epidemiology and etiology of EE is discussed.

This Month in Gastroenterology

This Month in Gastroenterology

Eosinophilic esophagitis: treatment in 2005

Eosinophilic esophagitis is an isolated, eosinophilic inflammation of the esophagus. The symptoms are often confused for those of gastroesophageal reflux. Over the past few years, there has been a significant increase in the literature surrounding eosinophilic esophagitis as more than two-thirds of the articles written on the subject have been published within the past 3 years. Because the incidence is rising and the condition is easily diagnosed by endoscopy with biopsy, it is important for physicians to understand the pathophysiology, clinical presentation, and treatment options available for patients. The etiology of eosinophilic esophagitis in children is reported to be associated with an allergic response to food antigens. Because allergy tests are often unable to determine the causative foods, complete elimination of all foods is often required. The diagnosis requires a biopsy of the esophagus, stomach and duodenum. The condition is diagnosed if the patient's esophageal biopsy depicts over 20 eosinophils per high-powered field despite the use of aggressive acid blockade, biopsies of the stomach antrum and duodenum are normal, and the tissue inflammation resolves when dietary antigens are removed from the diet. While the most commonly involved foods causing eosinophilic esophagitis include milk, eggs, nuts, beef, wheat, fish, shellfish, corn and soy, almost all foods have been implicated. Alternative treatments include esophageal dilatation and medical therapy. This article reviews the past year's literature, concentrating on the pathophysiology, and treatment of eosinophilic esophagitis in both children and adults.

EOSINOPHILIC ESOPHAGITIS

Purpose: To develop information about the etiology of Eosinophilic esophagitis. Methods: IgE and peripheral eosinophil data were reviewed from the charts of 9 patients with dysphagia and esophageal rings. Results: Conclusions: Four of nine (44%) patients had elevated IgE levels; Eight of nine (89%) patients had peripheral eosinophilia. These data are suggestive that an allergic etiology seems to be present in most of these patients with dysphagia and a ringed appearance of the esophagus. The implication is that there may be a role for topical corticosteroids or disodium cromoglycate in patients with eosinophilic esophagitis.Table