Carbohydrate Public Good Interactions in Healthy and Dysbiotic Bacteroidales Communities

该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 拟杆菌目在肠道微生物群的生态相互作用和组成中的作用。 成功完成研究和培训计划将使研究者能够获得 获得独立资金和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群 接近。研究目标和职业发展计划将致力于掌握和 在细菌遗传学方法的独立性，肠道厌氧菌和精通这两个 微生物群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-一个世界级的专家在细菌遗传学的拟杆菌 马修·沃尔多博士是下一代细菌测序方法的领导者， 都在布莱根妇女医院和哈佛医学院。协作和 导师团队由当地的多机构传染病专家组成， 疾病，理论生态学和建模，微生物生态学，进化生物学，粘膜 免疫学和炎症性肠病。 该研究计划旨在探讨 拟杆菌目是人类肠道的主要革兰氏阴性细菌，具有重要的生物学功能。 对宿主健康和疾病的影响。我们的初步研究结果表明，拟杆菌目使用 不同的策略，以生存的饮食多糖的基础上，在消化的变化， 这些碳水化合物和这些消化产物的释放和利用作为公共产品。 我们假设基于碳水化合物公益的相互作用以类杆菌目为中心 是个体和微生物群的组成和动态的基本决定因素 社区.在这项建议中，我们将使用高通量体外表型分析来分配 生态类型的共同居民的健康和生态失调的拟杆菌自然群落的成员， 利用细菌遗传学来鉴定与关键碳水化合物相互作用有关的基因， 确定自私和公共产品为基础的碳水化合物相互作用的影响 体内肠道微生物群的组成和动力学。这些拟议的研究 寻求提供有关自然人类生态决定因素的关键信息 拟杆菌目群落，将是重要的，我们了解的微生物群， 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.