Mechanism of colonization resistance

定植抵抗机制

基本信息

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
项目类别：
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

项目摘要

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（类杆菌门）和厚壁菌门（梭状芽胞杆菌类）的专性厌氧细菌为主。通过提供针对兼性厌氧肠杆菌科细菌（例如大肠杆菌）的生态位保护来提供益处。大肠杆菌或肠沙门氏菌），一种被称为“定植耐药性”的特性，抗生素治疗对肠道微生物群的干扰会破坏定植耐药性，从而导致病原体扩张。此外，手术或重复使用抗生素后通常会出现肠易激综合征。（IBS），一种以低水平肠道炎症、腹泻和微生物群失衡（菌群失调）为特征的疾病。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。中心假设是，专性厌氧梭状芽胞杆菌通过激活增殖物激活受体γ（PPAR-γ）介导对肠杆菌科细菌的定植耐药性，这有助于维持结肠上皮细胞（结肠细胞）的呼吸能量代谢，并通过抗生素治疗破坏这些微生物与宿主的相互作用。驱动结肠细胞通过发酵获取能量，同时伴随着上皮中氧含量的增加和诱导型一氧化氮表达的增加在目标 1 中，我们将确定抗生素后丁酸消耗是否会增加肠腔中肠杆菌科电子受体的可用性。在目标 2 中，我们将确定丁酸的机制。在目标 3 中，我们将确定上皮 PPAR-γ 信号传导减少对肠道相关微生物群落组成的影响。这项研究的基本原理是，更好地了解抗生素治疗后肠道稳态破坏的因素，将有助于了解抗生素后病原体扩张的机制和 IBS 的发病机制，这些信息将有助于设计缓解IBS的疗法。抗生素治疗的这些不良副作用。