Exacerbation of Colitis by Enterobacteriaceae

肠杆菌科细菌加剧结肠炎

• 批准号: 10595010
• 负责人: Andreas J Baumler
• 金额: $ 45.26万
• 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/10595010
• 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 Cells; Epithelium; Exposure to; Family member; Fermentation; Fiber; Foundations; Funding; 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; Productivity; Publications; Research; Salicylic Acids; Secondary to; Solid; Surface; Testing; Ulcerative Colitis; Work; absorption; 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 溃疡性结肠炎是一种由遗传危险因素综合引起的复杂疾病， 儿童时期暴露于环境风险因素和不明确的微生物群组成部分。 溃疡性结肠炎与微生物群失衡（菌群失调）有关，其特征是 肠杆菌科细菌增加，梭菌丰度减少。溃疡性结肠炎可以缓解 抗生素治疗，这表明生态失调会加剧肠道炎症，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 表明上皮缺氧和上皮释放过氧化氢代表宿主控制 维持结肠稳态和兼性厌氧的机制 当这些宿主控制机制减弱时，肠杆菌科会加剧结肠炎 遗传和环境风险因素的结合。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 加剧结肠炎，因为该家族的成员并未被生长条件排除在外 遇到的情况非常接近上皮表面。在具体目标 1 中，我们将测试工作情况 通过恢复上皮缺氧来重新平衡肠道微生物群的假设代表 恢复肠道稳态的可行方法。在具体目标 2 中，我们将确定如何 携带遗传危险因素的小鼠接触肠杆菌科细菌会加剧结肠炎 环境风险因素的组合。成功完成拟议工作将 对于肠道微生物生态学、肠道动态的研究具有广泛的意义 炎症期间相关的微生物群落和溃疡性结肠炎的发病机制。