Commensal bacterial metabolism of dietary phytate in host defense

项目摘要/摘要 肠道感染在全球范围内仍然高度流行，有20多亿病例和100多万人死亡。 每年。尽管饮食长期以来一直与感染易感性有关，但调节肠道的饮食因素 人们对辩方的理解仍然很少。在肠道中，有数以万亿计的微生物，统称为 微生物区系。不同的饮食可以改变这些驻留在体内的微生物的组成和代谢产物 肠子。此外，最近的工作突出了微生物区系定植和有效 粘膜部位的免疫反应。从而破译了饮食、微生物区系和肠道之间的相互作用 免疫将使新的和实用的饮食方法的发展，以预防和治疗肠道感染。 我的新数据引发了一种假设，即共生细菌对营养植酸的代谢可以 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)富含植酸的饮食如何增强小鼠和 人体肠道，以及(Ii)微生物区系是否需要植酸介导的肠道防御 感染。描绘饮食和微生物区系的贡献将极大地扩展我们对 参与肠道免疫调节和炎症的机制。 在我作为一名兽医的培训期间，我发现我对了解饮食-微生物区系如何 关系调节肠道感染。出于这个原因，我和特蕾莎博士一起发起了这个拟议的项目 这将建立在我的粘膜免疫学知识的基础上，并使我能够过渡到外地 营养和微生物区系。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的专业知识，饮食，灵知生物， 元基因组分析和人类肠道器官。我的导师阿伦哈特博士和詹姆斯·威尔斯博士 具有非凡的科学环境，将使我能够在我的 研究并与顶级调查人员合作。我对广泛物种中疾病的理解， 再加上我之前的研究，都为我提供了坚实而独特的基础。在接下来的五年， 我完全相信，这个背景加上我目前的研究计划，将使我能够成功地 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的指导和培训，以及 来自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 可以在营养、微生物区系和感染的界面上解决临床相关问题的科学家。

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.