Exacerbation of Colitis by Enterobacteriaceae

肠杆菌科细菌加剧结肠炎

• 批准号: 10392353
• 负责人: Andreas J Baumler
• 金额: $ 46.2万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392353
• 关键词: Anaerobic Bacteria; Animal Model; Anti-Inflammatory Agents; Antibiotic Therapy; Automobile Driving; Bacteria; Bioenergetics; Childhood; Colitis; Colon; Complex; Data; Disease; Ecology; Ecosystem; Enterobacteriaceae; Environment; Environmental Risk Factor; Epithelial; Epithelial Cells; Equilibrium; Exposure to; Family member; Fermentation; Fiber; Foundations; Funding; Genetic Risk; Goals; Growth; Health; Homeostasis; Human; Hydrogen Peroxide; Hypoxia; Inflammation; Journals; Mediating; Metabolism; Mitochondria; Mucous Membrane; Mucous body substance; Mus; Outcome; Oxidative Phosphorylation; Oxygen Consumption; Pathogenesis; Pharmaceutical Preparations; Publications; Research; Salicylic Acids; Secondary to; Solid; Surface; Testing; Ulcerative Colitis; Work; colon microbiota; dysbiosis; expectation; experimental study; genetic risk factor; gut homeostasis; gut inflammation; gut microbiota; host-associated microbial communities; innovation; knowledge of results; microbial; microbial community; microbiota; mucosal microbiota; nutrition; public health relevance; sound; tool

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.

抽象的 溃疡性结肠炎是由遗传危险因素组合引起的复杂疾病， 儿童期暴露于环境危险因素和微生物群的定义较差。 溃疡性结肠炎与微生物群（营养不良）的失衡有关，其特征是 肠杆菌科的增加并减少了梭状裂丰度。溃疡性结肠炎可以反应 抗生素治疗，这表明营养不良加剧了肠道炎症，因此 提出了如何恢复微生物群稳态的问题。我们的初步数据 表明上皮缺氧和过氧化氢的上皮释放代表宿主对照 维持结肠和兼性厌氧的稳态的机制 当这些宿主控制机制削弱时，肠杆菌科会加剧结肠炎 结合遗传和环境风险因素。我们的中心假设是 上皮氧合增加促进兼性厌氧肠杆菌科的扩展 这种加剧的结肠炎是因为该家族的成员不被增长条件排除 靠近上皮表面遇到。在特定目标1中，我们将测试工作 假设通过恢复上皮缺氧来重新平衡肠道菌群代表 可行的方法来恢复肠道稳态。在特定目标2中，我们将确定如何 携带遗传危险因素的小鼠中的肠杆菌科在暴露时 结合环境风险因素。成功完成拟议的工作将 对于肠道中的微生物生态学研究具有广泛的意义，肠道的动力学 炎症期间相关的微生物群落和溃疡性结肠炎的发病机理。