Bifidobacteria Stabilize Claudins at Tight Junctions and Prevent Intestinal Barrier Dysfunction in Mouse Necrotizing Enterocolitis
Bifidobacteria Stabilize Claudins at Tight Junctions and Prevent Intestinal Barrier Dysfunction in Mouse Necrotizing Enterocolitis
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DOI：
10.1016/j.ajpath.2013.01.013
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发表时间：
2013-05-01
影响因子：
6
通讯作者：
De Plaen, Isabelle G.
中科院分区：
文献类型：
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作者：
Bergmann, Kelly R.;Liu, Shirley X. L.;De Plaen, Isabelle G.
坏死性小肠结肠炎 (NEC) 中肠道屏障破坏是否先于肠道损伤还是其结果仍不清楚。使用新生小鼠 NEC 模型，我们检查了 NEC 之前肠道通透性和特定紧密连接 (TJ) 蛋白的变化，并询问婴儿双歧杆菌（一种已知可降低人类 NEC 发病率的益生菌）的施用是否可以预防这些变化。与母鼠喂养的对照组相比，接受 NEC 方案的幼崽 i) 在 12 小时和 24 小时内肠道通透性显着增加（通过 70-kDa 荧光素异硫氰酸酯-葡聚糖跨粘膜通量评估）； ii) 12小时时occludin和claudin 4内化（通过免疫荧光和低密度膜部分免疫印迹评估）； iii) 6小时时密蛋白2表达增加，24小时时密蛋白4和7表达减少； iv) 48 小时时密蛋白 2 蛋白增加。在人类 NEC 中也观察到类似的结果，密蛋白 2 蛋白增加。在小鼠中，给予婴儿双歧杆菌微生物可减弱肠道通透性的增加，保留 Claudin 4 和 Occludin 在 TJ 的定位，并降低 NEC 发生率。因此，肠道通透性的增加先于 NEC，并且与 Claudin 4 和 Occludin 的内化相关。施用婴儿双歧杆菌可预防这些变化并降低 NEC 发生率。婴儿双歧杆菌的有益作用至少部分归因于其 TJ 和屏障保护特性。
Whether intestinal barrier disruption precedes or is the consequence of intestinal injury in necrotizing enterocolitis (NEC) remains unknown. Using a neonatal mouse NEC model, we examined the changes in intestinal permeability and specific tight-junction (TJ) proteins preceding NEC and asked whether these changes are prevented by administration of Bifidobacterium infantis, a probiotic known to decrease NEC incidence in humans. Compared with dam-fed controls, pups submitted to the NEC protocol developed i) significantly increased intestinal permeability at 12 and 24 hours (as assessed by 70-kDa fluorescein isothiocyanate-dextran transmucosal flux); ii) occludin and claudin 4 internalization at 12 hours (as assessed by immunofluorescence and Low-density membrane fraction immunoblotting); iii) increased claudin 2 expression at 6 hours and decreased claudin 4 and 7 expression at 24 hours; and iv) increased claudin 2 protein at 48 hours. Similar results were seen in human NEC, with claudin 2 protein increased. In mice, administration of B. infantis micro-organisms attenuated increases in intestinal permeability, preserved claudin 4 and occludin localization at TJs, and decreased NEC incidence. Thus, an increase in intestinal permeability precedes NEC and is associated with internalization of claudin 4 and occludin. Administration of B. infantis prevents these changes and reduces NEC incidence. The beneficial effect of B. infantis is, at least in part, due to its TJ and barrier-preserving properties.