Mechanism of E. coli colonization resistance

大肠杆菌定植抗性机制

• 批准号: 8902448
• 负责人: Andreas J Baumler
• 金额: $ 38.16万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-20 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902448
• 关键词: Anaerobic Bacteria; Antibiotic Therapy; Antibiotics; Bacteria; Bacteroidetes; Cells; Clostridium; Communities; Data; Development; Disease; Equilibrium; Escherichia coli; Gastrointestinal tract structure; Generations; Goals; Growth; Health; Homeostasis; Human body; Immune; Immune response; Immune system; Inflammation; Inflammatory; Intestinal Mucosa; Intestines; Large Intestine; Mediating; Microbe; Modeling; Outcome; Oxidants; Predisposition; Production; Property; Proteobacteria; Research; Resistance; Resistance development; Respiration; Science; Testing; Volatile Fatty Acids; Work; base; gut microbiota; innovation; microbial; microbial community; novel; prevent; respiratory; therapy design; treatment strategy

DESCRIPTION (provided by applicant): The gastrointestinal tract is host to a dense microbial community, known as the gut microbiota, which is dominated by obligate anaerobic bacteria belonging to the phyla Bacteroidetes (class Bacteroidia) and Firmicutes (class Clostridia). This microbial community offers benefit by conferring niche protection against facultative anaerobic Proteobacteria (e.g. Escherichia coli), a property known as 'colonization resistance'. However, the precise mechanisms by which the gut microbiota confers colonization resistance remain obscure. The objectives of this application are to study how the gut microbiota influences colonization resistance against Proteobacteria, using E. coli as a prototypical representative. Our central hypothesis is that obligate anaerobic bacteria mediate colonization resistance against E. coli through microbe-host interactions that suppress inflammation. Disruption of these microbe-host interactions by antibiotic treatment (dysbiosis) increases the inflammatory tone of the intestinal mucosa and the concomitant production of radicals by the host response generates respiratory electron acceptors, which support growth of E. coli by anaerobic respiration. In Aim 1 we will determine whether a reduction in short-chain fatty acid (SCFA) concentrations after antibiotic treatment is responsible for lowering colonization resistance against E. coli. In Aim 2 we will develop approaches to treat dysbiosis induced by antibiotic therapy. Successful completion of our study will provide innovation by establishing a novel mechanism for colonization resistance (Aim 1) and facilitating the development of approaches to treat a loss of colonization resistance when a balanced community has been disrupted (Aim 2). This outcome will be significant because conceptual advances resulting from the proposed work are expected to establish a new paradigm that will influence research by others in the field.

描述（由申请人提供）：胃肠道是一个密集的微生物群落的宿主，称为肠道微生物群，其中以属于拟杆菌门（拟杆菌类）和厚壁菌门（梭状芽胞杆菌类）的专性厌氧细菌为主。该微生物群落通过提供针对兼性厌氧变形菌（例如大肠杆菌）的生态位保护来提供益处，这种特性被称为“定植抗性”。然而，肠道微生物群赋予定植抵抗力的确切机制仍然不清楚。本申请的目的是使用大肠杆菌作为典型代表，研究肠道微生物群如何影响变形菌的定植抗性。我们的中心假设是，专性厌氧细菌通过抑制炎症的微生物-宿主相互作用介导对大肠杆菌的定植抵抗力。通过抗生素治疗（生态失调）破坏这些微生物与宿主的相互作用，会增加肠粘膜的炎症张力，并且宿主反应会产生自由基，从而产生呼吸电子受体，从而通过无氧呼吸支持大肠杆菌的生长。在目标 1 中，我们将确定抗生素治疗后短链脂肪酸 (SCFA) 浓度的降低是否会降低大肠杆菌的定植耐药性。在目标 2 中，我们将开发治疗抗生素治疗引起的生态失调的方法。我们的研究的成功完成将通过建立一种新颖的定殖抵抗机制（目标 1）并促进开发在平衡的群落被破坏时治疗定殖抵抗丧失的方法（目标 2）来提供创新。这一结果将意义重大，因为拟议工作带来的概念进步预计将建立一个新的范式，从而影响该领域其他人的研究。