Identification of Bacteroides Fragilis Colonization during Host Mutualism

描述（由申请人提供）：在我们的胃肠道（GI）中，人类拥有高度多样化和复杂的微生物种群，这些微生物似乎对健康和疾病之间的平衡有着深远的影响。尽管最近的许多研究都集中在人类肠道内微生物群落的基于序列的分析上，但这些群落如何建立和维持的机制基础却没有得到很好的描述。我们最近报道了一个分子机制的第一个例子，通过这种机制，任何共生细菌都可以在哺乳动物宿主中建立初始定植。我们的研究表明，脆弱拟杆菌（Bacteroides fragilis）是人类肠道中数量显著的共生体，通过改变其表面荚膜多糖来建立哺乳动物肠道的定植（Liu, Lee et al.， PNAS, 2008）。这种有机体在其定植动物期间产生健康，因为脆弱B.防止肠道病原体引起的肠道炎症。因此，脆弱双歧杆菌增强我们的免疫系统，以帮助对抗传染病。我们的初步数据包括，在这个应用程序中，强烈表明定殖的维持是由不同于初始定殖的机制介导的。在保护脆弱芽孢杆菌免受疾病侵害的过程中，需要荚膜多糖以外的分子与宿主稳定结合。由于共生菌在胃肠道的定植有助于我们的免疫系统抵抗感染，我们建议研究脆弱芽孢杆菌在持续宿主定植过程中所需的分子机制。首先，我们将描述脆弱芽孢杆菌在实验动物肠道内占据的解剖生态位（目的1）。脆弱芽孢杆菌与其宿主之间的物理相互作用的证明将加强这种生物体已经进化出专门的分子来介导肠道定植的假设。随后，我们提出鉴定和表征维持肠道定植所需的分子机制（目的2）。促进宿主-共生体相互作用的分子的发现将促进由致病菌引起的人类疾病的新型益生菌疗法的开发和交付。

DESCRIPTION (provided by applicant): Humans harbor a highly diverse and complex population of microorganisms in our gastrointestinal (GI) tracts that appear to have profound influences on the balance between health and disease. Although many recent investigations have focused on sequence-based profiling of microbial communities within the human gut, the mechanistic basis for how these communities are established and maintained is poorly described. We recently reported the first example of a molecular mechanism by which any symbiotic bacteria establishes initial colonization of a mammalian host. Our studies show that Bacteroides fragilis, a numerically prominent gut symbiont of humans, establishes colonization of the mammalian gut by varying its surface capsular polysaccharides (Liu, Lee et al., PNAS, 2008). This organism engenders health during its colonization of animals, as B. fragilis prevents intestinal inflammation caused by enteric pathogens. Therefore, B. fragilis augments our immune system to help fight diseases by infectious agents. Our preliminary data included, in this application, strongly suggest that maintenance of colonization is mediated by mechanisms distinct from initial colonization. Molecules other than capsular polysaccharides are required for stable association of B. fragilis with its host during protection from disease. As colonization of the GI tract by commensal bacteria helps our immune system fight infections, we propose to investigate the molecular mechanisms required during sustained host colonization by B. fragilis. Initially, we will characterize the anatomical niche occupied by B. fragilis within the intestines of experimental animals (Aim 1). Demonstration of a physical interaction between B. fragilis and its host will reinforce the hypothesis that this organism has evolved dedicated molecules that mediate gut colonization. Subsequently, we propose to identify and characterize the molecular machinery required for maintained intestinal colonization (Aim 2). The discovery of molecules that promote host-symbiont interactions will facilitate the development and delivery of novel probiotic therapies for human diseases caused by pathogenic bacteria. PUBLIC HEALTH RELEVANCE: Decades of research in microbiology have identified numerous virulence factors from many diverse pathogens. However, the study of colonization factors employed by commensal bacteria has only recently been investigated. Bacteroides fragilis is an important commensal microorganism of the human gastrointestinal tract, and has emerged as a model symbiont due to its ability to prevent intestinal inflammation. Therefore, just as virulence factors are important for the biology of pathogens, colonization factors are important for symbiotic microbes to exert their profound benefits to their mammalian hosts. The discovery of molecules or molecular pathways that mediate host-symbiont association is a burgeoning and important area of research worthy of study.