Mechanism of colonization resistance

定植抵抗机制

• 批准号: 9110769
• 负责人: Andreas J Baumler
• 金额: $ 46.81万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110769
• 关键词: Adverse effects; Anaerobic Bacteria; Antibiotic Therapy; Antibiotics; Bacteria; Bacteroidetes; Butyrates; Carbon Dioxide; Cells; Clostridium; Communities; Diarrhea; Energy Metabolism; Enterobacteriaceae; Epithelial; Epithelial Cells; Epithelium; Escherichia coli; Fermentation; Gastrointestinal tract structure; Glucose; Goals; Growth; Homeostasis; Human body; Immune system; Inflammatory disease of the intestine; Intestines; Irritable Bowel Syndrome; Large Intestine; Mediating; Metabolism; Microbe; Mitochondria; Modeling; NOS2A gene; Nuclear Receptors; Operative Surgical Procedures; Oxidants; Oxygen; PPAR gamma; Pathogenesis; Property; Research; Resistance; Resistance development; Respiration; Salmonella enterica; Science; Signal Transduction; Testing; gut microbiota; innovation; insight; microbial; microbial community; microbiota; novel; oxidation; pathogen; public health relevance; receptor; 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 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.

 描述（由适用提供）：胃肠道是宿主的，被称为肠道微生物群，该群体由属于类菌类细菌（类拟杆菌）和Firmicicutes和Firmicicutes（classictia classicutes）的强制性厌氧菌细菌主导。这个微生物群落通过会议利基保护对辅助厌氧性肠杆菌科（例如大肠杆菌或肠道沙门氏菌）的利益保护，这是一种称为“殖民化抗性”的物业。通过抗生素处理对肠道菌群的扰动会破坏定殖抗性，这可以允许病原体扩张。此外，抗生素的手术或重复疗程通常是肠易激综合征（IBS），肠综合征（IBS），这种疾病的特征是低水平的肠炎，腹泻和微生物群体失衡（失调）。然而，肠道菌群赋予定殖抗性的精确机制仍然晦涩难懂。我们的中心假设是，通过激活增生剂激活的受体伽马（PPAR-γ）来帮助对肠杆菌科的厌氧性梭状芽胞杆菌定植抗性，这有助于维持结肠上皮细胞（结肠细胞）的呼吸能代谢。通过抗生素治疗对这些微生物宿主相互作用的破坏驱动结肠细胞通过发酵获得能量，这是通过上皮细胞中的氧气水平升高和诱导型一氧化氮合酶（INOS）的升高来实现的，从而通过呼气来促进肠杆菌的腔内生长。在AIM 1中，我们将确定抗生素后的丁酸酯部署是否会增加肠腔中肠杆菌科的电子受体的可用性。在AIM 2中，我们将确定丁酸酯控制结肠细胞代谢的机制。降低上皮PPAR-γ信号传导对肠道相关微生物群落组成的后果。拟议研究的理由是，更好地理解抗生素治疗后导致肠道内稳态的因素，将为抗生素病原体扩张的机制和IBS发病机理提供深入的了解。这些信息将有助于设计疗法，以减轻抗生素治疗的这些不良副作用。