Exacerbation of Colitis by Enterobacteriaceae

摘要 溃疡性结肠炎是一种复杂的疾病，由遗传风险因素的组合引起， 儿童暴露于环境风险因素和定义不清的微生物群组成。 溃疡性结肠炎与微生物群失衡（生态失调）有关，其特征是 增加肠杆菌科和减少梭菌丰度。溃疡性结肠炎会对 抗生素治疗，这表明生态失调加剧了肠道炎症， 提出了如何恢复微生物群稳态的问题。我们的初步数据 表明上皮缺氧和上皮释放过氧化氢代表宿主控制 维持结肠内稳态和兼性厌氧代谢的机制 当这些宿主控制机制变弱时，肠杆菌科会加重结肠炎 遗传和环境风险因素的结合。我们的核心假设是， 增加的上皮氧合驱动兼性厌氧肠杆菌科的扩增 因为这个家族的成员不受生长条件的限制， 在上皮表面附近遇到。在具体目标1中，我们将测试 假设通过恢复上皮缺氧来重新平衡肠道微生物群代表了一种 恢复肠道内稳态的可行方法。在具体目标2中，我们将确定如何 肠杆菌科在暴露时加剧携带遗传风险因子的小鼠的结肠炎 环境风险因素的组合。顺利完成拟议工作将 对肠道微生物生态学、肠道动力学、 相关的微生物群落在炎症和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.