Armour, C. | bioRxiv Science

bioRxiv2020

An integrated gene catalog of the zebrafish gut microbiome reveals significant homology with mammalian microbiomes

Gut microbiome research increasingly utilizes zebrafish (Danio rerio) given their amenability to high-throughput experimental designs. However, the utility of zebrafish for discerning translationally relevant host-microbiome interactions is constrained by a paucity of knowledge about the biological functions that zebrafish gut microbiota can execute, how these functions associate with zebrafish physiology, and the degree of homology between the genes encoded by the zebrafish and human gut microbiomes. To address this knowledge gap, we generated a foundational catalog of zebrafish gut microbiome genomic diversity consisting of 1,569,102 non-redundant genes from twenty-nine individual fish. We identified hundreds of novel microbial genes as well as dozens of biosynthetic gene clusters of potential clinical interest. The genomic diversity of the zebrafish gut microbiome varied significantly across diets and this variance associated with altered expression of intestinal genes involved in inflammation and immune activation. Zebrafish, mouse, and human fecal microbiomes shared > 50% of their total genomic diversity and the vast majority of gene family abundance for each individual metagenome ([~]99%) was accounted for by genes that comprised this shared fraction. These results indicate that the zebrafish gut houses a functionally diverse microbial community that manifests extensive homology to that of humans and mice despite substantial disparities in taxonomic composition. We anticipate that the gene catalog developed here will enable future mechanistic study of host-microbiome interactions using the zebrafish model. ImportanceZebrafish have emerged as an important model system for defining host-microbiome interactions. However, the utility of this model is blunted by limited insight into the functions that are carried by zebrafish gut microbiota, their relationship with zebrafish physiology, and their consistency with the functions carried by human gut microbiota. To address these limitations, we constructed the first genomic database of zebrafish gut microbiome diversity. We use this novel resource to demonstrate that the genomic diversity of the zebrafish gut microbiome varies with diet and this variance links with altered intestinal gene expression. We also identify substantial homology between zebrafish, human, and mouse metagenomic diversity, indicating that these microbiomes may operate similarly.

microbiology↗

bioRxiv2017

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

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.

microbiology↗