Elucidating the molecular and ecological design principles of stability and assembly of the human gut microbiota

项目摘要 人类肠道微生物组是一个密集的生态系统，其共同产生包括多种化学物质在内的功能。 转化分布在组成社区成员和殖民抵抗肠道 影响人类生理的病原体。详细和机械的理解生态和 形成肠道微生物群的组装、活性和稳定性的分子力在很大程度上是未知的。 这个问题的核心是系统地绘制未知的物种间相互作用， 社区一级的属性和发展预测计算模型来描述生态系统的行为。 我们正在开发一个通用框架来剖析肠道微生物群的组织原则， 形成群落组装和稳定性的分子机制，以应对环境 扰动我们的总体框架旨在破译人类组成成员之间的相互作用 肠道微生物组合成生态学，反映了自然系统的多样性， 排序组合来预测多物种的群落行为。我们将绘制生态行为图， 分子和遗传因子，通过阐明基因表达谱、单细胞表型、遗传 群落结构和功能的决定因素，并使用基因组尺度询问代谢活动 建模利用这些多方面的方法，我们将研究殖民化的原则 对C.艰难的，生态相互作用，影响丁酸生产的稳定性和活性， 细菌和分子机制，使益生菌实现稳定的生态功能。我们的工作将 最终导致数学和生物学原理，描述微生物的复杂行为， 社区的环境压力，并将在生物学的所有领域产生深远的影响， 药

PROJECT SUMMARY The human gut microbiome is a dense ecosystem that collectively yields functions including diverse chemical transformations distributed among constituent community members and colonization resistance to intestinal pathogens that influences human physiology. A detailed and mechanistic understanding of the ecological and molecular forces that shape the assembly, activity and stability of the gut microbiota are largely unknown. Central to this problem is systematically mapping unknown inter-species interactions that realize emergent community-level properties and developing predictive computational models to describe ecosystem behaviors. We are developing a general framework to dissect the organization principles of the gut microbiota to pinpoint molecular mechanisms that shape community assembly and stability in response to environmental perturbations. Our general framework aims to decipher interactions among constituent members of a human gut microbiome synthetic ecology that mirrors the diversity of the natural system using measurements of lower- order assemblages to predict multi-species community behaviors. We will map ecological behaviors to molecules and genetic factors by elucidating gene expression profiles, single-cell phenotypes, genetic determinants of community structure and function and interrogating metabolic activities using genome-scale modeling. Leveraging these multifaceted approaches, we will investigate the principles of colonization resistance to C. difficile, ecological interactions that influence the stability and activity of butyrate-producing bacteria and molecular mechanisms that enable probiotics to realize stable ecological functions. Our work will ultimately lead to mathematical and biological principles that describe the complex behaviors of microbial communities to environmental pressures and will have profound impact across all areas of biology and medicine.