Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice

ABSTRACT The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanism...

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Autores principales:	Thomas Sharpton, Svetlana Lyalina, Julie Luong, Joey Pham, Emily M. Deal, Courtney Armour, Christopher Gaulke, Shomyseh Sanjabi, Katherine S. Pollard
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	inflammatory bowel disease lipooligosaccharide transporter longitudinal metagenomics protein function statistics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2dc46ba55ca047c98562fdedba938cd8
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spelling	oai:doaj.org-article:2dc46ba55ca047c98562fdedba938cd82021-12-02T18:15:43ZDevelopment of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice10.1128/mSystems.00036-172379-5077https://doaj.org/article/2dc46ba55ca047c98562fdedba938cd82017-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00036-17https://doaj.org/toc/2379-5077ABSTRACT The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor β (TGF-β) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of Bacteroides, correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IMPORTANCE IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.Thomas SharptonSvetlana LyalinaJulie LuongJoey PhamEmily M. DealCourtney ArmourChristopher GaulkeShomyseh SanjabiKatherine S. PollardAmerican Society for Microbiologyarticleinflammatory bowel diseaselipooligosaccharide transporterlongitudinalmetagenomicsprotein functionstatisticsMicrobiologyQR1-502ENmSystems, Vol 2, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	inflammatory bowel disease lipooligosaccharide transporter longitudinal metagenomics protein function statistics Microbiology QR1-502
spellingShingle	inflammatory bowel disease lipooligosaccharide transporter longitudinal metagenomics protein function statistics Microbiology QR1-502 Thomas Sharpton Svetlana Lyalina Julie Luong Joey Pham Emily M. Deal Courtney Armour Christopher Gaulke Shomyseh Sanjabi Katherine S. Pollard Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice
description	ABSTRACT The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor β (TGF-β) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of Bacteroides, correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IMPORTANCE IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.
format	article
author	Thomas Sharpton Svetlana Lyalina Julie Luong Joey Pham Emily M. Deal Courtney Armour Christopher Gaulke Shomyseh Sanjabi Katherine S. Pollard
author_facet	Thomas Sharpton Svetlana Lyalina Julie Luong Joey Pham Emily M. Deal Courtney Armour Christopher Gaulke Shomyseh Sanjabi Katherine S. Pollard
author_sort	Thomas Sharpton
title	Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice
title_short	Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice
title_full	Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice
title_fullStr	Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice
title_full_unstemmed	Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice
title_sort	development of inflammatory bowel disease is linked to a longitudinal restructuring of the gut metagenome in mice
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/2dc46ba55ca047c98562fdedba938cd8
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Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice

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