Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier
Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier
复制标题
DOI：
10.1136/gutjnl-2012-302093
复制
发表时间：
2013-08-01
期刊：
影响因子：
24.5
通讯作者：
Vicario, Maria
中科院分区：
文献类型：
--
作者：
Martinez, Cristina;Lobo, Beatriz;Vicario, Maria
目的近年来，作者发现腹泻型肠易激综合征(IBS-D)患者空肠黏膜基因表达发生改变，特别是肥大细胞和细胞间顶端连接复合体(AJC)相关基因的表达与正常人不同。作者的目的是确定这些改变是否与AJC的结构异常有关，以及它们与肥大细胞激活和IBS-D临床表现的关系。设计对IBS-D患者(n=45)和健康受试者(n=30)进行临床评估和空肠活检。通过测定CD117(+)细胞/HPF和类胰蛋白酶的表达来确定粘膜肥大细胞的数量和活性。免疫印迹和共聚焦显微镜检测AJC特异性蛋白的表达和分布。结果与正常对照组相比，IBS-D患者表现为：(A)肥大细胞数量和激活增加；(B)claudin-2蛋白表达增加，阻滞素磷酸化减少，胞浆重分布增强；(C)肌球蛋白激酶表达增加，肌球蛋白磷酸酶降低，从而增强肌球蛋白的磷酸化。这些分子改变与AJC的超微结构异常有关，特别是交界处细胞骨架凝聚和顶端细胞间距增大。结论IBS-D患者空肠黏膜表现出与肥大细胞活化和临床症状相关的顶端连接复合体的完整性破坏。这些结果为IBS-D的器质性提供了证据，IBS-D是迄今为止功能性胃肠疾病的模型疾病。
ObjectiveRecently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations.DesignA clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117(+) cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy.ResultsCompared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms.ConclusionThe jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.