Mechanism of colonization resistance

 描述（由申请方提供）：胃肠道是密集微生物群落的宿主，称为肠道微生物群，其由属于拟杆菌门（拟杆菌纲）和厚壁菌门（梭菌纲）的专性厌氧菌占主导地位。这种微生物群落通过赋予针对兼性厌氧肠杆菌科（例如大肠杆菌或肠道沙门氏菌）的生态位保护而提供益处，该特性被称为“定植抗性”。抗生素治疗对肠道微生物群的干扰可以破坏定植抗性，这可以允许病原体扩张。此外，手术或重复抗生素疗程后通常会出现肠易激综合征（IBS），这是一种以低水平肠道炎症、腹泻和微生物群失衡（生态失调）为特征的疾病。然而，肠道微生物群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）介导对肠杆菌科的定植抗性，这有助于维持结肠上皮细胞（结肠细胞）的呼吸能量代谢。通过抗生素治疗破坏这些微生物-宿主相互作用驱动结肠细胞通过发酵获得能量，这伴随着上皮中氧水平的增加和诱导型一氧化氮合酶（iNOS）表达的升高，从而通过呼吸促进肠杆菌科的管腔生长。在目标1中，我们将确定抗生素后丁酸消耗是否增加肠腔中肠杆菌科的电子受体的可用性。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，我们将确定减少的上皮细胞PPAR-γ信号传导对肠道相关微生物群落组成的影响。拟议研究的基本原理是，更好地了解抗生素治疗后肠道稳态破坏的因素将为抗生素后病原体扩张和IBS发病机制提供见解。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良副作用。

 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.