Mouse genetic models of barrier immunity dysfunction: Role of the microbiome in modifying disease phenotype

人类微生物群是一个用来描述生活在人体上和体内的细菌和其他微生物的术语。这些微生物与我们共存。它们从出生起就伴随着我们，在塑造我们免疫系统的发育过程中发挥着重要作用。微生物群和免疫系统之间的大部分相互作用发生在特殊的屏障表面，例如肠道和肺部的屏障表面。这些表面是用来保护身体免受入侵的。它们还使人类免疫细胞能够与有益和潜在有害的微生物及其产生的物质(代谢物)相互作用。遗传病(由人类DNA序列错误引起的疾病)有时可能会导致屏障表面的正常功能中断。囊性纤维化(CF)和炎症性肠病(IBD)等疾病以及一些罕见的遗传疾病都是如此。在这种情况下，人体(特别是免疫系统)与其微生物群之间的正常相互作用的破坏可能会对疾病的发展产生重大影响。因此，了解人类微生物群对涉及屏障表面破坏的遗传病的贡献是重要的。这可能会使人们更好地了解这些疾病是如何发展的，以及新药开发的机会。这也可能导致有机会操纵微生物组本身作为一种新的治疗形式。限制我们理解微生物组在疾病发展中的作用的一个主要挑战是它的复杂性。数以万亿计的微生物生活在一个人体内，微生物群在不同的人之间可能会有很大的差异。因此，小鼠模型是微生物组研究中必不可少的工具，因为它们允许微生物组被严格控制甚至完全移除(所谓的无菌小鼠)，以便研究和了解其对疾病的影响。作为MRC小鼠遗传学网络的一部分，我们将汇集来自英国各地的一系列临床、免疫学和微生物组专业知识，以形成一个集群，研究微生物组在涉及屏障表面功能障碍的遗传疾病中的作用。我们的“微生物组和屏障功能”集群将实现两个互补的目标：第一，它将开发一个实验管道，用于创建和研究涉及屏障表面的人类遗传病的小鼠模型，重点是了解微生物组在这些疾病中的影响。其次，它将为尖端的小鼠微生物组研究建立一个国家基础设施，所有英国研究人员都可以访问。目标1的关键成果包括研究三种不同的人类遗传病小鼠模型，涉及肠道和肺部的屏障表面破坏。我们将在每种模型上应用最先进的微生物组研究技术(如培育无菌小鼠和合成微生物群落)，并进行深入的免疫学分析。这些方法结合在一起，将帮助我们准确地确定微生物组如何促进疾病的发展，并确定新的治疗机会。为了更好地了解这些结果与人类疾病的相关性，我们将同时应用计算方法来更好地描述小鼠微生物组，并将其功能潜力与相关疾病组中的人类微生物组进行比较。AIM 2的主要交付成果包括与玛丽·里昂中心合作，建立小鼠微生物组研究的新标准和最佳做法。此外，我们还将为其他英国研究人员提供由我们的集群开发的计算和实验技术方面的培训。最后，我们将把我们的实验渠道扩展到其他涉及屏障表面功能障碍的相关遗传病模型，以及其他被认为微生物组发挥关键作用的疾病模型(例如结直肠癌)。

The human microbiome is a term used to describe the bacteria and other microorganisms that live on, and in, the human body. These microorganisms coexist with us. They are with us from birth and they play an important role in shaping the development of our immune system. Much of the interaction between the microbiome and the immune system occurs at specialised barrier surfaces, such as those found in the gut and lung. These surfaces are adapted to protect the body from invasion. They also enable human immune cells to interact with both good and potentially harmful microbes and the substances (metabolites) they produce. Genetic diseases (diseases caused by errors in human DNA sequence) may sometimes result in disruption of normal function at barrier surfaces. This is true of diseases such as cystic fibrosis (CF) and inflammatory bowel disease (IBD), as well as a number of rare genetic conditions. Under these circumstances, the breakdown of normal interactions between the body (in particular the immune system) and its microbiome may contribute significantly to disease development. Understanding the contribution of the human microbiome to genetic diseases involving disruption to barrier surfaces is therefore important. It may lead to a better understanding of how these diseases develop and opportunities for new drug development. It may also lead to opportunities to manipulate the microbiome itself as a novel form of treatment.A major challenge that limits our ability to understand the role of the microbiome in disease development is its complexity. Trillions of microbes inhabit a single human body and microbiomes can vary greatly between individuals. Mouse models are therefore an essential tool in microbiome research because they allow for the microbiome to be tightly controlled or even removed entirely (so called germ-free mice) so that its impact on disease can be studied and understood.As part of the MRC Mouse Genetics Network, we will bring together a range of clinical, immunological, and microbiome expertise from across the UK to form a cluster that addresses the role of the microbiome in genetic diseases involving barrier surface malfunction. Our 'Microbiome and Barrier Function' cluster will achieve two complementary goals: First, it will develop an experimental pipeline for creating and studying mouse models of human genetic diseases involving barrier surfaces, with a focus on understanding the impact of the microbiome in these diseases. Second, it will establish a national infrastructure for cutting-edge mouse microbiome research that will be accessible to all UK researchers.Key deliverables for Aim 1 include studying three different mouse models of human genetic diseases involving barrier surface disruption in the gut and lung. We will apply state-of-the-art microbiome research techniques (such as generating germ-free mice and generating synthetic microbiome communities) to each model along with in-depth immunological analysis. In combination, these approaches will help us to identify precisely how the microbiome contributes to disease development and identify new treatment opportunities. To better understand the relevance of these results to human disease, we will simultaneously apply computational approaches to better characterize the mouse microbiome and compare its functional potential to human microbiomes in relevant disease groups. Key deliverables for Aim 2 include working with the Mary Lyon Centre to establish new standards and best practices in mouse microbiome research. In addition, we will provide training to other UK researchers in the computational and experimental techniques developed by our cluster. Finally, we will expand our experimental pipeline to other related genetic disease models involving barrier surface malfunction, as well as other models of diseases where the microbiome is thought to play a key role (e.g. colorectal cancer).