Children with eosinophilic esophagitis non-responsive to combination therapy have distinct esophageal transcriptomic and microbiome profile.

IF 12.6 1区医学 Q1 ALLERGY Allergy Pub Date : 2024-10-01 Epub Date: 2024-07-12 DOI:10.1111/all.16208

Girish Hiremath, Yash Choksi, Hernan Correa, Justin Jacobse, Suman R Das, Siyuan Ma, Jeremy A Goettel, Seesandra V Rajagopala

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Abstract

Background: A combination of proton-pump inhibitors (PPI) and topical steroids (TS) is used to treat children with eosinophilic esophagitis (EoE). However, a subset of children do not respond to this combination therapy. We aimed to identify the esophageal transcriptional, cell composition, and microbial differences between the non-responders (EoE-PPI-TSnr; n = 7) and responders (EoE-PPI-TSr; n = 7) to the combination therapy for EoE and controls (n = 9) using metatranscriptomics.

Methods: Differential gene expression analysis was used to identify transcriptional differences, validated using the EoE diagnostic panel (EDP). Deconvolution analysis was performed to identify differences in their cell type composition. Microbiome analysis was conducted from esophageal biopsies RNAseq data, and microbial abundance was correlated with esophageal gene expression.

Results: In all, 3164 upregulated and 3154 downregulated genes distinguished EoE-PPI-TSnr from EoE-PPI-TSr. Eosinophilic inflammatory response, cytokine signaling, and collagen formation pathways were significantly upregulated in EoE-PPI-TSnr. There was a 56% overlap in dysregulated genes between EoE-PPI-TSnr and EDP, with a perfect agreement in the directionality of modulation. Eosinophils, dendritic cells (DCs), immature DCs, megakaryocytic-erythroid progenitors, and T helper type 1 cells were significantly higher in EoE-PPI-TSnr. There was no significant difference in microbiome diversity. The relative abundance of Fusobacterium sp. and Acinetobacter sp. notably differed in EoE-PPI-TSnr and correlated with the key pathways.

Conclusion: Our results provide critical insights into the molecular, cellular, and microbial factors associated with the lack of response to PPI and TS combination therapy in children with EoE. This study advances our understanding of the pathobiology of EoE while guiding personalized treatment strategies.

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对联合疗法无反应的嗜酸性粒细胞食管炎患儿具有独特的食管转录组和微生物组特征。

背景：质子泵抑制剂（PPI）和局部类固醇（TS）的联合疗法用于治疗嗜酸性粒细胞食管炎（EoE）患儿。然而，有一部分儿童对这种联合疗法没有反应。我们的目的是利用元转录组学找出食管炎联合疗法无应答者（EoE-PPI-TSnr；n = 7）和有反应者（EoE-PPI-TSr；n = 7）与对照组（n = 9）之间的食管转录、细胞组成和微生物差异：方法：使用差异基因表达分析来确定转录差异，并通过EoE诊断面板（EDP）进行验证。进行解卷积分析以确定其细胞类型组成的差异。根据食管活检 RNAseq 数据进行了微生物组分析，并将微生物丰度与食管基因表达相关联：嗜酸性粒细胞炎症反应、细胞因子信号转导和胶原形成通路在 EoE-PPI-TSnr 中显著上调。EoE-PPI-TSnr和EDP的失调基因有56%的重叠，调控的方向性完全一致。嗜酸性粒细胞、树突状细胞（DC）、未成熟DC、巨核细胞-红细胞祖细胞和T辅助1型细胞在EoE-PPI-TSnr中明显增多。微生物组的多样性没有明显差异。在EoE-PPI-TSnr中，Fusobacterium sp.和Acinetobacter sp.的相对丰度明显不同，并与关键通路相关：我们的研究结果为我们深入了解与EoE患儿对PPI和TS联合疗法缺乏反应相关的分子、细胞和微生物因素提供了重要依据。这项研究加深了我们对咽喉炎病理生物学的理解，同时为个性化治疗策略提供了指导。

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来源期刊

Allergy 医学-过敏

CiteScore

26.10

自引率

9.70%

发文量

393

审稿时长

2 months

期刊介绍： Allergy is an international and multidisciplinary journal that aims to advance, impact, and communicate all aspects of the discipline of Allergy/Immunology. It publishes original articles, reviews, position papers, guidelines, editorials, news and commentaries, letters to the editors, and correspondences. The journal accepts articles based on their scientific merit and quality. Allergy seeks to maintain contact between basic and clinical Allergy/Immunology and encourages contributions from contributors and readers from all countries. In addition to its publication, Allergy also provides abstracting and indexing information. Some of the databases that include Allergy abstracts are Abstracts on Hygiene & Communicable Disease, Academic Search Alumni Edition, AgBiotech News & Information, AGRICOLA Database, Biological Abstracts, PubMed Dietary Supplement Subset, and Global Health, among others.