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: 10432560
• 负责人: Girish Hiremath
• 金额: $ 25.95万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432560
• 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; Epithelial; 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; Lead; Longitudinal Studies; Mediating; Molecular; Mucous Membrane; Operative Surgical Procedures; Outcome; Outcome Study; Pathologic; 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; base; 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 嗜酸性粒细胞性食管炎（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。其特点是出现食管症状和食管受损 嗜酸性粒细胞炎症中的上皮屏障。患有EoE的孩子患有 使人衰弱的症状，如呕吐、喂食困难、吞咽困难和发育迟缓。 局部吞咽类固醇 (TSS) 是 EoE 治疗的支柱，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% 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，这可能会导致 对他们的生活质量产生负面影响。此外，不受控制的嗜酸性粒细胞炎症可以进一步 损害食管上皮特性并导致上皮下纤维化，从而导致 食管狭窄和食管食物嵌塞需要紧急内窥镜检查或手术 干涉。迄今为止，对于儿童 TSS 反应的相关因素知之甚少 与 EoE。特别是食管微生物组的作用及其与食管的相互作用 尚未研究上皮细胞对 EoE 儿童对 TSS 反应的影响。重要的是 随着 EoE 发病率和患病率的迅速增加，强烈理解这种关系 表明食道微生物组等环境因素可能在 调节 EoE 的治疗反应。该应用程序的目的是研究 TSS 应答者 (EoE-TSSr) 中的食管微生物组及其与宿主上皮的串扰， TSS 无反应者 (EoE-TSSnr) 和非 EoE 对照。它将首次确定是否 TSS 治疗结果部分取决于食道常驻微生物群的结构和功能， 可能会改变食管屏障的完整性和免疫功能。使用 EoE 儿科队列- TSSr、EoE-TSSnr 和非 EoE 对照我们将： a) 表征微生物组组成并 食道组织样本中物种水平的功能能力，b) 确定机制 活跃食管微生物组、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这些因素的理解 与儿童 EoE 对 TSS 的反应相关。从长远来看，本研究将为 儿科 EoE 的个性化护理。