Molecular Mechanisms that Shape Gut Microbial Communities

描述（由申请人提供）：哺乳动物在无菌出生后立即在几乎所有环境暴露表面上组装复杂的细菌群落（称为微生物群）。虽然几十年来人们一直认为人类体内有大量的细菌，但最近的研究已经开始揭示我们的微生物生态系统的非凡多样性和复杂性。美国国立卫生研究院资助的人类微生物组项目旨在通过对微生物群的DNA序列进行编目来定义健康和疾病中人类的“细菌指纹”。然而，肠道细菌介导肠道持久性的分子机制仍然几乎完全未知。拟杆菌属是人类微生物群中数量最多且生物学上最重要的属之一。这些（或任何其他组）细菌如何稳定地定殖哺乳动物肠道尚不清楚。为了了解肠道中宿主-微生物群关联的动态，我们开发了一种功能性体内方法来鉴定介导肠道定植的机制。我们确定了一个基因座，编码一组新的基因，这些基因在许多测序的肠道类杆菌中高度保守。最重要的是，基因的缺失消除了拟杆菌属的稳定定殖。总的来说，我们的创新发现强烈表明，我们已经发现了一种新的和进化上保守的系统，用于类杆菌持续的肠道定植。我们的总体假设是，一个明确的分子机制介导的哺乳动物肠道内的微生物生态学的动态。 公共卫生相关性：微生物群对人类重要生物过程的重要性是无可争议的，微生物群的变化与许多疾病有关。该项目将研究一类重要的人类肠道细菌建立和维持长期肠道定植的分子机制。对复杂微生物在健康过程中如何形成的分子理解可能对未来人类疾病的治疗方法至关重要。

DESCRIPTION (provided by applicant): Immediately upon a sterile birth, mammals assemble complex bacterial communities on almost all environmentally exposed surfaces (called the microbiota). Though it has been appreciated for decades that humans harbor multitudes of commensal bacteria, recent studies have begun to reveal the extraordinary diversity and complexity of our microbial ecosystems. The NIH funded Human Microbiome Project aims to define the "bacterial fingerprint" of humans in health and disease by cataloging DNA sequences of the microbiota. However, molecular mechanism(s) employed by commensal bacteria to mediate persistence in the gut remain almost entirely unknown. Bacteroides are one of the most numerically prominent and biologically important genera in the human microbiota. How these (or any other group of) bacteria stably colonize the mammalian gut is unknown. To understand the dynamics of host-microbiota associations in the gut, we developed a functional in vivo approach to identify mechanisms that mediate intestinal colonization. We identified a locus that encodes for a novel set of genes that are highly conserved in many sequenced intestinal Bacteroides. Most importantly, deletion of the genes abolishes stable colonization by Bacteroides. Collectively, our innovative findings strongly suggested we have uncovered a novel and evolutionarily conserved system for persistent gut colonization by the Bacteroides. Our overarching hypothesis is that a defined molecular mechanism mediates the dynamics of microbial ecology within the mammalian intestine. PUBLIC HEALTH RELEVANCE: The importance of the microbiota to vital biological processes in humans is indisputable, and changes in the microbiota are associated with numerous diseases. This project will examine the molecular mechanisms by which an important class of human commensal bacteria establish and maintain long-term gut colonization. A molecular understanding for how complex microbiotas are shaped during health may be critical in future therapeutic approaches for human diseases.