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

• 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
• 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

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（由申请方提供）：炎症性肠病（IBD）是一种严重的医学疾病，其特征是人体胃肠道内的异常免疫应答，并导致受累患者出现严重的临床结局。压倒性的临床和实验室研究表明，人类患者和动物肠道内的肠道细菌是炎症反应的目标。此外，许多研究人员预测，肠道微生物区系的成员可能会调节IBD的发展，某些共生细菌的子集可能会直接保护粘膜免疫反应。然而，这些有益微生物的身份以及它们在预防疾病过程中所采用的分子机制在很大程度上是未知的。我们已经表明，在动物与普遍存在的肠道微生物脆弱拟杆菌共生期间，细菌多糖（PSA）指导发育中的免疫系统的细胞和物理成熟。最重要的是，这个过程对健康的重要性是由我们的研究结果表明，定植与B。fragilis保护动物免受实验性结肠炎。因此，第一次，一个单一的共生细菌物种已被实验证明，以指导一个有益的免疫程序，在保护免受疾病。初步数据表明，一种新的肠道免疫调节和抗炎反应的过程中引起的胃肠道保护动物。然而，控制B. fragilis对健康的促进作用几乎完全没有定义。通过将免疫学和微生物学方法合并到广泛相关的动物模型中，我们试图确定在宿主-细菌共生期间介导肠道健康和疾病之间的关键平衡所需的免疫细胞和分子。公共卫生相关性：炎症性肠病影响全球数百万人，造成广泛的痛苦和死亡。我们试图确定是否有益的肠道微生物，脆弱拟杆菌，可以作为益生菌，以保护实验动物从实验性结肠炎。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的抗炎反应，以建立动物的肠道健康。最重要的是，这些信息可能为开发人类IBD的新治疗方法提供基础。