Esophageal Microbiome, Epithelial Gene Expression, and Response to Topical Swallowed Steroids in Pediatric Eosinophilic Esophagitis

小儿嗜酸粒细胞性食管炎的食管微生物群、上皮基因表达以及对局部吞咽类固醇的反应

• 批准号: 10558624
• 负责人: Girish Hiremath
• 金额: $ 21.63万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558624
• 关键词: Acinetobacter; Address; Allergens; Biopsy; Biopsy Specimen; Child; Childhood; Classification; Clinical; Collagen; Control Groups; Cytokine Signaling; Deglutition; Disease remission; Distal; Distress; Down-Regulation; Ecology; Endoscopy; Environmental Risk Factor; Eosinophilic Esophagitis; Epithelium; Esophageal Stenosis; Esophageal Tissue; Esophagus; Extracellular Matrix; Failure to Thrive; Fibrosis; Food; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; High Prevalence; Histologic; Homeostasis; Impairment; Incidence; Inflammatory Response; Knowledge; Mediating; Molecular; Mucous Membrane; Operative Surgical Procedures; Outcome; Outcome Study; Pathway interactions; Patients; Pediatric cohort; Peptide Hydrolases; Play; Prevalence; Property; Protocols documentation; Quality of life; Research; Role; Sampling; Steroid therapy; Steroids; Structure; Symptoms; Testing; Time; Tissue Sample; Treatment Efficacy; Up-Regulation; Vomiting; bacterial community; cohort; disabling symptom; eosinophil; eosinophilic inflammation; feeding; high risk; host microbiome; immune function; improved; insight; metagenome; metagenomic sequencing; metatranscriptomics; microbial; microbial community; microbiome; microbiome composition; microbiome signature; microbiota; novel; personalized care; personalized therapeutic; predicting response; response; restoration; therapy outcome; transcriptome; treatment response; Acinetobacter; Address; Allergens; Biopsy; Biopsy Specimen; Child; Childhood; Classification; Clinical; Collagen; Control Groups; Cytokine Signaling; Deglutition; Disease remission; Distal; Distress; Down-Regulation; Ecology; Endoscopy; Environmental Risk Factor; Eosinophilic Esophagitis; Epithelium; Esophageal Stenosis; Esophageal Tissue; Esophagus; Extracellular Matrix; Failure to Thrive; Fibrosis; Food; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; High Prevalence; Histologic; Homeostasis; Impairment; Incidence; Inflammatory Response; Knowledge; Mediating; Molecular; Mucous Membrane; Operative Surgical Procedures; Outcome; Outcome Study; Pathway interactions; Patients; Pediatric cohort; Peptide Hydrolases; Play; Prevalence; Property; Protocols documentation; Quality of life; Research; Role; Sampling; Steroid therapy; Steroids; Structure; Symptoms; Testing; Time; Tissue Sample; Treatment Efficacy; Up-Regulation; Vomiting; bacterial community; cohort; disabling symptom; eosinophil; eosinophilic inflammation; feeding; high risk; host microbiome; immune function; improved; insight; metagenome; metagenomic sequencing; metatranscriptomics; microbial; microbial community; microbiome; microbiome composition; microbiome signature; microbiota; novel; personalized care; personalized therapeutic; predicting response; response; restoration; therapy outcome; transcriptome; treatment response

Summary Eosinophilic esophagitis (EoE) is an increasingly prevalent allergen-mediated clinico-pathologic condition. It is characterized by the presence of esophageal symptoms and impaired esophageal epithelial barrier in the setting of eosinophilic inflammation. The children with EoE suffer from debilitating symptoms such as vomiting, feeding difficulties, inability to swallow, and failure to thrive. Topical swallowed steroids (TSS) are the mainstay of EoE therapy and can lead to improvement in symptoms, histologic remission, and restoration of the epithelial barrier function. However, over 50% of children with EoE may not respond to TSS and continue to suffer from unremitting symptoms which can negatively impact their quality of life. Additionally, the uncontrolled eosinophilic inflammation can further compromise the esophageal epithelial properties and lead to sub-epithelial fibrosis resulting in esophageal stricture and esophageal food impactions requiring emergent endoscopy or surgical intervention. To date, very little is known about the factors associated with response to TSS in children with EoE. In particular, the role of esophageal microbiome and how it interacts with the esophageal epithelium to impact the response to TSS in children with EoE has not been studied. It is important to understand this relationship as the rapid increase in the incidence and prevalence of EoE strongly indicates that environmental factors such as esophageal microbiome may have an essential role in modulating the treatment response in EoE. The objective of this application is to investigate the role of the esophageal microbiome and its cross-talk with the host epithelium in TSS responders (EoE-TSSr), TSS non-responders (EoE-TSSnr) and non-EoE controls. For the first time, it would determine whether TSS therapy outcomes are derived in part by resident esophagus microbiota structure and function that can potentially alter esophageal barrier integrity and immune function. Using a pediatric cohort of EoE- TSSr, EoE-TSSnr and non-EoE controls we will: a) characterize the microbiome composition and functional capability at the species level in the esophagus tissue samples, b) determine the mechanistic association between active esophagus microbiome, host epithelium expression profiles, and TSS therapy efficacy. The outcomes of this study will expand our understanding about the factors associated with response to TSS in pediatric EoE. In the long term, this study will lay the foundation for personalizing the care in pediatric EoE.

概括 嗜酸性食管炎（EOE）是一种越来越普遍的过敏原介导的临床病理学 健康）状况。它的特征是存在食管症状和食管受损 嗜酸性炎症的环境中的上皮屏障。 EOE的孩子遭受 使人衰弱的症状，例如呕吐，进食困难，无能为力和不壮成长。 局部吞咽类固醇（TSS）是EOE疗法的中流型，可以改善 症状，组织学缓解和上皮屏障功能的恢复。但是，超过50％ EOE的儿童可能不会对TSS做出反应，并且会继续患有不懈的症状 负面影响其生活质量。另外，不受控制的嗜酸性炎症可以进一步 妥协食管上皮特性并导致下皮纤维化，导致 食管狭窄和食管食品影响需要紧急内窥镜检查或手术 干涉。迄今为止，关于儿童对TSS的反应相关的因素知之甚少 与eoe。特别是，食管微生物组的作用及其与食管的相互作用 尚未研究上皮影响EOE儿童对TSS的反应。重要的是 理解这种关系是因为EOE的发病率和患病率迅速增加 表明食管微生物组等环境因素可能在 调节EOE中的治疗反应。此应用的目的是调查 食管微生物组及其与TSS响应者（EOE-TSSR）中的宿主上皮的串扰， TSS非反应器（EOE-TSSNR）和非EOE控件。这是第一次决定是否 TSS治疗结果部分由居民食管菌群结构和功能得出 可能会改变食管屏障完整性和免疫功能。使用EOE的儿科队列 TSSR，EOE-TSSNR和非EOE控件我们将：a）表征微生物组组成和 食道组织样品中物种水平的功能能力，b）确定机械 活跃的食道微生物组，宿主上皮表达谱和TSS之间的关联 治疗功效。这项研究的结果将扩大我们对因素的理解 与小儿EOE中对TSS的反应有关。从长远来看，这项研究将为 个性化小儿EOE的护理。