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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要嗜酸性食管炎(EoE)是一种日益流行的由变应原介导的临床病理条件。它的特点是出现食道症状和食道受损。上皮屏障在嗜酸性炎症中的作用。患有EoE的儿童患有令人虚弱的症状，如呕吐、进食困难、吞咽困难和无法茁壮成长。局部吞服类固醇(TSS)是EoE治疗的主要手段，可以改善症状、组织学缓解和上皮屏障功能的恢复。然而，超过50%的患有EoE的儿童可能对TSS没有反应，并继续遭受持续不断的症状，这可能对他们的生活质量产生负面影响。此外，失控的嗜酸性炎症可进一步损害食道上皮特性并导致亚上皮下纤维化需要急诊内窥镜或外科手术的食道狭窄和食道食物嵌塞干预。到目前为止，对儿童对TSS反应的相关因素知之甚少。使用EoE。特别是，食道微生物组的作用以及它如何与食道相互作用上皮细胞对EoE儿童TSS反应的影响尚未被研究。重要的是要将这种关系理解为EoE发病率和流行率的快速增长提示食道微生物群等环境因素可能在食道感染中起重要作用调节EoE的治疗反应。此应用程序的目标是调查 TSS反应者的食道微生物组及其与宿主上皮的交互作用(EoE-TSSr)， TSS无响应器(EoE-TSSnr)和非EoE控制。这将是第一次决定是否 TSS治疗结果在一定程度上是由驻留的食道微生物区系结构和功能得出的可能会改变食道屏障的完整性和免疫功能。使用EoE的儿科队列- TSSR、EoE-TSSnr和非EoE对照我们将：a)表征微生物组组成和食道组织样本在物种水平上的功能能力，b)决定机制活跃的食道微生物群、宿主上皮细胞表达谱与TSS的关系治疗效果。这项研究的结果将扩大我们对这些因素的理解与儿童EoE对TSS的反应有关。从长远来看，这项研究将为儿科急诊室的个性化护理。