Mechanism of E. coli colonization resistance

描述(申请人提供)：胃肠道是一个密集的微生物群落的宿主，被称为肠道微生物区系，主要是属于杆菌门(杆菌纲)和细菌门(梭状芽孢杆菌门)的专性厌氧细菌。这种微生物群落提供了针对兼性厌氧变形杆菌(如大肠杆菌)的利基保护，这种特性被称为“耐定殖性”。然而，肠道微生物区系赋予定植抗性的确切机制仍然不清楚。这项应用的目标是研究肠道微生物区系如何影响对变形杆菌的定植抗性，以大肠杆菌为典型代表。我们的中心假设是，专性厌氧菌通过抑制炎症的微生物-宿主相互作用来介导对大肠杆菌的定植耐药性。抗生素治疗(生物失调)破坏了这些微生物与宿主的相互作用，增加了肠道粘膜的炎症强度，宿主反应伴随产生的自由基的产生产生了呼吸电子受体，通过厌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)浓度的降低是否与降低对大肠杆菌的定植抗性有关。在目标2中，我们将开发治疗由抗生素治疗引起的生物失调的方法。我们的研究的成功完成将提供创新，建立一种新的抵抗殖民的机制(目标1)，并促进制定在平衡的社区被破坏时处理殖民抵抗丧失的方法(目标2)。这一结果将是重要的，因为拟议工作产生的概念上的进展预计将建立一种新的范式，将影响该领域其他人的研究。

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.