BACKGROUND AND AIMS Based on genetics and natural history, Crohn's disease can be separated into two entities, an ileal and a colonic disease. Protein-based approaches are needed to elucidate whether such subphenotypes are related to distinct pathophysiological processes. METHODS The proteome of ulcer edges was compared with that of paired control tissue samples [n = 32 biopsies] by differential proteomics in the ileum and the colon of Crohn's disease patients [n = 16]. The results were analysed using a hypothesis-driven approach [based on the literature] and a hypothesis-free approach [pathway enrichment analyses] to determine common and segment-specific pathophysiological processes associated with ileal and colonic CD ulcer edges. To confirm the involvement of a key pathway highlighted by proteomics, two proteins were also studied by immunochemistry. RESULTS In the ileum and the colon, 4428 and 5204 proteins, respectively, were identified and quantified. Ileal and colonic ulcer edges differed in having a distinct distribution of proteins associated with epithelial-mesenchymal transition, neutrophil degranulation, and ribosomes. Ileal and colonic ulcer edges were similarly characterized by an increase in the proteins implicated in the endoplasmic reticulum protein-processing pathway and a decrease in mitochondrial proteins. Immunochemistry confirmed the presence of endoplasmic reticulum stress in the mucosa of ileal and colonic ulcer edges. CONCLUSION This study provides protein-based evidence for partially distinct pathophysiological processes being associated with ileal and colonic ulcer edges in Crohn's disease patients. This could constitute a first step toward the development of gut segment-specific diagnostic markers and therapeutics.

中文翻译：

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蛋白质组学突出显示了与克罗恩病回肠和结肠溃疡相关的常见和不同的病理生理过程。

背景和目的基于遗传学和自然历史，克罗恩氏病可以分为两个实体，回肠和结肠疾病。需要基于蛋白质的方法来阐明这种亚表型是否与不同的病理生理过程有关。方法通过差异蛋白质组学，比较回肠和克罗恩病患者结肠中溃疡边缘的蛋白质组与配对对照组织样品的蛋白质组（n = 32活检）[n = 16]。使用假说驱动的方法[基于文献]和无假说的方法[途径富集分析]来分析结果，以确定与回肠和结肠CD溃疡边缘相关的常见的和节段特异性的病理生理过程。为了确认蛋白质组学强调的关键途径的参与，还通过免疫化学研究了两种蛋白质。结果在回肠和结肠中，分别鉴定和定量了4428和5204蛋白。回肠和结肠溃疡边缘的区别在于具有与上皮-间质转化，嗜中性粒细胞脱粒和核糖体相关的蛋白质的独特分布。回肠和结肠溃疡边缘的特征同样在于内质网蛋白加工途径中涉及的蛋白质增加和线粒体蛋白质减少。免疫化学证实回肠和结肠溃疡边缘的粘膜中存在内质网应激。结论这项研究为克罗恩病患者回肠和结肠溃疡边缘相关的部分不同的病理生理过程提供了基于蛋白质的证据。