Research Project
9295535
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.
