Microbial Influence on Mucosal Homeostasis

摘要/摘要 胃肠道粘膜起着管腔内容物和下层组织之间的接口作用。 因此，对维持粘膜和系统的动态平衡是至关重要的。内脏腔容纳了一个 数量庞大且分类多样的原核微生物区系。在健康的情况下，粘膜和微生物区系茁壮成长 在互惠共生的安排中。宿主和微生物都进化出了一个复杂的系统 相互感知、反应和反应。这些事件在一定程度上是由肠道的能力所调节的 上皮细胞通过产生活性氧物种(ROS)来对微生物群的特定成员做出反应， 用来激活与维持肠道内环境平衡有关的多条细胞通路。这项建议 将使用体内系统，包括广泛使用无菌小鼠，或以灵知生物定植的小鼠 已知的ROS诱导菌。此外，新生小鼠的微生物区系分类分析将用于 确定对肠道粘膜有功能影响的其他细菌。该提案将研究微生物对 已知的和新的信号通路，并表征了对肠道存活、分化和 扩散。我们的总体目标是定义涉及的参与者、事件和流程 宿主微生物接触以及这种相互作用如何影响肠道内环境平衡、发育和 赔偿。ROS和氧化还原刺激的通路可能代表了一种保守的机制，宿主通过这种机制 与其共生微生物区系相互作用，从而为治疗操作提供了一个有吸引力的目标。

SUMMARY/ABSTRACT The gastrointestinal mucosa functions as an interface between the luminal contents and the underlying tissue compartments, and is thus vital in maintaining mucosal and systemic homeostasis. The gut lumen houses a numerically vast and taxonomically diverse prokaryotic microbiota. In health, the mucosa and microbiota thrive in a mutually beneficial symbiotic arrangement. Both host and microbe have evolved a complex system of mutual perception, response and reaction. These events are mediated in part by the ability of the intestinal epithelia to respond to specific members of the microbiota by the production of reactive oxygen species (ROS), that serve to activate multiple cellular pathways involved in the maintenance of gut homeostasis. This proposal will employ in vivo systems including extensive use of germ-free mice, or mice gnotobiotically colonized with known ROS inducing bacteria. Additionally, taxonomic analysis of microbiota in neonatal mice will be used to identify other bacteria with functional effects on the gut mucosa. The proposal will study microbial influences on known and novel signaling pathway, and characterize the regulatory effects on gut survival, differentiation and proliferation. Our overall objectives are to define the participants, events, and processes involved in host microbial contact and how this interaction influences intestinal homeostasis, development and restitution. ROS and redox-stimulated pathways likely represent a conserved mechanism by which the host interacts with its commensal microbiota, and thus presents an attractive target for therapeutic manipulation.