Commensal bacterial metabolism of dietary phytate in host defense

项目概要/摘要 肠道感染在世界范围内仍然非常普遍，有超过20亿例病例和超过100万例死亡 每一年。虽然饮食长期以来一直与感染易感性有关，但调节肠道免疫的饮食因素， 防御仍然知之甚少。在肠道中，有数万亿的微生物，统称为 微生物群不同的饮食可以改变这些常驻微生物的组成和代谢产物， 肠。此外，最近的工作强调了微生物群定殖和有效治疗之间的明确联系。 粘膜部位的免疫反应。从而破译饮食，微生物群和肠道之间的相互作用， 免疫力将使得能够开发新的和实用的饮食方法来预防和治疗肠道感染。 我的新数据提出了这样一个假设，即营养物质植酸盐被细菌代谢， 减少肠道感染，增强宿主防御机制。本提案中概述的研究将直接 通过确定（i）富含肌醇六磷酸饮食如何增强小鼠中宿主肠道防御， （ii）微生物群是否是肌醇六磷酸介导的针对肠的防御所需要的， 感染描述饮食和微生物群的贡献将大大扩展我们对 肠道免疫调节和炎症机制。 在我作为一名兽医的培训期间，我发现我对了解饮食微生物群是如何 关系调节肠道感染。出于这个原因，我与Theresa博士发起了拟议的项目 这将建立在我的粘膜免疫学知识的基础上，使我能够过渡到该领域， 营养和微生物群。我的论文和最初的博士后工作为我提供了良好的基础 在免疫学和上皮生物学，但我仍然缺乏技术技能和概念知识，在饮食，gnotobiotics， 宏基因组分析和人类肠道类器官。我的导师，阿伦哈特博士和詹姆斯威尔斯博士，沿着 与特殊的科学环境，将使我能够利用现代，创新的方法在我的 研究并与顶级研究人员合作。我对疾病的理解在广泛的物种中， 加上我之前的研究，为我提供了一个强大而独特的基础。在接下来的五年里， 我完全期望，这种背景与我目前的研究计划相结合，将使我成功地 执行拟议的项目。我将从阿伦哈特博士和威尔斯博士那里得到指导和培训， 从更广泛的辛辛那提儿童社区，将使我能够成功地过渡到一个独立的 科学家，可以解决营养，微生物群和感染界面的临床相关问题。

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.