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

项目概要 人类肠道微生物群是一个密集的生态系统，共同产生包括多种化学物质在内的功能 分布在组成群落成员之间的转化和对肠道的定植抵抗 影响人体生理的病原体。对生态和环境的详细和机械的理解 塑造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，从而实现紧急的 社区层面的属性并开发预测计算模型来描述生态系统行为。 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理，以查明 塑造群落组装和稳定性以响应环境的分子机制 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，利用较低的测量值反映自然系统的多样性 秩序组合来预测多物种群落行为。我们将生态行为映射到 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以及使用基因组规模询问代谢活动 建模。利用这些多方面的方法，我们将研究殖民化的原理 对艰难梭菌的抗性，影响丁酸生产稳定性和活性的生态相互作用 使益生菌实现稳定生态功能的细菌和分子机制。我们的工作将 最终导致描述微生物复杂行为的数学和生物学原理 社区面临环境压力，并将对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.