Harmonized metagenomic signatures of the gut microbiome reveal robust species, functions, and strain links to inflammatory bowel disease.

Abstract

Coupled with well-characterized host genetic and environmental risk factors, alterations of gut microbial communities contribute to risk and severity of inflammatory bowel disease (IBD) and its subtypes, Crohn's disease (CD) and ulcerative colitis (UC). In a rapidly advancing field in which diverse multinational cohorts and molecular methods have been created, highly-resolved microbial traits such as protein function and strain genetics can now be investigated through meta-analysis. We integrated 2,371 stool metagenomes from 542 individuals with IBD and their referent counterparts from the United States, Canada, and Europe, utilizing all seven IBD cohorts in the Human Microbiome Bioactives Resource, which we interrogated using taxonomic, functional, and strain profiling. We systematically identified the mass expansion of pro-inflammatory, oral-predominant taxa in the IBD gut, such as Veillonella and Streptococcus spp. We also accurately discriminate CD from UC, a clinically challenging problem, using highly-resolved microbial strain genetics (AUC=0.69). Further, we observed disease-specific shifts in carbohydrate metabolism, a likely consequence of small bowel dysfunction in CD, but not UC, as well as perturbations in mucin utilization, increased microbial virulence and invasion cassettes, and loss of carnitine degradation pathways in IBD. Finally, we observed novel and significant differences in the gene carriage among both IBD- and non-IBD-associated taxa, suggesting that strain-specific functional variation may contribute to pathogenesis and disease-related bacterial fitness. Microbial clades responsible for IBD-linked dysbiosis are not uniform, and their functionality in IBD and CD/UC subsets are driven by species and strain lineage-specific variants.