Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt Children's Hospital, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Allergy. 2024 Oct;79(10):2798-2811. doi: 10.1111/all.16208. Epub 2024 Jul 12.
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.
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.
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.
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.
质子泵抑制剂（PPI）和局部皮质类固醇（TS）联合用于治疗嗜酸细胞性食管炎（EoE）患儿。然而，有一部分患儿对此联合治疗无反应。我们旨在通过宏转录组学，鉴定出 EoE 患儿对 PPI 和 TS 联合治疗无反应（EoE-PPI-TSnr，n=7）和有反应（EoE-PPI-TSr，n=7）的食管转录、细胞组成和微生物差异，并与对照组（n=9）进行比较。
采用差异基因表达分析鉴定转录差异，并使用 EoE 诊断试剂盒（EDP）进行验证。采用去卷积分析鉴定其细胞组成差异。对食管活检 RNAseq 数据进行微生物组分析，同时将微生物丰度与食管基因表达相关联。
EoE-PPI-TSnr 与 EoE-PPI-TSr 相比，共有 3164 个上调基因和 3154 个下调基因。EoE-PPI-TSnr 中嗜酸性粒细胞炎症反应、细胞因子信号和胶原形成途径显著上调。EoE-PPI-TSnr 与 EDP 之间有 56%的失调基因重叠，且在调控方向上完全一致。EoE-PPI-TSnr 中嗜酸性粒细胞、树突状细胞（DCs）、未成熟 DCs、巨核细胞-红细胞祖细胞和 T 辅助细胞 1 细胞显著增加。微生物组多样性无显著差异。EoE-PPI-TSnr 中梭杆菌属和不动杆菌属的相对丰度显著不同，且与关键途径相关。
我们的研究结果提供了关于与儿童 EoE 患儿对 PPI 和 TS 联合治疗无反应相关的分子、细胞和微生物因素的重要见解。本研究加深了我们对 EoE 发病机制的认识，同时为个体化治疗策略提供了指导。
