Microbial Ecology of Helicobacter-induced Colitis

项目概述：炎症性肠病（IBD）的特点是在胃肠道中发生异常炎症反应。肠道的微生物群，部分通过与宿主上皮和免疫系统的相互作用，被认为驱动这种促炎状态。肠道菌群代表了一个复杂的细菌群落，直到最近才被部分描述。使用非培养技术来检查复杂的微生物群落已经开始揭示肠道微生物群的结构和组成的细节。迄今为止，关于肠道粘膜相关微生物群结构差异的研究很少，这些差异是由宿主免疫系统的改变、病原体的存在、抗生素治疗或有益（益生菌）生物的存在引起的。在本提案中，对微生物生态学和传染病/细菌发病机制感兴趣的科学家之间的现有合作计划利用由肝幽门螺杆菌存在引发的IL-10-/-小鼠IBD小鼠模型，研究肠道微生物群在IBD中的作用。具体来说，我们建议1)确定宿主免疫系统对形成粘膜相关肠道微生物群的影响2)确定肝炎嗜血杆菌感染和结肠炎的发展如何改变粘膜相关肠道微生物群3)确定抗生素是否可以改变感染肝炎嗜血杆菌的IL-10-/-动物的IBD发展4)确定益生菌是否可以通过诱导肠道变化来预防和/或改善结肠炎微生物群。拟议的实验将提供深入了解传染因子可以触发本地微生物群的变化，从而导致异常宿主反应和疾病状态的机制。这一信息将直接影响炎症性肠病患者，从而更好地了解潜在的疾病机制和发展新的治疗方式。人类的炎症性肠病被认为是由免疫系统与通常居住在肠道中的微生物之间的异常相互作用引起的。该项目旨在确定易导致炎症性肠病的肠道微生物群落的异常，为这种慢性疾病的新疗法指明方向，这种疾病在发达国家的发病率为千分之一。

DESCRIPTION (provided by applicant): Project Summary Inflammatory bowel disease (IBD) is characterized by the development of an abnormal inflammatory response in the gastrointestinal tract. The microbiota of the intestinal tract, in part via interactions with the host epithelium and immune system are thought to drive this proinflammatory state. The gut microbiota represents a complex community of bacteria that until recently has only been partly characterized. The use of culture-independent techniques to examine complex microbial communities has started to reveal details about the structure and composition of the gut microbiota. To date, minimal work has been done to define differences in the structure of the mucosa-associated microbiota of the intestinal tract secondary to alterations in the host immune system, the presence of pathogens, antibiotic treatment or the presence of beneficial (probiotic) organisms. In this proposal, an existing collaboration between scientists with interests in microbial ecology and infectious diseases/bacterial pathogenesis plan to investigate the role of the intestinal microbiota in IBD utilizing a well developed murine model of IBD in IL-10-/- mice triggered by the presence of the bacterium Helicobacter hepaticus. Specifically we propose to 1) determine the influence of the host immune system on shaping the community structure of the mucosa-associated intestinal microbiota 2) determine how H. hepaticus infection and the development of colitis changes the mucosa-associated intestinal microbiota 3) determine if antibiotics can modify the development of IBD in H. hepaticus-infected IL-10-/- animals and 4) determine if probiotic bacteria prevent and/or ameliorate colitis by inducing shifts in the intestinal microbiota. The proposed experiments will provide insight into the mechanism by which infectious agents can trigger shifts in the indigenous microbiota that lead to aberrant host responses and disease states. This information will directly impact patients with inflammatory bowel disease, leading to a greater understanding of the underlying disease mechanisms and the development of novel treatment modalities. Relevance Inflammatory bowel disease in humans is thought to arise from an abnormal interaction between the immune system and the microbes that normally inhabit the gut. This project intends to define abnormalities in the community of gut microbes that predispose to the development of inflammatory bowel disease, pointing the way towards new therapies for this chronic disease that affects 1 in 1000 people in developed countries.