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

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).

Maladaptation between host and microbiome at barrier surfaces, leading to local and systemic inflammation underlies a number of genetic diseases, for example, cystic fibrosis (CF) and inflammatory bowel disease (IBD). There is an unmet need to understand the mechanisms by which the microbiome contributes to development of these diseases so that underlying pathways can be targeted for therapeutic gain. More broadly, there is a need to better understand and control for the impact of the microbiome on host phenotype in order to refine use of mouse models and improve reproducibility in mouse genetics research.

The 'Microbiome and Barrier Function' cluster will bring together diverse expertise to establish a pipeline for creating and manipulating mouse models of human genetic diseases involving epithelial barrier immunobiology and the microbiome. Initial focus will be on three monogenic human disease models, representing IBD (Syk), CF (Cftr), and combined immunodeficiency syndrome (Arpc1b). The pipeline will subsequently be extended to other monogenic disease models that impact different layers of epithelial barrier biology.

The cluster will develop cutting-edge laboratory, gnotobiotic, and bioinformatic techniques, including rederivation of strains under germ-free conditions, humanized and novel synthetic microbial communities, models of infection and challenge to barrier surfaces, and in-depth genomic and metabolomic characterization of the host and microbiome. The outcome will be identification of causative roles for the microbiome in exemplary disease models, which will then be mapped back to relevant human disease cohorts.

Through collaboration with the Mary Lyon Centre, the cluster will establish new standards and capacity for mouse microbiome research. These resources will be made available to academic and industry partners across the UK who wish to understand and control for the microbiome in their own research.