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BACKGROUND: Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown. OBJECTIVE: We aimed to perform a comprehensive molecular and spatial characterization of esophageal MCs in EoE. METHODS: Esophageal biopsies obtained from patients with active EoE, patients with EoE in histologic remission, and individuals with histologically normal esophageal biopsies and no history of esophageal disease (i.e., control individuals) were subject to scRNA-sequencing, flow cytometry, and immunofluorescence analyses. RESULTS: We probed 39,562 single esophageal cells by single-cell RNA sequencing; approximately 5% of these cells were MCs. We identified dynamic MC expansion across disease states. During homeostasis, TPSAB1(high)AREG(high) resident MCs were mainly detected in the lamina propria and exhibited a quiescent phenotype. In patients with active EoE, resident MCs assumed an activated phenotype, and two additional pro-inflammatory MC populations emerged in the intraepithelial compartment, each linked to a proliferating MKI67(high) cluster. One pro-inflammatory activated MC population, marked as KIT(high)IL1RL1(high)FCER1A(low), was not detected in disease remission (termed transient MC), whereas the other population, marked as CMA1(high)CTSG(high), was detected in disease remission where it maintained an activated state (termed persistent MC). MCs were prominent producers of esophageal IL-13 mRNA and protein, a key therapeutic target in EoE. CONCLUSIONS: Esophageal MCs comprise heterogeneous populations with transcriptional signatures associated with distinct spatial compartmentalization and EoE disease status. In active EoE, they assume a pro-inflammatory state and locally proliferate, and remain activated and poised to re-initiate inflammation even during disease remission.

BACKGROUND AND AIMS: Colonic eosinophilia, an enigmatic finding often referred to as eosinophilic colitis (EoC), is a poorly understood condition. Whether EoC is a distinct disease or a colonic manifestation of eosinophilic gastrointestinal diseases (EGIDs) or inflammatory bowel disease (IBD) is undetermined. METHODS: Subjects with EoC (n=27) and controls (normal [NL, n=20], Crohn disease [CD, n=14]) were enrolled across sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). EoC was diagnosed as colonic eosinophilia (ascending ≥100, descending ≥85, sigmoid ≥65 eosinophils/high-power field) with related symptoms. Colon biopsies were subjected to RNA sequencing. Associations between gene expression and histologic features were analyzed with Spearman correlation; operational pathways and cellular constituents were computationally derived. RESULTS: We identified 987 differentially expressed genes (EoC transcriptome) between EoC and NL (>1.5-fold change, P < .05). Colonic eosinophil count correlated with 31% of EoC transcriptome, most notably with CCL11 and CLC (r=0.78 and 0.77, P < .001). Among EoC and other EGIDs, there was minimal transcriptomic overlap; and minimal evidence of a strong allergic type 2 immune response compared with other EGIDs. Decreased cell-cycle and increased apoptosis in EoC compared with NL were identified by functional enrichment analysis and immunostaining using Ki-67 and cleaved caspase-3. Pericryptal circumferential eosinophil collars were associated with the EoC transcriptome (P < .001). EoC transcriptome-based scores were reversible with disease remission and differentiated EoC from IBD, even after controlling for colonic eosinophil levels (P < .0001). CONCLUSION: We established EoC transcriptomic profiles, identified mechanistic pathways, and integrated findings with parallel IBD and EGID data. These findings establish EoC as a distinct disease compared with other EGIDs and IBD, thereby providing a basis for improving diagnosis and treatment.

Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences.Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro.TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P.001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P.001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P.001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling.Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.

Despite effective dietary treatments, physicians prefer medications for eosinophilic esophagitis (EoE).We conducted a web-based survey of providers to assess the perceived effectiveness, practice patterns, and barriers to EoE dietary therapy.Providers view diet as the least effective treatment. The greatest barrier was the belief that patients are disinterested and unlikely to adhere (58%). With less access to dietitians (56%), nonacademic providers often manage diets without dietitian guidance (41%).Given high patient acceptance for diets and multiple treatment options for EoE, clinicians need evidence-based knowledge on EoE diets, access to dietitians, and awareness of patient preferences.

Recent advances in rare disease research are accelerated by the work of consortia that have been supported by the National Institutes of Health. Development of such consortia rely on multidisciplinary relationships and engagement with patient advocacy groups, as well as the National Institutes of Health and industry and academic partners. In this rostrum we present the development of such a process that focuses on eosinophilic gastrointestinal diseases. Principal investigators, patient advocacy groups, research assistants, and trainees work together to perform natural history studies that promote clinical trial readiness tools, conduct clinical trials, train a new generation of investigators, and perform innovative pilot studies.

The Consortium of Eosinophilic Gastrointestinal Diseases and the International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the recent 2018 Annual Meeting of the American Academy of Allergy, Asthma & Immunology, which was coupled for the first time with the World Allergy Organization meeting to create an international platform. The symposium featured experts in many facets of eosinophilic gastrointestinal diseases, including allergy, immunology, gastroenterology, pathology, and nutrition, and was a well-attended event. The basic science, genetics, cellular immunology, and clinical features of the diseases, with a focus on epithelial, eosinophil, and mast cell responses, as well as current and emerging treatment options, were reviewed. Here we briefly review some of the highlights of the material presented at the meeting.

Eosinophilic esophagitis (EoE) is a food antigen-mediated disorder of the esophagus characterized by eosinophil predominant inflammation and symptoms of esophageal dysfunction. Dietary antigen elimination induces clinical and histological remission in patients with EoE. The most restrictive of elimination diets (the elemental diet) removes all possible food antigens while empiric elimination diets remove all (or a subset) of food antigens most commonly reported to cause esophageal eosinophilia and food allergies (milk, egg, wheat, soy, peanuts, tree nuts, fish, or legumes). Elimination diets are effective treatments for EoE but pose psychosocial and financial challenges to patients and consequently may impair quality of life. Foods that are commonly eliminated, especially milk, are also nutrient-dense and therefore their elimination may result in inadequate nutrient intake or deficiencies without careful diet planning to include nutritionally comparable and safe food substitutes. After remission is achieved with elimination diets, foods can be reintroduced sequentially to identify specific food triggers, but this reintroduction is not standardized. Food elimination and food reintroductions should consider the patient's lifestyle, nutrition needs, and skills and ideally be managed by a team with knowledge of eosinophilic gastrointestinal disorders and nutrition.

Eosinophilic esophagitis (EoE), a food antigen-mediated disease, is effectively treated with the dietary elimination of six foods commonly associated with food allergies (milk, wheat, egg, soy, tree nuts/peanuts and fish/shellfish). Because wheat shares homologous proteins (including gluten) with barley and rye and may also be processed with these grains, some clinicians have suggested barley and rye may also trigger EoE as a result of cross-reaction and/or cross-contamination with wheat. In this opinion paper, we discuss the theoretical risks of cross-reactivity and cross-contamination among wheat, barley, and rye proteins (including gluten), assess common practices at EoE treatment centers, and provide recommendations for dietary treatment and future studies of EoE.

Eosinophilic esophagitis (EoE) is a chronic/immune-antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Dietary elimination therapy has been shown to be an effective, drug-free prescription for the treatment of EoE. A range of different dietary elimination therapies have been used. Regardless of the elimination diet chosen, dietary therapy requires in-depth nutrition assessment and management. Elimination diets are not without risk and may impact nutritional status, eating pleasure, and overall quality of life. With adequate guidance, dietary therapy can be effective and nutritionally balanced, and the adverse impact on lifestyle can be minimized. This work group report addresses the potential challenges of implementing an elimination diet for the management of EoE and provides instructions and tools for physicians, dietitians, and other allied health professionals to help guide them in planning elimination diets for both children and adults.