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

Lead Research Organisation: University of Oxford

Abstract

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).

Technical Summary

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.

People

ORCID iD

Publications

10 25 50
 
Description UK Knowledge Transfer Network (KTN) Microbiome Biobanking report
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
 
Description UK Knowledge Transfer Network -- Human Intestinal Microbiome Therapies and Diagnostics, The Science, Opportunities and Challenges
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://iuk.ktn-uk.org/wp-content/uploads/2023/02/0489_KTN_HIMDD_Final2_AW_Updated-230228.pdf
 
Description 2022 Studentships
Amount £1,369,921 (GBP)
Funding ID KENN202118 
Organisation The Kennedy Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2022 
End 09/2026
 
Description Assessing Gut Microbiome Heterogeneity Across the National Mouse Genetics Network
Amount £35,046 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2023 
End 04/2025
 
Description Microbial Partnerships: Investigating Gut Microbiome and Immune Responses to Inactivated Whole-Cell Vaccines
Amount £41,495 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2024 
End 09/2024
 
Title MGnify Super Study - National Mouse Genetics Network (NMGN) Microbiome Cluster 
Description The Microbiome Cluster of the National Mouse Genetics Network will achieve two complementary goals: 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 and it will establish a national infrastructure for cutting edge mouse microbiome research that will be accessible to all UK researchers. This superstudy links NMGN-generated data analyses, as well as analyses of other publicly-available relevant datasets. 
Type Of Material Database/Collection of data 
Year Produced 2024 
Provided To Others? Yes  
Impact None as yet 
URL https://www.ebi.ac.uk/metagenomics/super-studies/nmgn-microbiome
 
Description National Mouse Genetics Network 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution We established this national consortium to analyse the role of the microbiome in monogenic inflammatory diseases including cystic fibrosis, arthritis, inflammatory bowel disease and parasitic infections. In addition to establishing the consortium infrastructure and implementing Standard Operating Procedures, the Powrie lab and Oxford Centre for Microbiome Studies have set up germ free rederivation protocols, allowing the creation of new mouse models that both completely lack microorganisms, or harbour specific strains. This makes possible the identification of potentially disease-causing bacteria and fungi within monogenic disease models. The Powrie group has rederived the first model into germ free. Further collaborative efforts will allow the creation, rederivation and sharing of models across the consortium and beyond.
Collaborator Contribution Our clinical partners in Oxford and Exeter will contribute samples from patients with monogenic diseases including cystic fibrosis and very early onset inflammatory bowel disease, and EMBL-EBI offers a biobank. To gain new insights into the gut microbial and metabolite contributions to disease, these samples can be used to reconstitute germ free models and assess the impact on the phenotype. Richard Grencis' lab in Manchester will investigate the microbial and parasitic contributions to a monogenic combined immunodeficiency syndrome. Adilia Warris and Gordon Brown in Exeter will investigate the microbe-fungal interactions in cystic fibrosis. These models are being rederived into germ free by the MRC Mary Lyon Centre, who will also generate germ free cell-specific inducible models to probe the immune-microorganism interactions in disease. Beyond the bacterial, parasites and fungi themselves, the metabolites they make can also affect disease, and this is being investigated by Marc-Emmanuel Dumas' lab at Imperial College through NMR and mass spectrometry metabolomics approaches. The analysis and interpretation of mouse microbiome datasets generated by Rob Finn's group at EMBL-EBI is addressing bottlenecks in the analysis pipelines, and these collaborations together are developing new synthetic microbiomes.
Impact This is a multi-disciplinary collaboration between immunologists, microbiologists and bioinformaticians.
Start Year 2022
 
Description National Mouse Genetics Network 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We established this national consortium to analyse the role of the microbiome in monogenic inflammatory diseases including cystic fibrosis, arthritis, inflammatory bowel disease and parasitic infections. In addition to establishing the consortium infrastructure and implementing Standard Operating Procedures, the Powrie lab and Oxford Centre for Microbiome Studies have set up germ free rederivation protocols, allowing the creation of new mouse models that both completely lack microorganisms, or harbour specific strains. This makes possible the identification of potentially disease-causing bacteria and fungi within monogenic disease models. The Powrie group has rederived the first model into germ free. Further collaborative efforts will allow the creation, rederivation and sharing of models across the consortium and beyond.
Collaborator Contribution Our clinical partners in Oxford and Exeter will contribute samples from patients with monogenic diseases including cystic fibrosis and very early onset inflammatory bowel disease, and EMBL-EBI offers a biobank. To gain new insights into the gut microbial and metabolite contributions to disease, these samples can be used to reconstitute germ free models and assess the impact on the phenotype. Richard Grencis' lab in Manchester will investigate the microbial and parasitic contributions to a monogenic combined immunodeficiency syndrome. Adilia Warris and Gordon Brown in Exeter will investigate the microbe-fungal interactions in cystic fibrosis. These models are being rederived into germ free by the MRC Mary Lyon Centre, who will also generate germ free cell-specific inducible models to probe the immune-microorganism interactions in disease. Beyond the bacterial, parasites and fungi themselves, the metabolites they make can also affect disease, and this is being investigated by Marc-Emmanuel Dumas' lab at Imperial College through NMR and mass spectrometry metabolomics approaches. The analysis and interpretation of mouse microbiome datasets generated by Rob Finn's group at EMBL-EBI is addressing bottlenecks in the analysis pipelines, and these collaborations together are developing new synthetic microbiomes.
Impact This is a multi-disciplinary collaboration between immunologists, microbiologists and bioinformaticians.
Start Year 2022
 
Description National Mouse Genetics Network 
Organisation Medical Research Council (MRC)
Department Neuromouse - MRC Mouse Network
Country United Kingdom 
Sector Academic/University 
PI Contribution OCMS members (Powrie, Johnson, Pearson) are leading the 'Microbiome and Barrier Function' cluster, which is one of six disease challenge-focussed clusters funded as part of the new MRC National Mouse Genetics Network (NMGN). Within the Microbiome and Barrier Function cluster, we are collaborating with a team of Co-Investigators based at Manchester, Oxford, Exeter, Imperial, and EMBL-EBI. We are also working to establish a broader collaborative network of leading national and international researchers interested in host-microbiome interactions at mucosal barrier surfaces. As part of the broader network we are integrating with other disease challenge-focused clusters to help improve and refine mouse models in medical reserach.
Collaborator Contribution Co-Investigators from Exeter bring expertise in medical mycology and clinical expertise in cystic fibrosis . Co-Investigators from Oxford bring basic and clinical expertise in gastrointestinal immunology and, in particular, rare monogenic forms of inflammatory bowel disease. Co-Investigators from Manchester bring expertise in mucosal immunology, the microbiome and mouse models of infectious disease. Co-Investigators from EMBL-EBI bring expertise in data science, computational biology and curation of large-scale microbiome datasets. Co-Investigators from Imperial bring expertise in the microbiome and high-throughput metabolomics.
Impact The main outcome to date is establshing a national collaborative network. Early indicators of success include participation in a training course in the use of germ-free and gnotobiotic animal models and successful germ-free rederivation of a mouse genetic model carying a gain of function mutation in the spleen-associated tyrosine kinase gene (Syk), which will be the subject of future study.
Start Year 2022
 
Description National Mouse Genetics Network 
Organisation University of Exeter
Country United Kingdom 
Sector Academic/University 
PI Contribution We established this national consortium to analyse the role of the microbiome in monogenic inflammatory diseases including cystic fibrosis, arthritis, inflammatory bowel disease and parasitic infections. In addition to establishing the consortium infrastructure and implementing Standard Operating Procedures, the Powrie lab and Oxford Centre for Microbiome Studies have set up germ free rederivation protocols, allowing the creation of new mouse models that both completely lack microorganisms, or harbour specific strains. This makes possible the identification of potentially disease-causing bacteria and fungi within monogenic disease models. The Powrie group has rederived the first model into germ free. Further collaborative efforts will allow the creation, rederivation and sharing of models across the consortium and beyond.
Collaborator Contribution Our clinical partners in Oxford and Exeter will contribute samples from patients with monogenic diseases including cystic fibrosis and very early onset inflammatory bowel disease, and EMBL-EBI offers a biobank. To gain new insights into the gut microbial and metabolite contributions to disease, these samples can be used to reconstitute germ free models and assess the impact on the phenotype. Richard Grencis' lab in Manchester will investigate the microbial and parasitic contributions to a monogenic combined immunodeficiency syndrome. Adilia Warris and Gordon Brown in Exeter will investigate the microbe-fungal interactions in cystic fibrosis. These models are being rederived into germ free by the MRC Mary Lyon Centre, who will also generate germ free cell-specific inducible models to probe the immune-microorganism interactions in disease. Beyond the bacterial, parasites and fungi themselves, the metabolites they make can also affect disease, and this is being investigated by Marc-Emmanuel Dumas' lab at Imperial College through NMR and mass spectrometry metabolomics approaches. The analysis and interpretation of mouse microbiome datasets generated by Rob Finn's group at EMBL-EBI is addressing bottlenecks in the analysis pipelines, and these collaborations together are developing new synthetic microbiomes.
Impact This is a multi-disciplinary collaboration between immunologists, microbiologists and bioinformaticians.
Start Year 2022
 
Description National Mouse Genetics Network 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution We established this national consortium to analyse the role of the microbiome in monogenic inflammatory diseases including cystic fibrosis, arthritis, inflammatory bowel disease and parasitic infections. In addition to establishing the consortium infrastructure and implementing Standard Operating Procedures, the Powrie lab and Oxford Centre for Microbiome Studies have set up germ free rederivation protocols, allowing the creation of new mouse models that both completely lack microorganisms, or harbour specific strains. This makes possible the identification of potentially disease-causing bacteria and fungi within monogenic disease models. The Powrie group has rederived the first model into germ free. Further collaborative efforts will allow the creation, rederivation and sharing of models across the consortium and beyond.
Collaborator Contribution Our clinical partners in Oxford and Exeter will contribute samples from patients with monogenic diseases including cystic fibrosis and very early onset inflammatory bowel disease, and EMBL-EBI offers a biobank. To gain new insights into the gut microbial and metabolite contributions to disease, these samples can be used to reconstitute germ free models and assess the impact on the phenotype. Richard Grencis' lab in Manchester will investigate the microbial and parasitic contributions to a monogenic combined immunodeficiency syndrome. Adilia Warris and Gordon Brown in Exeter will investigate the microbe-fungal interactions in cystic fibrosis. These models are being rederived into germ free by the MRC Mary Lyon Centre, who will also generate germ free cell-specific inducible models to probe the immune-microorganism interactions in disease. Beyond the bacterial, parasites and fungi themselves, the metabolites they make can also affect disease, and this is being investigated by Marc-Emmanuel Dumas' lab at Imperial College through NMR and mass spectrometry metabolomics approaches. The analysis and interpretation of mouse microbiome datasets generated by Rob Finn's group at EMBL-EBI is addressing bottlenecks in the analysis pipelines, and these collaborations together are developing new synthetic microbiomes.
Impact This is a multi-disciplinary collaboration between immunologists, microbiologists and bioinformaticians.
Start Year 2022
 
Description Girls do Science workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Girls Do Science 2023 was part of UN International Day of Women & Girls in Science and included inspirational speakers and interactive workshops to celebrate all things STEM. The aim was to encourage more girls to consider scientific careers, and inlcuded a talk from Fiona Powrie which sparked questons and discussion afterwards.
Year(s) Of Engagement Activity 2023
URL https://www.eventbrite.co.uk/e/girls-do-science-2023-tickets-484326422367
 
Description NIHR Oxford Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The open day offers an opportunity for members of the public, patients and local schools to find out about some of the world-leading research that's going on at Oxford University Hospitals NHS Foundation Trust, in partnership with the University of Oxford. The Powrie lab presented the Giant Gut Wall and related activities which demonstrate in an engaging way how the bacteria that inhabit our bodies impact health and disease. Visitors to the exhibit asked questions and developed a better understanding of how research in the laboratory can lead to new therapies that change lives.
Year(s) Of Engagement Activity 2022
 
Description School visits (Oxford) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We visited 5 local primary schools to talk to years 3, 4 and 6 about the microbiome and read stories about the immune system and microbiome to the students. Copies of books (written by lab members and printed with support from the British Society of Immunology) were left at each school. Schools reported that the books were being borrowed from the library and there were many questions and discussions about the topic both during and after the events.
Year(s) Of Engagement Activity 2023
 
Description Story book for children 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact A story book aimed at children called "Immune Encounters" was written and illustrated by Claire Pearson and Sarah McCuaig and published on the British Society for Immunology website under their "information for the public" page. The story describes the immune response to a bacterial infection and how it differs to the response to the gut microbiome.
Year(s) Of Engagement Activity 2021
URL https://www.immunology.org/public-information/immunology-related-activities-and-resources