Molina-Jiménez Francisca, Ugalde-Triviño Lola, Arias-González Laura, Armenteros Elisa, Relaño-Rupérez Carlos, Casabona Sergio, Moreno-Monteagudo José Andrés, Pérez-Fernández María Teresa, Martín-Domínguez Verónica, Fernández-Pacheco Jennifer, Laserna-Mendieta Emilio José, Muñoz-Hernández Patricia, García-Martínez Jorge, Muñoz Javier, Lucendo Alfredo J, Santander Cecilio, Majano Pedro
Molecular Biology Unit, Hospital Universitario de la Princesa, Madrid, Spain.
Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-IP), Madrid, Spain.
Allergy. 2024 Dec;79(12):3448-3463. doi: 10.1111/all.16261. Epub 2024 Aug 2.
Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients including proteins associated with inflammation and epithelial barrier function; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response.
We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n = 25) patients and healthy controls (C) (n = 10). In EoE patients, esophageal biopsies were taken before (pre) and after (post) an 8-week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non-responders (non-responder) and < 15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins were characterized to identify altered biological processes and signaling pathways.
Comparative analysis of differentially accumulated proteins between groups revealed common signatures between three groups of patients with inflammation (responder-PrePPI, non-responder-PrePPI, and non-responder-PostPPI) and without inflammation (controls and responder-PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in responder-PostPPI. Furthermore, we identified a set of candidate proteins to differentiate responder-PrePPI and non-responder-PrePPI EoE patients before treatment.
These findings provide evidence that PPI therapy reverses the alterations in esophageal inflammatory and epithelial proteins characterizing EoE, thereby providing new insights into the mechanism of PPI clinical response. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE.
最近，我们在嗜酸性食管炎（EoE）患者的食管上皮中发现了一种失调的蛋白质特征，包括与炎症和上皮屏障功能相关的蛋白质；然而，质子泵抑制剂（PPI）治疗对这一特征的影响尚不清楚。在此，我们采用蛋白质组学方法进行研究：（1）PPI治疗是否会改变EoE患者中观察到的食管上皮蛋白质谱，以及（2）基线时的蛋白质特征是否能预测PPI反应。
我们使用一组成年EoE患者（n = 25）和健康对照（C）（n = 10）评估食管活检组织的蛋白质特征。在EoE患者中，在8周PPI治疗前（pre）和治疗后（post）取食管活检组织，确定组织学反应。使用治疗后嗜酸性粒细胞计数将患者分类：≥15个嗜酸性粒细胞/高倍视野为无反应者（non-responder），<15个嗜酸性粒细胞/高倍视野为反应者（R）。确定蛋白质特征，并对差异积累的蛋白质进行表征，以识别改变的生物学过程和信号通路。
组间差异积累蛋白质的比较分析揭示了三组有炎症患者（反应者-治疗前PPI、无反应者-治疗前PPI和无反应者-治疗后PPI）和无炎症患者（对照和反应者-治疗后PPI）之间的共同特征。PPI治疗几乎逆转了反应者-治疗后PPI中EoE特异性食管蛋白质特征，该特征富含与炎症和上皮屏障功能相关的通路。此外，我们确定了一组候选蛋白质，以区分治疗前反应者-治疗前PPI和无反应者-治疗前PPI的EoE患者。
这些发现提供了证据，表明PPI治疗可逆转表征EoE的食管炎症和上皮蛋白的改变，从而为PPI临床反应机制提供了新的见解。有趣的是，我们的结果还表明，在EoE中可以在基线时预测PPI反应。
