Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population
Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental, and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD....
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/87569 |
| _version_ | 1827789500115320832 |
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| author | Xiaoxu Li Jean-David Morel Giorgia Benegiamo Johanne Poisson Alexis Bachmann Alexis Rapin Jonathan Sulc Evan Williams Alessia Perino Kristina Schoonjans Maroun Bou Sleiman Johan Auwerx |
| author_facet | Xiaoxu Li Jean-David Morel Giorgia Benegiamo Johanne Poisson Alexis Bachmann Alexis Rapin Jonathan Sulc Evan Williams Alessia Perino Kristina Schoonjans Maroun Bou Sleiman Johan Auwerx |
| author_sort | Xiaoxu Li |
| collection | DOAJ |
| description | Inflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental, and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans. |
| first_indexed | 2024-03-11T17:20:07Z |
| format | Article |
| id | doaj.art-8be70e9354e742299013c37a8d97b8b1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T17:20:07Z |
| publishDate | 2023-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8be70e9354e742299013c37a8d97b8b12023-10-19T14:31:45ZengeLife Sciences Publications LtdeLife2050-084X2023-10-011210.7554/eLife.87569Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference populationXiaoxu Li0https://orcid.org/0000-0001-5121-9190Jean-David Morel1Giorgia Benegiamo2https://orcid.org/0000-0001-7164-6771Johanne Poisson3https://orcid.org/0000-0002-0183-845XAlexis Bachmann4Alexis Rapin5Jonathan Sulc6Evan Williams7https://orcid.org/0000-0002-9746-376XAlessia Perino8Kristina Schoonjans9https://orcid.org/0000-0003-1247-4265Maroun Bou Sleiman10Johan Auwerx11https://orcid.org/0000-0002-5065-5393Laboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLuxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgLaboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Metabolic Signaling, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandLaboratory of Integrative Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, SwitzerlandInflammatory gut disorders, including inflammatory bowel disease (IBD), can be impacted by dietary, environmental, and genetic factors. While the incidence of IBD is increasing worldwide, we still lack a complete understanding of the gene-by-environment interactions underlying inflammation and IBD. Here, we profiled the colon transcriptome of 52 BXD mouse strains fed with a chow or high-fat diet (HFD) and identified a subset of BXD strains that exhibit an IBD-like transcriptome signature on HFD, indicating that an interplay of genetics and diet can significantly affect intestinal inflammation. Using gene co-expression analyses, we identified modules that are enriched for IBD-dysregulated genes and found that these IBD-related modules share cis-regulatory elements that are responsive to the STAT2, SMAD3, and REL transcription factors. We used module quantitative trait locus analyses to identify genetic loci associated with the expression of these modules. Through a prioritization scheme involving systems genetics in the mouse and integration with external human datasets, we identified Muc4 and Epha6 as the top candidates mediating differences in HFD-driven intestinal inflammation. This work provides insights into the contribution of genetics and diet to IBD risk and identifies two candidate genes, MUC4 and EPHA6, that may mediate IBD susceptibility in humans.https://elifesciences.org/articles/87569BXD miceUK Biobanksystems geneticsinflammatory bowel disease (IBD)high-fat dietmodule quantitative trait locus (ModQTL) mapping |
| spellingShingle | Xiaoxu Li Jean-David Morel Giorgia Benegiamo Johanne Poisson Alexis Bachmann Alexis Rapin Jonathan Sulc Evan Williams Alessia Perino Kristina Schoonjans Maroun Bou Sleiman Johan Auwerx Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population eLife BXD mice UK Biobank systems genetics inflammatory bowel disease (IBD) high-fat diet module quantitative trait locus (ModQTL) mapping |
| title | Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population |
| title_full | Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population |
| title_fullStr | Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population |
| title_full_unstemmed | Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population |
| title_short | Genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the BXD mouse genetic reference population |
| title_sort | genetic and dietary modulators of the inflammatory response in the gastrointestinal tract of the bxd mouse genetic reference population |
| topic | BXD mice UK Biobank systems genetics inflammatory bowel disease (IBD) high-fat diet module quantitative trait locus (ModQTL) mapping |
| url | https://elifesciences.org/articles/87569 |
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