Molecular Mechanisms that Shape Gut Microbial Communities

塑造肠道微生物群落的分子机制

基本信息

批准号：
8211978
负责人：
Sarkis K Mazmanian
金额：
$ 41万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8211978
关键词：
Address Anatomy Animals Bacteria Bacteroides Bacteroides fragilis Base Sequence Biochemical Genetics Biological Process Biology Birth Cataloging Catalogs Communities Complex DNA Sequence Data Development Disease Disease model Ecology Ecosystem Evolution Fingerprint Funding Funding Opportunities Future Gastrointestinal tract structure Gene Deletion Genes Genetic Genetic Screening Genome Gnotobiotic Health Human Human Microbiome Immune system Intestines Investigation Laboratory culture Link Location Mammals Mediating Metagenomics Microbe Microscopic Molecular Mono-S Mucous Membrane Names Organism Pattern Population Positioning Attribute Process Research Project Grants Resistance Shapes Sterility Surface Symbiosis System Techniques Testing Therapeutic Tissues United States National Institutes of Health Virulence Factors Work base commensal microbes genetic manipulation gut microbiota human disease in vivo innovation member microbial microbial colonization microbial community microbial host microorganism mutant novel pathogen

项目摘要

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.

描述（由申请人提供）：哺乳动物在无菌分娩后立即在几乎所有暴露于环境的表面上组装复杂的细菌群落（称为微生物群）。尽管几十年来人们一直认识到人类拥有大量共生细菌，但最近的研究已经开始揭示我们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 (NIH) 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人类健康和疾病的“细菌指纹”。然而，共生细菌用于介导肠道持久性的分子机制仍然几乎完全未知。拟杆菌是人类微生物群中数量最多、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在哺乳动物肠道中尚不清楚。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识别介导肠道定植的机制。我们鉴定了一个编码一组新基因的基因座，这些基因在许多已测序的肠道拟杆菌中高度保守。最重要的是，基因的删除消除了拟杆菌的稳定定植。总的来说，我们的创新发现强烈表明我们发现了一种新颖的、进化上保守的系统，用于拟杆菌在肠道的持续定植。我们的首要假设是，一种明确的分子机制介导哺乳动物肠道内微生物生态的动态。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共生细菌建立和维持长期肠道定植的分子机制。对健康过程中复杂微生物群如何形成的分子理解可能对于未来人类疾病的治疗方法至关重要。