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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
背景：质子泵抑制剂（PPI）和局部类固醇（TS）的组合用于治疗嗜酸性粒细胞性食管炎（EoE）的儿童。然而,一部分儿童对这种联合治疗没有反应.我们的目的是鉴定食管转录，细胞组成,非应答者（EoE-PPI-TSnr;n=7）和应答者（EoE-PPI-TSr;n=7）之间的微生物差异使用转移切除术对EoE和对照（n=9）的联合治疗。
方法：使用差异基因表达分析来鉴定转录差异，使用EoE诊断面板(EDP)进行验证。进行去卷积分析以鉴定其细胞类型组成的差异。从食管活检RNAseq数据进行微生物组分析，微生物丰度与食管基因表达相关。
结果：总而言之，3164个上调和3154个下调的基因将EoE-PPI-TSnr与EoE-PPI-TSr区分开。嗜酸性粒细胞炎症反应，细胞因子信号，EoE-PPI-TSnr中胶原形成途径显著上调。EoE-PPI-TSnr和EDP之间失调的基因有56%的重叠，在调制的方向性上有完美的一致性。嗜酸性粒细胞,树突状细胞（DC），未成熟DCs,巨核细胞-红细胞祖细胞，1型辅助性T细胞在EoE-PPI-TSnr中显著增高。微生物组多样性没有显著差异。梭杆菌属的相对丰度。和不动杆菌。EoE-PPI-TSnr明显不同，与关键通路相关。
结论：我们的结果提供了对分子，细胞，和与EoE儿童对PPI和TS联合治疗缺乏反应相关的微生物因素。这项研究提高了我们对EoE病理生物学的理解，同时指导个性化治疗策略。
方法：使用差异基因表达分析来鉴定转录差异，使用EoE诊断面板(EDP)进行验证。进行去卷积分析以鉴定其细胞类型组成的差异。从食管活检RNAseq数据进行微生物组分析，微生物丰度与食管基因表达相关。
结果：总而言之，3164个上调和3154个下调的基因将EoE-PPI-TSnr与EoE-PPI-TSr区分开。嗜酸性粒细胞炎症反应，细胞因子信号，EoE-PPI-TSnr中胶原形成途径显著上调。EoE-PPI-TSnr和EDP之间失调的基因有56%的重叠，在调制的方向性上有完美的一致性。嗜酸性粒细胞,树突状细胞（DC），未成熟DCs,巨核细胞-红细胞祖细胞，1型辅助性T细胞在EoE-PPI-TSnr中显著增高。微生物组多样性没有显著差异。梭杆菌属的相对丰度。和不动杆菌。EoE-PPI-TSnr明显不同，与关键通路相关。
结论：我们的结果提供了对分子，细胞，和与EoE儿童对PPI和TS联合治疗缺乏反应相关的微生物因素。这项研究提高了我们对EoE病理生物学的理解，同时指导个性化治疗策略。
