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 regards 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 dampened TGF-{beta} 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 dampened 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, lipooligosaccharide transporter abundance diverges prior to immune activation, indicating that it could be a pre-disease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundance 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 potential mechanisms through which the gut microbiome becomes altered in IBD.\n\nImportanceIBD patients harbor distinct microbial communities with different functional capabilities compared to healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading up 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 is novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.