Commensal bacterial metabolism of dietary phytate in host defense

点击翻译按钮获取中文摘要

Project summary/abstract Enteric infections remain highly prevalent worldwide with more than two billion cases and over one million deaths per year. Although diet has long been linked to infection susceptibility, the dietary factors that regulate intestinal defense remain poorly understood. In the intestine, there are trillions of microbes, collectively called the microbiota. Different diets can alter the composition and metabolites produced by these resident microbes in the intestine. In addition, recent work has highlighted clear links between microbiota colonization and effective immune responses at mucosal sites. Thus deciphering the interactions between diet, microbiota, and intestinal immunity will enable development of novel and practical dietary approaches to prevent and treat enteric infection. My new data provoke the hypothesis that metabolism of the nutrient phytate by commensal bacteria can decrease intestinal infection and boost host defense mechanisms. Studies outlined in this proposal will directly test this hypothesis by determining (i) how phytate-enriched diet enhances host intestinal defense in mouse and human intestine, and (ii) whether the microbiota is needed for phytate-mediated defense against intestinal infection. Delineating the contribution of diet and microbiota will significantly expand our understanding of mechanisms involved in intestinal immune regulation and inflammation. During my training as a veterinarian, I discovered my strong interest in understanding how the diet-microbiota relationship regulates intestinal infection. For this reason, I initiated the proposed project with Dr. Theresa Alenghat that will build upon my knowledge of mucosal immunology and enable me to transition into the fields of nutrition and microbiota. My thesis and initial postdoctoral work have provided me with an excellent foundation in immunology and epithelial biology, but I still lack technical skills and conceptual expertise in diet, gnotobiotics, metagenomic analyses, and human intestinal organoids. My mentors, Dr. Alenghat and Dr. James Wells, along with an exceptional scientific environment, will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. My understanding of disease in a broad range of species, coupled with my prior research, have provided me with a strong and unique foundation. Over the next five years, I fully anticipate that this background in conjunction with my current research plan will allow me to successfully carry out the proposed project. The mentoring and training I will receive from Dr. Alenghat and Dr. Wells, and from the wider Cincinnati Children’s community, will enable me to successfully transition into an independent scientist that can address clinically relevant questions at the interface of nutrition, microbiota, and infection.