Antibiotics and Human Microbial Community Dynamics

描述(申请人提供)：人类与一个复杂的互惠微生物区系共同进化，在一系列身体栖息地组织成不同的群落，我们的健康依赖于这些群落。这些微生物群落定期接触强效抗生素在发达国家和发展中国家都很常见，这种情况在我们的进化史上是史无前例的。这种暴露导致人类微生物区系的组成立即发生了深刻的变化。尽管这些群落总体上看起来很健壮，但抗生素引起的一些成分变化似乎是稳定的。社区的功能变化也可能发生，但几乎没有被研究过。这些变化令人担忧，因为微生物和人类宿主之间的许多有益互动是特定菌株特有的；填充社区内相同生态位的相关菌株可能与宿主没有相同的有益互动。对抗生素对人-微生物相互作用的影响的了解仍然支离破碎，部分原因是最近才有有效的高通量工具来研究这种复杂群落内的组成、功能潜力和相互作用，而在没有干扰的情况下解决肠道微生物区系组成和功能的常规时间变化的数据很少。拟议工作的广泛和长期目标是了解人类肠道微生物区系组成和功能的常规时间变异性，发现有助于这些群落在受到抗生素疗程干扰后保持稳定和弹性(或缺乏弹性)的因素，并表征组成和功能动态以及组成和功能之间随时间的关系的个体间差异。具体目的1.基于对10名受试者每周粪便样本中16S rRNA基因的深度测序，以及多变量和时间序列分析，表征在没有故意干扰的情况下，健康成人肠道微生物区系在36周内的分类组成的时间动态。具体目标2.根据AIM 1每周粪便样本的子集的鸟枪式DNA测序和代谢组学分析，以及基于多变量共惯性的工具，表征在没有故意干扰的情况下，健康成人肠道微生物区系在36周内功能基因含量和化学环境的时间动态。具体目的3.基于16S rRNA基因的深度测序、鸟枪DNA测序和对20名健康受试者(在第13周期间服用环丙沙星)每周粪便样本的代谢分析，表征短程抗生素对健康成人肠道微生物区系分类组成、功能基因含量和化学环境的影响。

DESCRIPTION (provided by applicant): Humans have co-evolved with a complex mutualistic microbiota, organized into distinct communities in a range of body habitats, upon which we rely for our health. Periodic exposure of these microbial communities to potent antibiotics has become common in both the developed and developing world, a situation that is unprecedented in our evolutionary history. Such exposures lead to immediate, profound changes in the composition of the human microbiota. Despite the apparent overall robustness of these communities, some antibiotic-induced changes in composition appear to be stable. Functional changes in the community may also occur, but have scarcely been examined. These changes are worrisome, because many beneficial interactions between microbes and the human host are specific to particular strains; related strains that fill the same ecological niche within the community may not have the same beneficial interactions with the host. An understanding of the effects of antibiotics on human-microbe interactions remains fragmentary in part because effective, high-throughput tools for addressing the composition, functional potential and interactions within such complex communities have only recently become available, and data addressing the routine temporal variation in the composition and function of the gut microbiota in the absence of disturbance are scarce. The broad, long-term objectives of the proposed work are to understand the routine temporal variability in composition and function of the human gut microbiota, to discover factors contributing to the stability and resilience (or lack thereof) of these communities after disturbance by a course of antibiotics, and to characterize inter-individual differences in the compositional and functional dynamics, and in the relationship between composition and function over time. Specific Aim 1. Characterize the temporal dynamics of the taxonomic composition of the gut microbiota in healthy human adults over 36 weeks in the absence of deliberate disturbance, based on deep sequencing of 16S rRNA genes in weekly fecal samples in 10 subjects, and multivariate and time series analyses. Specific Aim 2. Characterize the temporal dynamics of the functional gene content and of the chemical milieu of the gut microbiota in healthy human adults over 36 weeks in the absence of deliberate disturbance, based on shotgun DNA sequencing and metabolomic analysis of a subset of the weekly fecal samples from Aim 1, and multivariate coinertia-based tools. Specific Aim 3. Characterize the impact of a short course of an antibiotic on the taxonomic composition, functional gene content, and chemical milieu of the gut microbiota in healthy human adults, based on deep sequencing of 16S rRNA genes, shotgun DNA sequencing and metabolomic analysis of weekly fecal samples from 20 healthy subjects collected over 25 weeks (with a course of ciprofloxacin during week 13).