Protection from Mucosal Pathology by Gut Microflora during Experimental Colitis

描述(申请人提供)：炎症性肠病(IBD)是一种严重的医学疾病，以人体胃肠道内异常的免疫反应为特征，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，隐藏在人类患者和动物肠道内的共生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调节IBD的发展，共生细菌的某些亚群可能指导保护性粘膜免疫反应。然而，这些有益微生物的身份以及它们在预防疾病过程中使用的分子机制在很大程度上是未知的。我们已经证明，在动物与普遍存在的肠道微生物脆弱类杆菌共生的过程中，一种细菌多糖(PSA)指导着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一过程对健康的重要性，即定居脆弱芽孢杆菌可以保护动物免受实验性结肠炎的影响。因此，第一次，一个单一的共生细菌物种被实验证明在疾病保护期间指导一个有益的免疫学程序。初步数据表明，在受保护动物的胃肠道中引发了一种新的肠道免疫调节和抗炎反应过程。然而，控制脆弱杆菌如何促进健康的生物学机制几乎完全不清楚。通过将免疫学和微生物学方法结合到一个广泛相关的动物模型中，我们试图确定在宿主-细菌共生期间调节肠道健康和疾病之间的关键平衡所需的免疫细胞和分子。与公共卫生相关：炎症性肠病影响全世界数百万人，造成广泛的痛苦和死亡。我们试图确定有益的肠道微生物脆弱类杆菌是否可以作为益生菌来保护实验动物免受实验性结肠炎的影响。基于强有力的初步证据，我们认为这种独特的微生物可以激发宿主的抗炎反应，以建立动物的肠道健康。最重要的是，这些信息可能为开发治疗人类IBD的新疗法提供基础。

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.