Mechanism of 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。这种微生物群落通过提供针对兼性厌氧肠杆菌(例如，大肠杆菌或肠沙门氏菌)的利基保护，这种特性被称为“耐定殖性”。抗生素治疗对肠道微生物区系的干扰可以破坏定植耐药性，从而允许病原体扩张。此外，手术或反复使用抗生素后，通常会出现肠易激综合征(IBS)，这种疾病的特征是低水平的肠道炎症、腹泻和微生物区系失衡(微生物失调)。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。我们的中心假设是，专性厌氧梭菌通过激活增殖物激活受体γ(PPAR-γ)来介导对肠杆菌科细菌的定植抵抗，该受体有助于维持结肠上皮细胞(结肠细胞)的呼吸能量代谢。抗生素处理破坏了这些微生物与宿主的相互作用，促使结肠细胞通过发酵获得能量，同时伴随着上皮细胞氧气水平的增加和诱导型一氧化氮合酶(INOS)的表达，从而通过呼吸促进肠杆菌科细菌的腔内生长。在目标1中，我们将确定抗生素后丁酸耗竭是否增加肠杆菌科肠道中电子受体的利用率。在目标2中，我们将确定丁酸盐控制结肠细胞代谢的机制。在目标3中，我们将确定上皮性PPAR-γ信号减少对肠道相关微生物群落组成的影响。这项研究的理论基础是，更好地了解抗生素治疗后导致肠道内稳态破坏的因素将有助于深入了解抗生素后病原菌扩张的机制和IBS的发病机制。这些信息将有助于设计治疗方法，以减轻抗生素治疗的这些不受欢迎的副作用。

 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 Enterobacteriaceae (e.g. Escherichia coli or Salmonella enterica), a property known as "colonization resistance". Perturbation of the gut microbiota by antibiotic treatment can disrupt colonization resistance, which can permit pathogen expansion. Furthermore, surgery or repeated courses of antibiotics are often followed by irritable bowel syndrome (IBS), a condition characterized by low-level intestinal inflammation, diarrhea and a microbiota imbalance (dysbiosis). However, the precise mechanisms by which the gut microbiota confers colonization resistance remain obscure. Our central hypothesis is that obligate anaerobic Clostridia mediate colonization resistance against Enterobacteriaceae by activating proliferator-activated receptor gamma (PPAR-γ), which helps maintain a respiratory energy metabolism of colonic epithelial cells (colonocytes). Disruption of these microbe-host interactions by antibiotic treatment drives colonocytes to obtain energy through fermentation, which is accompanied by increased oxygen levels in the epithelium and elevated expression of inducible nitric oxide synthase (iNOS), thereby promoting luminal growth of Enterobacteriaceae by respiration. In Aim 1 we will determine whether post-antibiotic butyrate depletion increases the availability of electron acceptors for Enterobacteriaceae in the intestinal lumen. In Aim 2 we will determine the mechanism by which butyrate controls colonocyte metabolism. In Aim 3 we will determine the consequences of reduced epithelial PPAR-γ signaling for the composition of gut- associated microbial communities. The rationale for the proposed research is that a better understanding of the factors responsible for disruption of gut homeostasis after antibiotic treatment will provide insights into mechanisms of post-antibiotic pathogen expansion and the pathogenesis of IBS. This information will aid in the design of therapies to alleviate these unwanted side effects of antibiotic therapy.