Disease-associated DNA methylation signatures in esophageal biopsies of children diagnosed with Eosinophilic Esophagitis.
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ABSTRACT:
SUBMITTER: Strisciuglio C
PROVIDER: S-EPMC8052828 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
Publications
Disease-associated DNA methylation signatures in esophageal biopsies of children diagnosed with Eosinophilic Esophagitis.
Strisciuglio Caterina C Payne Felicity F Nayak Komal K Andreozzi Marialuisa M Vitale Alessandra A Miele Erasmo E Zilbauer Matthias M
Clinical epigenetics 20210417 1
Eosinophilic esophagitis (EoE) is a leading cause of dysphagia and food impaction in children and adults. The diagnosis relies on histological examination of esophageal mucosal biopsies and requires the presence of > 15 eosinophils per high-powered field. Potential pitfalls include the impact of biopsy sectioning as well as regional variations of eosinophil density. We performed genome-wide DNA methylation analyses on 30 esophageal biopsies obtained from children diagnosed with EoE (n = 7) and m ...[more]
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Project description:Eosinophilic oesophagitis (EoE) is a leading cause of dysphagia and food impaction in children and adults. In this pilot study, we performed genome-wide DNA methylation analyses on oesophageal biopsies obtained from children diagnosed with EoE (at diagnosis and after treatment) and matched controls. Analyses reveal striking disease associated differences in the DNA methylation profile of mucosal biopsies in children diagnosed with EoE, highlighting the great potential for epigenetic signatures to be developed into clinically applicable biomarkers.
2021-07-01 | E-MTAB-9824 | biostudies-arrayexpress
Project description:ObjectiveThe microbiome has been implicated in the pathogenesis of a number of allergic and inflammatory diseases. The mucosa affected by eosinophilic esophagitis (EoE) is composed of a stratified squamous epithelia and contains intraepithelial eosinophils. To date, no studies have identified the esophageal microbiome in patients with EoE or the impact of treatment on these organisms. The aim of this study was to identify the esophageal microbiome in EoE and determine whether treatments change this profile. We hypothesized that clinically relevant alterations in bacterial populations are present in different forms of esophagitis.DesignIn this prospective study, secretions from the esophageal mucosa were collected from children and adults with EoE, Gastroesophageal Reflux Disease (GERD) and normal mucosa using the Esophageal String Test (EST). Bacterial load was determined using quantitative PCR. Bacterial communities, determined by 16S rRNA gene amplification and 454 pyrosequencing, were compared between health and disease.ResultsSamples from a total of 70 children and adult subjects were examined. Bacterial load was increased in both EoE and GERD relative to normal subjects. In subjects with EoE, load was increased regardless of treatment status or degree of mucosal eosinophilia compared with normal. Haemophilus was significantly increased in untreated EoE subjects as compared with normal subjects. Streptococcus was decreased in GERD subjects on proton pump inhibition as compared with normal subjects.ConclusionsDiseases 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.
| S-EPMC4447451 | biostudies-literature
Project description:IntroductionUnder homeostatic conditions, esophageal epithelium displays a proliferation/differentiation gradient that is generated as proliferative basal cells give rise to suprabasal cells then terminally differentiated superficial cells. This proliferation/differentiation gradient is often perturbed in esophageal pathologies. Basal cell hyperplasia may occur in patients with gastroesophageal reflux disease (GERD), a condition in which acid from the stomach enters the esophagus, or eosinophilic esophagitis (EoE), an emerging form of food allergy. While GERD is a primary risk factor for esophageal cancer, epidemiological data suggests that EoE patients do not develop esophageal cancer.MethodsIn order to investigate the impact of EoE and esophageal cancer specifically on the cellular landscape of esophageal epithelium, we perform single cell RNA-sequencing in murine models of EoE and esophageal cancer, specifically esophageal squamous cell carcinoma (ESCC). We further evaluate modules of co-expressed genes in EoE- and ESCC-enriched epithelial cell clusters. Finally, we pair EoE and ESCC murine models to examine the functional relationship between these pathologies.ResultsIn mice with either EoE or ESCC, we find expansion of cell populations as compared to normal esophageal epithelium. In mice with EoE, we detect distinct expansion of 4 suprabasal populations coupled with depletion of 2 basal populations. By contrast, mice with ESCC display unique expansion of 2 basal populations and 1 suprabasal population, as well as depletion of 2 suprabasal populations. Senescence, glucocorticoid receptor signaling, and granulocyte-macrophage colony-stimulating factor pathways are associated with EoE-enriched clusters while pathways associated with cell proliferation and metabolism are identified in ESCC-enriched clusters. Finally, our in vivo data demonstrate that exposure to EoE inflammation limits tumor burden of esophageal carcinogenesis.DiscussionOur findings provide the first functional investigation of the relationship between EoE and esophageal cancer and suggest that esophageal epithelial remodeling events occurring in response to EoE inflammation may limit esophageal carcinogenesis. This investigation may have future implications for leveraging allergic inflammation-associated alterations in epithelial biology to prevent and/or treat esophageal cancer.
| S-EPMC10090679 | biostudies-literature
Project description:BackgroundA high prevalence of eosinophilic esophagitis (EoE) has been preliminarily reported in patients after repair of esophageal atresia (EA), but the basis of this association is unknown.ObjectivesWe aimed to (1) characterize the EoE transcriptome in patients with EA, (2) compare the EoE transcriptome in patients with EoE and EA with that in patients with EoE alone, and (3) identify transcripts that could predispose patients with EA to EoE.MethodsThis single-center, population-based, retrospective study identified 4 EoE study cohorts: healthy control subjects, patients with EA and EoE (EA+EoE+), patients with EA without EoE (EA+EoE-), and patients with EoE without EA (EA-EoE+). Molecular signatures were assessed by using the EoE diagnostic panel, a 94-gene expression quantitative PCR array.ResultsIn a cohort of 110 pediatric patients with surgically repaired EA, 20 (18%) patients were given a diagnosis of EoE, representing a 364-fold enrichment of EoE in patients with EA compared with the general pediatric population. EoE diagnostic panel analyses revealed a major overlap between the EA+EoE+ and EA-EoE+ cohorts. A proportion (approximately 25%) of EoE signature genes were dysregulated in patients with EA+EoE- compared with healthy control subjects, including those involved in epithelial barrier function and type 2-associated inflammatory responses. Patients with EA+EoE+ exhibit a more severe EoE clinical phenotype than those with EA-EoE+ in terms of dysphagia and dilation need.ConclusionsPatients with EA have increased risk of EoE. Patients with EoE with EA have a similar molecular profile compared with that of patients with EoE without EA. Dysregulated baseline epithelial barrier and type 2-associated genes in EA monomorbidity might explain the higher EoE prevalence in patients with EA.
| S-EPMC6461044 | biostudies-literature
Project description:The incidence of eosinophilic esophagitis (EoE) has increased in the past several years, yet our understanding of its pathogenesis remains limited. To test the hypothesis that microRNAs (miRNAs) are altered in children with EoE, miRNAs were profiled in esophageal mucosa biopsies obtained from patients with active disease (n = 5) and healthy control subjects (n = 6). Fourteen miRNAs were significantly altered between groups; four of these miRNAs were decreased in EoE patients. A panel of five miRNAs (miR-203, miR-375, miR-21, miR-223, and miR-142-3p) were selected for validation in an independent set of samples from control (n = 22), active disease (n = 22), inactive disease (n = 22), and gastroesophageal reflux disease (n = 6) patients. Each panel miRNA was significantly altered among groups. miRNA changes in esophageal biopsies were not reflected in the circulating RNA pool, as no differences in panel miRNA levels were observed in sera collected from the four patient groups. In addition, in contrast to previous studies, no change in esophageal miRNA levels was detected following treatment that resolved esophageal eosinophilia. In an effort to identify the ramifications of reduced esophageal miR-203, miR-203 activity was inhibited in cultured epithelial cells via expression of a tough decoy miRNA inhibitor. Luciferase reporter assays demonstrated that miR-203 does not directly regulate human IL-15 through targeting of the IL-15 3'-untranslated region. From these experiments, it is concluded that miRNAs are perturbed in the esophageal mucosa, but not the serum, of pediatric EoE patients. Further investigation is required to decipher pathologically relevant consequences of miRNA perturbation in this context.
| S-EPMC4200319 | biostudies-literature
Project description:Background & aimsAn association of eosinophilic esophagitis (EoE) with esophageal dysmotility has been described, however, the related mechanism remains unclear. We aimed to evaluate clinical and physiologic characteristics, including esophageal distensibility, associated with secondary peristalsis in patients with EoE.MethodsA total of 199 consecutive adult patients with EoE (age, 18-78 y; 32% female) who completed a 16-cm functional luminal imaging probe (FLIP) during endoscopy were evaluated in a cross-sectional study. FLIP panometry contractile response (CR) patterns were classified as normal CR or borderline CR if antegrade contractions were present, and abnormal CRs included impaired/disordered CR, absent CR, or spastic-reactive CR. The distensibility plateau of the esophageal body and esophagogastric junction distensibility was measured with FLIP.ResultsFLIP CR patterns included 68 (34%) normal CR, 65 (33%) borderline CR, 44 (22%) impaired/disordered CR, 16 (8%) absent CR, and 6 (3%) spastic-reactive CR. Compared with normal CRs, abnormal CRs more frequently had reduced esophageal distensibility (distensibility plateau <17 mm in 56% vs 32%), greater total EoE reference scores (median, 5; interquartile range [IQR], 3-6 vs median, 4; IQR, 3-5) with more severe ring scores, and a greater duration of symptoms (median, 10 y; IQR, 4-23 y vs median, 7 y; IQR, 3-15 y). Mucosal eosinophil density, however, was similar between abnormal CRs and normal CRs (median, 34 eosinophils/high-power field [hpf]; IQR, 14-60 eosinophils/hpf vs median, 25 eosinophils/hpf; IQR, 5-50 eosinophils/hpf).ConclusionsAlthough normal secondary peristalsis was observed frequently in this EoE cohort, abnormal esophageal CRs were related to EoE disease severity, especially features of fibrostenosis. This study evaluating secondary peristalsis in EoE suggests that esophageal wall remodeling, rather than eosinophilic inflammatory intensity, was associated with esophageal dysmotility in EoE.
| S-EPMC9081296 | biostudies-literature
Project description:Eosinophilic esophagitis and esophageal squamous cell carcinoma both feature epithelial remodeling in the form of hyperplasia. We used scRNA-Seq to examine the cellular and molecular alterations between these distinct pathologies.
2022-11-21 | GSE218118 | GEO
Project description:Background & aimsEosinophilic esophagitis (EoE) is a patchy disease of the esophagus with significant variability in intraepithelial eosinophilia. Three biopsies each from distal and proximal esophagus are recommended for identification of active EoE. Recent work suggests 3 biopsy sites are more optimal. We sought to evaluate 2-site vs 3-site esophageal biopsy combinations for utility to identify active EoE.MethodsWe prospectively obtained 3-site esophageal biopsies based on rigorous endoscopic measurements of the proximal, mid, and distal esophagus and gastroesophageal junction. Biopsies were reviewed by a pathologist, and those with at least 15 eosinophils per high-power field were considered active EoE. The sensitivity of one or more sites to identify active EoE was determined, and endoscopic measurements were correlated to height and age.ResultsFive hundred ninety-six endoscopies were performed in 217 patients; of these, 304 endoscopies in 167 patients had active EoE. Among the initial esophagogastroduodenoscopies with active EoE, distal biopsies had greater than 80% sensitivity, whereas mid and proximal biopsies had sensitivity of 65% and 62%, respectively, and distal + proximal biopsies had the highest diagnostic sensitivity for a 2-site combination. Among the 304 endoscopies with active EoE, 9 had focal eosinophilia restricted to the mid esophagus, and 8 were restricted to the proximal esophagus. For patients with multiple endoscopies with active EoE, nearly one fourth had reduced sites with eosinophilia at the second time point. Endoscopic measurements strongly correlated with height and age.ConclusionsThis study supports endoscopic measurement-guided 3-site biopsies for optimal disease assessment of active EoE in children.
| S-EPMC9552248 | biostudies-literature
Project description:This study sought to evaluate the diffferential gene expression of human Eosinophilic Esophagitis (EoE) patients compared to control patients. Abstract from associated publication: Eosinophilic Esophagitis (EoE) is a chronic allergic disease characterized by progressive inflammation of the esophageal mucosa. While the transcriptome of EoE has been reported, few studies have examined the genetics among both adult and pediatric EoE populations. Here, we use microarray analysis to interrogate gene expression using esophageal biopsies from EoE and Control subjects with a wide age distribution. Analysis of differential gene expression and prediction of impaired pathways was compared using conventional transcriptome analysis programs and an artificial intelligence-based ADVAITA program. Principal Components Analysis revealed samples cluster by disease status (EoE and Control) irrespective of clinical features like sex, age, and disease severity. Global transcriptomic analysis revealed differential expression of several genes previously reported in EoE (CCL26, CPA3, POSTN, CTSC, ANO1, CRISP3, SPINK7). In addition, we identified differential expression of several genes from the MUC and SPRR families, which has not been previously reported. Our findings suggest their involvement in impaired barrier integrity and loss of epidermal cell differentiation in EoE patients. These findings present two new gene families that are differentially expressed in EoE patients in both adult and pediatric populations, which presents an opportunity for a future therapeutic targets that would be useful in a large demographic of patients.
2023-08-10 | GSE228083 | GEO
Project description:ObjectivesEosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disorder of the esophagus. Consensus guidelines recommend obtaining esophageal, gastric, and duodenal biopsies at diagnostic endoscopy when EoE is suspected. The utility of repeated gastric and duodenal biopsies during follow-up endoscopy in patients previously diagnosed with EoE is not established. The aim of the present study was to explore the role of gastric and duodenal biopsies in children with an established diagnosis of EoE undergoing repeat endoscopy to assess histological response to treatment.MethodsRetrospective chart review of children diagnosed with EoE at a tertiary care center was conducted. A total of 160 patients with EoE with demographic clinical, endoscopic, and histological data at diagnosis and follow-up endoscopy were included. The frequency of gastric and duodenal biopsies at follow-up endoscopy with abnormal histology and their correlation to endoscopic findings was determined.ResultsAt follow-up endoscopy, 83% (132/160) of patients had gastric and 74% (118/160) had duodenal biopsies. Histology was normal in 81% of gastric and 92% of duodenal biopsies. The most frequent gastric abnormalities were chemical and inactive chronic gastritis. The most frequent duodenal abnormality was villous blunting with increased intraepithelial lymphocytes. Two patients with normal gastric and duodenal histology progressed to eosinophilic gastroenteritis at follow-up endoscopy.ConclusionsGastric and duodenal biopsies obtained in EoE patients during follow-up endoscopy show pathology in a minority of patients, increase costs, and may add potential risk of adverse events. Large multicenter, prospective studies of endoscopic practice during follow-up of EoE are warranted to provide evidence supporting best practices.
| S-EPMC6524785 | biostudies-literature