Gut microbiome evolution via nature verses nurture: the iaffect of changing environments on the developing mammalian gut microbial ecosystem and immunity.

人类胃肠道定植有多种共生细菌和其他微生物，统称为肠道微生物群。这些微生物及其遗传物质被称为肠道微生物组。肠道微生物组与人类新陈代谢、肠道发育和正常生理机能、免疫成熟和耐受性以及最近的大脑过程和行为有关。肠道微生物组是一个微生物生态系统，其运作方式很像一个器官，其功能是促进正常的人体生理机能。当前的计划将寻求了解哺乳动物肠道中肠道细菌群落结构组合如何形成的基础，重点关注环境和遗传学的作用。虽然有证据支持肠道微生物群是从母亲垂直传播的，但人们也认为环境是肠道中通过水平传播获得的微生物的来源。然而，人们对外部环境在肠道微生物组发育中的作用知之甚少。在这项提案中，我们着手对先天与后天如何影响哺乳动物肠道中微生物的水平和垂直转移有一个基本的了解。总的来说，我的研究旨在了解外部环境、肠道微生物群和肠道粘膜免疫之间的复杂关系。在很大程度上，我假设微生物群的肠道定植是一个控制点，它决定了免疫耐受性，从而影响免疫成熟。因此，我将研究影响肠道微生物组的因素及其对免疫发育的影响。我的长期研究目标是了解微生物如何在分子水平上占据肠道中的特定生态位。在了解这一领域之前，我首先需要研究哪些因素影响构成肠道群落组合的微生物类型。反过来，我试图了解这些群落变化如何影响肠道的免疫发育和耐受性。在接下来的 5 年里，我将重点关注以下内容：******目标 1：了解环境对哺乳动物肠道中肠道微生物组发育的影响。******目标 2：了解环境对影响免疫的肠道微生物-宿主界面的影响。******意义：这项研究将帮助我们了解各种环境和遗传因素对肠道微生物群组成、多样性和组装的作用，确定自然与培养肠道微生物组研究的主要研究挑战，以及这如何影响肠道中的微生物-宿主动态。这将有助于描绘微生物组如何影响肠道免疫成熟和免疫耐受背后的机制，对于了解肠道微生物群如何影响局部和全身免疫结果非常重要。总体而言，我将培养2名硕士生和3名博士生。*****

The human gastrointestinal tract is colonized with a diverse range of symbiotic bacteria and other microorganisms, collectively known as the gut microbiota. This population of microorganisms and their genetic material is referred to as the gut microbiome. The gut microbiome has been linked to human metabolism, gut development and normal physiology, immune maturation and tolerance, and more recently with brain processes and behavior. The gut microbiome is a microbial ecosystem that operates much like an organ, functioning to promote normal human physiology. This current program will seek to understand the basis of how the gut bacterial community structural assemblages form in the mammalian gut with a focus on the role of the environment and genetics. While there is evidence to support that the gut microbiota is vertically transmitted from the mother, it is also considered that the environment is a source of microbes that are acquired in the gut through horizontal transmission. Yet, the role of the external environment in gut microbiome development is poorly understood. In this proposal, we set out to gain a fundamental understanding of how nature vs. nurture influences horizontal and vertical transfer of microbes in the mammalian gut. Overall, my research serves to understand the complex relationship between the external environment, the intestinal microbiota and gut mucosal immunity. Largely, I hypothesize that intestinal colonization by the microbiota is a control point that shapes immune tolerance and consequently, immune maturation. Thus, I will examine factors that affect the gut microbiome and its impact on immune development. My long-term research goal is to understand how microbes occupy specific niches in the gut on a molecular level. Before I can gain understanding in this area, I first need to study what factors influence the types of microbes that make up community assemblages in the gut. In turn, I seek to understand how these community changes might affect immune development and tolerance in the gut. Over the next 5 years, I will focus on the following:******Objective 1: To understand the effects of the environment on the development of the gut microbiome in the mammalian gut.******Objective 2: To understand the effects of the environment on the gut microbe-host interface impacting immunity.******Significance: This research will shape our understanding about the role of various environmental and genetic factors on the gut microbiota composition, diversity and assembly, identify major research challenges for nature vs. nurture gut microbiome studies and how this effects the microbe-host dynamic in the gut. This will help delineate the mechanism(s) behind how the microbiome affects intestinal immune maturation and immunotolerance important for understanding how the gut microbiota influences not only local but also systemic immune outcomes. Overall, I will train 2 Masters and 3 PhD students.*****