Protection from Mucosal Pathology by Gut Microflora during Experimental Colitis

实验性结肠炎期间肠道菌群对粘膜病理的保护作用

基本信息

批准号：
8245742
负责人：
Sarkis K Mazmanian
金额：
$ 34.53万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245742
关键词：
Adverse effects Affect Alternative Therapies Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Bacteria Bacterial Polysaccharides Bacteroides fragilis Biological CD4 Positive T Lymphocytes Cells Clinical Clinical Research Colitis Complex Data Defect Dendritic Cells Development Disease Disease Progression Ecosystem Equilibrium Gastrointestinal tract structure Health Human Immune Immune response Immune system Immunologics In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interleukin-10 Intestines Investigation Laboratory Animals Laboratory Research Lead Location Mediating Medical Microbe Modeling Molecular Mucosal Immune Responses Names Organism Outcome Pathology Patients Phenotype Polysaccharides Probiotics Process Production Regulation Regulatory T-Lymphocyte Reporting Research Personnel Role Symbiosis T-Cell Proliferation T-Lymphocyte Time Tissues Wasting Syndrome base cell type commensal microbes cytokine gastrointestinal gut microflora immunoregulation in vivo member microorganism mortality novel novel therapeutics programs response therapy development

项目摘要

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) represents a serious medical disorder marked by aberrant immune responses within the human gastrointestinal tract, and results in severe clinical outcomes in affected patients. Overwhelming clinical and laboratory research has shown that commensal bacteria, harbored within the intestines of human patients and animals, are the targets of inflammatory responses. Furthermore, many researchers have predicted that members of the gut microflora may modulate the development of IBD, and that certain subsets of symbiotic bacteria may direct protective mucosal immune responses. However, the identity of these beneficial microbes and the molecular mechanisms they employ during protection from disease are largely unknown. We have shown that during symbiosis of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Most significantly, the importance of this process to health is demonstrated by our findings that colonization with B. fragilis protects animals from experimental colitis. Thus, for the first time, a single symbiotic bacterial species has been experimentally demonstrated to direct a beneficial immunologic program during protection from disease. Preliminary data suggest a novel process of intestinal immune regulation and anti-inflammatory responses elicited in the gastrointestinal tract of protected animals. However, the biological mechanisms which govern how B. fragilis promotes health remain almost entirely undefined. Through the merger of immunologic and microbiologic approaches incorporated into a widely-relevant animal model, we seek to identify the immune cells and molecules required to mediate the critical balance between intestinal health and disease during host-bacterial symbiosis. PUBLIC HEALTH RELEVANCE: Inflammatory bowel disease affects millions of people world-wide, causing widespread suffering and mortality. We seek to determine if the beneficial intestinal microorganism, Bacteroides fragilis, can serve as a probiotic to protect laboratory animals from experimental colitis. Based on strong preliminary evidence, we propose this unique microbe can elicit host anti-inflammatory responses to establish intestinal health in animals. Most importantly, this information may potentially provide the basis for development of novel therapeutic treatments for IBD in humans.

描述（由申请人提供）：炎症性肠病（IBD）代表了一种严重的医学疾病，其标志是人类胃肠道内异常的免疫反应，并导致受影响患者的严重临床结果。压倒性的临床和实验室研究表明，在人类患者和动物的肠道内藏有的共生细菌是炎症反应的靶标。此外，许多研究人员已经预测，肠道菌群的成员可能会调节IBD的发展，并且共生细菌的某些亚群可以指导保护性粘膜免疫反应。但是，这些有益的微生物的身份以及它们在免受疾病保护期间采用的分子机制是未知的。我们已经表明，在具有普遍存在的肠道微生物的动物共生期间，细菌多糖（PSA）指导了发育中的免疫系统的细胞和物理成熟。最重要的是，我们的发现证明了这种过程对健康的重要性，即我们与脆弱链球菌的定殖保护动物免受实验性结肠炎的影响。因此，首次在实验中证明了一种共生细菌物种在保护疾病期间指导有益的免疫程序。初步数据表明，在受保护动物的胃肠道中引起的肠道免疫调节和抗炎反应的新过程。但是，支配脆弱链球菌如何促进健康的生物学机制几乎完全不确定。通过合并到广泛相关的动物模型中的免疫和微生物方法的合并，我们试图确定在宿主 - 细菌共生过程中介导肠道健康与疾病之间临界平衡所需的免疫细胞和分子。公共卫生相关性：炎症性肠病会影响全球数百万的人，从而引起广泛的痛苦和死亡率。我们试图确定有益的肠道微生物（fragilis）是否可以用作保护实验动物免受实验性结肠炎的益生菌。基于强有力的初步证据，我们提出这种独特的微生物可以引起宿主抗炎反应以在动物中建立肠道健康。最重要的是，这些信息可能有可能为人类IBD的新型治疗方法开发提供基础。