Carbohydrate Public Good Interactions in Healthy and Dysbiotic Bacteroidales Communities

这份提案描述了一个为期5年的职业指导研究项目，目标是 确定合作和自私利用膳食和宿主来源的碳水化合物的作用 由拟杆菌属在肠道微生物区系中的生态相互作用和组成。 成功完成研究和培训计划将使调查员能够获得 获得独立资金并过渡到独立医生所需的技能- 科学家的长期目标是通过多学科探索人类肠道微生物区系 接近了。研究目标和职业发展计划将努力掌握和 对肠道厌氧菌的细菌遗传学方法的独立性和对两者的熟练程度 微生物区系的生态进化和生物信息学/计算分析。主要的合作伙伴- 导师是劳里·康斯托克博士，他是拟杆菌目细菌遗传学的世界专家 马修·瓦尔多博士是下一代细菌测序方法的领导者， 在布里格姆医院和妇女医院/哈佛医学院。协作和 导师小组由当地的多机构传染病专家小组组成。 疾病，理论生态学和模型，微生物生态学，进化生物学，粘膜 免疫学和炎症性肠病。 这项研究计划旨在探索 类杆菌，人类肠道中的主要革兰氏阴性细菌，具有重要的 对宿主健康和疾病的影响。我们的初步发现表明，类杆菌属使用 基于消化变化的膳食多糖生存的不同策略 这些碳水化合物和这些被消化的产品作为公共产品的释放和利用。 我们假设基于碳水化合物公共产品的相互作用以拟杆菌属为中心 是个体和微生物区系组成和动态的基本决定因素 社区。在这项提案中，我们将使用高通量的体外表型分析来分配 共居的健康和非生物类杆菌类杆菌自然群落成员的生态型， 使用细菌遗传学来确定关键的碳水化合物相互作用所涉及的基因，以及 确定自私和基于公共产品的碳水化合物相互作用对 活体肠道微生物区系的组成和动态。总的来说，这些拟议的研究 寻求提供关于自然人类生态决定因素的关键信息 对于我们理解微生物区系和 试图在健康和疾病方面塑造这个社区。

This proposal describes a 5-year career mentored research project with the goal of defining the role of cooperative and selfish utilization of dietary- and host- derived carbohydrates by the Bacteroidales in the ecological interactions and composition of the gut microbiota. Successful completion of the research and training plan will enable the investigator to gain the skills necessary to secure independent funding and transition into an independent physician- scientist with the long term goals of exploring the human gut microbiota through multidisciplinary approaches. The research aims and career development plan will work towards mastery and independence in bacterial genetics approaches to gut anaerobic bacteria and proficiency in both eco-evolutionary and bioinformatic/computational analysis of the microbiota. The primary co- mentors are Dr. Laurie Comstock – a world expert in the bacterial genetics of the Bacteroidales and Dr. Matthew Waldor – a leader in next-generational sequencing approaches to bacteria, both at the Brigham and Women's Hospital/Harvard Medical School. The collaborative and mentorship team is comprised of a local, multi-institutional group of experts in infectious diseases, theoretical ecology and modeling, microbial ecology, evolutionary biology, mucosal immunology and inflammatory bowel disease. The research proposal seeks to explore ecological interactions among the Bacteroidales, the predominant Gram negative bacteria of the human gut, which have important impacts on host health and disease. Our preliminary findings suggest that the Bacteroidales use diverse strategies to survive on dietary polysaccharides based on variation in the digestion of these carbohydrates and liberation and utilization of these digested products as public goods. We hypothesize that carbohydrate public good based interactions centered on the Bacteroidales are fundamental determinants of the composition and dynamics of individuals and microbiota communities. In this proposal we will use high throughput in vitro phenotypic analysis to assign ecotypes to members of co-resident healthy and dysbiotic Bacteroidales natural communities, use bacterial genetics to identify the genes involved in key carbohydrate-based interactions, and determine the impact of selfish and public goods-based carbohydrate interactions on the composition and dynamics of the gut microbiota in vivo. Collectively these proposed studies seek to provide critical information on the ecological determinants of naturally human Bacteroidales communities and will be important for our understanding of the microbiota and attempts to shape this community in health and disease.