Genome-based Modeling and Design of Microbial Communities

新陈代谢是为所有生物的细胞过程提供动力所需的能量来源。以综合的方式了解新陈代谢，使我们有机会利用自然新陈代谢网络的力量，用于多种应用，包括制造可再生燃料和非天然化学品、清理受污染的地下水，并有可能通过营养和益生菌干预来维持健康的肠道微生物群。然而，对于这些实际应用，在工程新陈代谢方面存在一些挑战。一个关键的限制是定量描述细胞内代谢瞬变的动态以及与微生物群落中其他物种的代谢相互作用的能力。基因组测序和组学方法的进步使细胞代谢得到了前所未有的表征，并为开发基因组规模的代谢模型铺平了道路。虽然这种基因组规模的建模方法已被广泛应用于研究与工业相关的微生物(如大肠杆菌)的新陈代谢，但与肠道微生物组相关的细菌模型相对较少，微生物群落模型更是少之又少。因此，我们研究的长期目标之一是开发人类新陈代谢的集成模型和与肠道相关的基因组规模的微生物模型。具体地说，在短期内，我们将专注于开发肠道微生物组和常见益生菌的微生物模型，并将它们集成到群落模型中，以模拟群落随饮食变化的动态变化。该提案的成功完成将使我们能够开发新的工具，用于模拟单个细胞和群落中的新陈代谢，并导致1)用于非天然化学生产的强大微生物群落，以及2)用于维持健康肠道微生物群的潜在营养策略。此外，开发的计算和实验工具将为更好地理解和设计复杂环境中的新陈代谢提供基础，并将推动将其应用于其他重要问题，包括将二氧化碳生物转化为增值化学品、生物修复和个性化营养和药物。最终目标是应用这些工具开发可商业化的非天然化学品制造生物过程和个性化营养和药物的基于模型的设计。

Metabolism is the source of energy required for powering cellular processes in all living things. Understanding metabolism in an integrated way allows the opportunity to harness the power of natural metabolic networks for several applications including the manufacture of renewable fuels and non-natural chemicals, clean-up of contaminated groundwater, and potentially for maintaining a healthy gut microbiome through nutritional and probiotic interventions. However, there are several challenges in engineering metabolism for these practical applications. A key limitation is the ability to quantitatively describe the dynamics of metabolic transience within the cells and the metabolic interactions with other species in microbial communities. Advances in genome sequencing and omics methods have enabled the unprecedented characterization of cellular metabolism and have paved the way for developing genome-scale metabolic models. While such genome-scale modeling methods have been extensively applied to studying metabolism in industrially relevant microbes such as Escherichia coli, there are relatively few models of bacteria relevant to gut microbiome and even fewer models of microbial communities. Hence, one of the longer term objectives of our research is to develop integrated models of human metabolism and genome-scale models of microbes relevant to the gut. Specifically, in the shorter term, we will focus on developing models of the microbes present in gut microbiome and common probiotics and integrate them into a community model in order to simulate the dynamics of community in response to dietary changes.The successful completion of the proposal will enable the development of novel tools for modeling and engineering metabolism in individual cells and communities and lead to 1) robust microbial communities for non-natural chemical production and 2) potential nutritional strategies for maintaining a healthy gut microbiome. Further, the computational and experimental tools developed will provide the foundations for improved understanding and engineering of metabolism in complex environments and will drive the application to other significant problems including bioconversion of CO2 to value-added chemicals, bioremediation and personalized nutrition and medicine.The ultimate objective is the application of these tools for the development of commercializable bioprocess for the manufacture of non-natural chemicals and model-based design for personalized nutrition and medicine.