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

人体微生物组是一个术语，用于描述生活在人体上和人体内的细菌和其他微生物。这些微生物与我们共存。它们从出生起就与我们同在，在塑造我们免疫系统的发展方面发挥着重要作用。微生物组和免疫系统之间的大部分相互作用发生在专门的屏障表面，例如在肠道和肺中发现的屏障表面。这些表面适合于保护身体免受入侵。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。遗传疾病（由人类DNA序列错误引起的疾病）有时可能导致屏障表面的正常功能中断。这是真正的疾病，如囊性纤维化（CF）和炎症性肠病（IBD），以及一些罕见的遗传条件。在这种情况下，身体（特别是免疫系统）与其微生物组之间正常相互作用的破坏可能会显著促进疾病的发展。因此，了解人类微生物组对涉及破坏屏障表面的遗传疾病的贡献是重要的。它可能会导致更好地了解这些疾病如何发展和新药开发的机会。它也可能导致操纵微生物组本身作为一种新的治疗形式的机会。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其复杂性。数万亿的微生物居住在一个人体内，微生物组在个体之间可能存在很大差异。因此，小鼠模型是微生物组研究的重要工具，因为它们允许严格控制甚至完全去除微生物组作为MRC小鼠遗传学网络的一部分，我们将汇集一系列临床，免疫学，来自英国各地的微生物组专业知识，形成一个集群，解决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：首先，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疾病的小鼠模型，重点是了解微生物组在这些疾病中的影响。第二，它将建立一个尖端小鼠微生物组研究的国家基础设施，所有英国研究人员都可以使用。Aim 1的关键成果包括研究三种不同的人类遗传疾病小鼠模型，这些疾病涉及肠道和肺部屏障表面破坏。我们将应用最先进的微生物组研究技术（如生成无菌小鼠和生成合成微生物组群落）对每个模型进行沿着深入的免疫学分析。结合起来，这些方法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表征小鼠微生物组，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。目标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实践。此外，我们还将为其他英国研究人员提供我们集群开发的计算和实验技术的培训。最后，我们将扩大我们的实验管道到其他涉及屏障表面功能障碍的相关遗传疾病模型，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).