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Novel gut pathobionts confound results in a widely used mouse model of human inflammatory disease

View ORCID ProfileSamuel C. Forster, Simon Clare, View ORCID ProfileBenjamin S. Beresford-Jones, Katherine Harcourt, George Notley, Mark Stares, Nitin Kumar, Amelia T. Soderholm, Anne Adoum, Hannah Wong, Bélen Morón, Cordelia Brandt, Gordon Dougan, David J. Adams, View ORCID ProfileKevin J. Maloy, View ORCID ProfileVirginia A. Pedicord, View ORCID ProfileTrevor D. Lawley
doi: https://doi.org/10.1101/2021.02.09.430393
Samuel C. Forster
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
2Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
3Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
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Simon Clare
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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Benjamin S. Beresford-Jones
4Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, United Kingdom
5Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
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Katherine Harcourt
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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George Notley
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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Mark Stares
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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Nitin Kumar
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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Amelia T. Soderholm
4Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, United Kingdom
5Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
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Anne Adoum
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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Hannah Wong
6Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, United Kingdom
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Bélen Morón
7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
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Cordelia Brandt
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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Gordon Dougan
4Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, United Kingdom
5Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
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David J. Adams
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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Kevin J. Maloy
7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
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Virginia A. Pedicord
4Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, United Kingdom
5Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
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Trevor D. Lawley
1Host-Microbiota Interactions Lab, Wellcome Sanger Institute, Hinxton, United Kingdom
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  • For correspondence: tl2@sanger.ac.uk
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Abstract

The mammalian gut microbiota consists of hundreds of anaerobic bacterial species that shape intestinal homeostasis and influence host immune responses. Although the causal roles of specific human gut bacterial species in health and disease are emerging, the role of indigenous gut bacteria in driving immunophenotypic variability in mouse models of human disease remains poorly understood. We performed a large-scale experiment using 579 laboratory mice designed to identify and validate the causes of disease variability in the widely used dextran sulphate sodium (DSS) mouse model of inflammatory bowel disease. Using microbiome analysis, coupled with machine learning and targeted anaerobic culturing, we identified and isolated the novel gut pathobiont species Duncaniella muricolitica and Alistipes okayasuensis and fulfilled Koch’s postulates in mice to show that each pathobiont exerts dominant effects in the DSS model leading to variable treatment responses. We show these pathobiont species are common, but not ubiquitous, in mouse facilities around the world, raising experimental design opportunities for improved mouse models of human intestinal diseases.

Competing Interest Statement

TDL is a founder and CSO of Microbiotica. The other authors declare no competing financial interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 09, 2021.
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Novel gut pathobionts confound results in a widely used mouse model of human inflammatory disease
Samuel C. Forster, Simon Clare, Benjamin S. Beresford-Jones, Katherine Harcourt, George Notley, Mark Stares, Nitin Kumar, Amelia T. Soderholm, Anne Adoum, Hannah Wong, Bélen Morón, Cordelia Brandt, Gordon Dougan, David J. Adams, Kevin J. Maloy, Virginia A. Pedicord, Trevor D. Lawley
bioRxiv 2021.02.09.430393; doi: https://doi.org/10.1101/2021.02.09.430393
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Novel gut pathobionts confound results in a widely used mouse model of human inflammatory disease
Samuel C. Forster, Simon Clare, Benjamin S. Beresford-Jones, Katherine Harcourt, George Notley, Mark Stares, Nitin Kumar, Amelia T. Soderholm, Anne Adoum, Hannah Wong, Bélen Morón, Cordelia Brandt, Gordon Dougan, David J. Adams, Kevin J. Maloy, Virginia A. Pedicord, Trevor D. Lawley
bioRxiv 2021.02.09.430393; doi: https://doi.org/10.1101/2021.02.09.430393

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