Janker Lukas, Schuster Dina, Bortel Patricia, Hagn Gerhard, Meier-Menches Samuel M, Mohr Thomas, Mader Johanna C, Slany Astrid, Bileck Andrea, Brunmair Julia, Madl Christian, Unger Lukas, Hennlich Barbara, Weitmayr Barbara, Del Favero Giorgia, Pils Dietmar, Pukrop Tobias, Pfisterer Nikolaus, Feichtenschlager Thomas, Gerner Christopher
Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
Joint Metabolome Facility, University of Vienna, Vienna, Austria.
J Crohns Colitis. 2023 Oct 20;17(9):1514-1527. doi: 10.1093/ecco-jcc/jjad052.
Ulcerative colitis [UC] is a chronic disease with rising incidence and unclear aetiology. Deep molecular phenotyping by multiomics analyses may provide novel insights into disease processes and characteristic features of remission states.
UC pathomechanisms were assessed by proteome profiling of human tissue specimens, obtained from five distinct colon locations for each of the 12 patients included in the study. Systemic disease-associated alterations were evaluated thanks to a cross-sectional setting of mass spectrometry-based multiomics analyses comprising proteins, metabolites, and eicosanoids of plasma obtained from UC patients during acute episodes and upon remission, in comparison with healthy controls.
Tissue proteome profiling indicated colitis-associated activation of neutrophils, macrophages, B and T cells, fibroblasts, endothelial cells and platelets, and hypoxic stress, and suggested a general downregulation of mitochondrial proteins accompanying the establishment of apparent wound healing-promoting activities including scar formation. Whereas pro-inflammatory proteins were apparently upregulated by immune cells, the colitis-associated epithelial cells, fibroblasts, endothelial cells, and platelets seemed to predominantly contribute anti-inflammatory and wound healing-promoting proteins. Blood plasma proteomics indicated chronic inflammation and platelet activation, whereas plasma metabolomics identified disease-associated deregulations of gut and gut microbiome-derived metabolites. Upon remission several, but not all, molecular candidate biomarker levels recovered back to normal.
The findings may indicate that microvascular damage and platelet deregulation hardly resolve upon remission, but apparently persist as disease-associated molecular signatures. This study presents local and systemic molecular alterations integrated in a model for UC pathomechanisms, potentially supporting the assessment of disease and remission states in UC patients.
溃疡性结肠炎（UC）是一种发病率不断上升且病因不明的慢性疾病。通过多组学分析进行深度分子表型分析可能会为疾病进程和缓解状态的特征提供新的见解。
通过对人体组织标本进行蛋白质组分析来评估UC的发病机制，这些标本取自该研究纳入的12名患者中每个患者的五个不同结肠部位。借助基于质谱的多组学分析的横断面设置，评估全身疾病相关的改变，该分析包括UC患者急性发作期和缓解期血浆中的蛋白质、代谢物和类花生酸，并与健康对照进行比较。
组织蛋白质组分析表明，中性粒细胞、巨噬细胞、B和T细胞、成纤维细胞、内皮细胞和血小板存在与结肠炎相关的激活以及缺氧应激，并表明伴随着明显促进伤口愈合的活动（包括瘢痕形成）的建立，线粒体蛋白普遍下调。虽然免疫细胞明显上调了促炎蛋白，但与结肠炎相关的上皮细胞、成纤维细胞、内皮细胞和血小板似乎主要贡献抗炎和促进伤口愈合的蛋白。血浆蛋白质组学表明存在慢性炎症和血小板激活，而血浆代谢组学确定了肠道和肠道微生物群衍生代谢物的疾病相关失调。缓解后，一些但并非所有分子候选生物标志物水平恢复正常。
这些发现可能表明，微血管损伤和血小板失调在缓解后几乎不会消除，但显然作为疾病相关分子特征持续存在。本研究展示了整合在UC发病机制模型中的局部和全身分子改变，可能有助于评估UC患者的疾病和缓解状态。
