Discovery of bioactive microbial gene products in inflammatory bowel disease

Abstract

Microbial communities and their associated bioactive compounds are often disrupted in conditions such as the inflammatory bowel diseases (IBD). However, even in well-characterized environments (e.g. the human gastrointestinal tract), more than one-third of microbial proteins are uncharacterized and often expected to be bioactive. Here, we systematically identified >340,000 protein families as potentially bioactive with respect to gut inflammation during IBD, about half of which are without prior homology-based functional characterization. To validate our prioritized microbial gene products, we used a combination of metagenomics, metatranscriptomics, and metaproteomics to provide evidence of bioactivity for a subset of proteins involved in host and microbial cell-cell communication, such as adherence/invasion processes and novel extracellular von Willebrand-like binding factors in the microbiome. Predictions from high-throughput data were validated using targeted experiments showing differential immunogenicity of prioritized Enterobacteriaceae pilins and the contribution of von Willebrand factor homologs to mucin-dependent Bacteroides biofilm formation. Prioritized results here provide thousands of new candidate microbial proteins likely to interact with the host immune system in IBD, expanding our understanding of potentially bioactive gene products in chronic disease states and offering a rational compendium of potential therapeutic compounds and targets.