Exacerbation of Colitis by Enterobacteriaceae

摘要 溃疡性结肠炎是一种复杂的疾病，由多种遗传风险因素组合而成， 儿童时期暴露于环境风险因素和定义不清的微生物区系成分。 溃疡性结肠炎与微生物区系失衡(生物失调)有关，其特征是 增加肠杆菌科细菌和减少梭状芽孢杆菌的丰度。溃疡性结肠炎会有反应 抗生素治疗，这表明生物失调会加剧肠道炎症，因此 提出了如何恢复微生物区系动态平衡的问题。我们的初步数据 提示上皮性缺氧和上皮性过氧化氢的释放代表宿主控制 维持结肠内动态平衡和兼性厌氧的机制 当这些寄主控制机制减弱时，肠杆菌科会加重结肠炎 是遗传和环境风险因素共同作用的结果。我们的中心假设是 上皮氧合增加导致兼性厌氧肠杆菌科细菌的扩张 这会加重结肠炎，因为这个家庭的成员不会被生长条件排除在外 在非常接近上皮表面的地方遇到。在具体目标1中，我们将测试工作 通过恢复上皮性缺氧来重新平衡肠道微生物区系的假说代表着一种 恢复肠道内环境平衡的可行途径。在具体目标2中，我们将确定如何 肠杆菌科细菌暴露时可加重携带遗传危险因素的小鼠的结肠炎 环境风险因素的综合作用。成功完成拟议的工作将 对肠道微生物生态学、肠道动力学的研究具有广泛的意义。 炎症过程中的相关微生物群落与溃疡性结肠炎的发病机制。

ABSTRACT Ulcerative colitis is a complex disease caused by a combination of genetic risk factors, childhood exposure to environmental risk factors and a poorly defined microbiota component. Ulcerative colitis is associated with imbalance in the microbiota (dysbiosis) characterized by increased Enterobacteriaceae and reduced Clostridia abundance. Ulcerative colitis can respond to antibiotic treatment, which suggests that dysbiosis exacerbates intestinal inflammation, thus raising the question as to how microbiota homeostasis can be restored. Our preliminary data suggest that epithelial hypoxia and epithelial release of hydrogen peroxide represent host control mechanisms that maintain homeostasis in the colon and that facultative anaerobic Enterobacteriaceae exacerbates colitis when these host control mechanisms become weakened by a combination of genetic and environmental risk factors. Our central hypothesis is that increased epithelial oxygenation drives an expansion of facultative anaerobic Enterobacteriaceae that exacerbate colitis because members of this family are not excluded by growth conditions encountered in close proximity to the epithelial surface. In specific aim 1 we will test the working hypothesis that rebalancing the gut microbiota by reinstating epithelial hypoxia represents a feasible approach for restoring gut homeostasis. In specific aim 2 we will determine how Enterobacteriaceae exacerbate colitis in mice carrying a genetic risk factor while being exposed to a combination of environmental risk factors. Successful completion of the proposed work will be of broad significance for research on microbial ecology in the gut, the dynamics of gut- associated microbial communities during inflammation and the pathogenesis of ulcerative colitis.