Reduced Epithelial Na+/H+ Exchange Drives Gut Microbial Dysbiosis and Promotes Inflammatory Response in T Cell-Mediated Murine Colitis.
Reduced Epithelial Na+/H+ Exchange Drives Gut Microbial Dysbiosis and Promotes Inflammatory Response in T Cell-Mediated Murine Colitis.
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DOI：
10.1371/journal.pone.0152044
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kiela PR
中科院分区：
文献类型：
--
作者：
Laubitz D;Harrison CA;Midura-Kiela MT;Ramalingam R;Larmonier CB;Chase JH;Caporaso JG;Besselsen DG;Ghishan FK;Kiela PR
炎症性肠病（IBD）与上皮Na+/H+交换的功能性抑制有关。在小鼠中，NHE3 （Slc9a3）的选择性破坏，一种主要的顶端Na+/H+交换物，也会促进ibd样症状和肠道微生物生态失调。我们假设Na+/H+交换的破坏对于生态失调的发展是必要的，这促进了黏膜炎症反应的加剧。因此，我们对肠道菌群组成进行了时间分析，并在使用和不使用广谱抗生素的Rag2-/-和NHE3-/-/Rag2-/- (DKO)小鼠中评估了粘膜对过继T细胞转移的免疫反应。分析微生物组（16S谱）、结肠组织学、T细胞和中性粒细胞浸润、粘膜炎症张力和上皮通透性。在过继性T细胞转移结肠炎模型中，Slc9a3状态是肠道微生物群落的最重要决定因素。在DKO小鼠中，nhe3缺乏和生态失调与疾病显著加速和加重有关，伴有体重迅速减轻、粘膜T细胞和中性粒细胞内流增加、粘膜细胞因子表达增加、通透性增加和CD25-FoxP3+ Tregs扩增；口服广谱抗生素可减轻这种增强的敏感性。基于这些结果和我们之前的工作，我们假设上皮电解质稳态是结肠炎进展中的重要调节剂，通过重塑肠道微生物群落发挥作用。
Inflammatory bowel diseases (IBD) are associated with functional inhibition of epithelial Na+/H+ exchange. In mice, a selective disruption of NHE3 (Slc9a3), a major apical Na+/H+ exchanger, also promotes IBD-like symptoms and gut microbial dysbiosis. We hypothesized that disruption of Na+/H+ exchange is necessary for the development of dysbiosis, which promotes an exacerbated mucosal inflammatory response. Therefore, we performed a temporal analysis of gut microbiota composition, and mucosal immune response to adoptive T cell transfer was evaluated in Rag2-/- and NHE3-/-/Rag2-/- (DKO) mice with and without broad-spectrum antibiotics. Microbiome (16S profiling), colonic histology, T cell and neutrophil infiltration, mucosal inflammatory tone, and epithelial permeability were analyzed. In adoptive T cell transfer colitis model, Slc9a3 status was the most significant determinant of gut microbial community. In DKO mice, NHE3-deficiency and dysbiosis were associated with dramatically accelerated and exacerbated disease, with rapid body weight loss, increased mucosal T cell and neutrophil influx, increased mucosal cytokine expression, increased permeability, and expansion of CD25-FoxP3+ Tregs; this enhanced susceptibility was alleviated by oral broad-spectrum antibiotics. Based on these results and our previous work, we postulate that epithelial electrolyte homeostasis is an important modulator in the progression of colitis, acting through remodeling of the gut microbial community.