Discovery of bioactive microbial gene products in inflammatory bowel disease

Yancong Zhang, Amrisha Bhosle, Sena Bae, Lauren J. McIver, Gleb Pishchany, Emma K. Accorsi, Kelsey N. Thompson, Cesar Arze, Ya Wang, Ayshwarya Subramanian, Sean M. Kearney, April Pawluk, Damian R. Plichta, Ali Rahnavard, Afrah Shafquat, Ramnik J. Xavier, Hera Vlamakis, Wendy S. Garrett, Andy Krueger, Curtis Huttenhower () and Eric A. Franzosa ()
Additional contact information
Yancong Zhang: Broad Institute of MIT and Harvard
Amrisha Bhosle: Broad Institute of MIT and Harvard
Sena Bae: Harvard T.H. Chan School of Public Health
Lauren J. McIver: Harvard T.H. Chan School of Public Health
Gleb Pishchany: Broad Institute of MIT and Harvard
Emma K. Accorsi: Harvard T.H. Chan School of Public Health
Kelsey N. Thompson: Broad Institute of MIT and Harvard
Cesar Arze: Harvard T.H. Chan School of Public Health
Ya Wang: Broad Institute of MIT and Harvard
Ayshwarya Subramanian: Broad Institute of MIT and Harvard
Sean M. Kearney: Massachusetts Institute of Technology
April Pawluk: Harvard T.H. Chan School of Public Health
Damian R. Plichta: Broad Institute of MIT and Harvard
Ali Rahnavard: Broad Institute of MIT and Harvard
Afrah Shafquat: Broad Institute of MIT and Harvard
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Hera Vlamakis: Broad Institute of MIT and Harvard
Wendy S. Garrett: Broad Institute of MIT and Harvard
Andy Krueger: Takeda Pharmaceutical Company
Curtis Huttenhower: Broad Institute of MIT and Harvard
Eric A. Franzosa: Broad Institute of MIT and Harvard

Nature, 2022, vol. 606, issue 7915, 754-760

Abstract: Abstract Microbial communities and their associated bioactive compounds1–3 are often disrupted in conditions such as the inflammatory bowel diseases (IBD)4. However, even in well-characterized environments (for example, the human gastrointestinal tract), more than one-third of microbial proteins are uncharacterized and often expected to be bioactive5–7. Here we systematically identified more than 340,000 protein families as potentially bioactive with respect to gut inflammation during IBD, about half of which have not to our knowledge been functionally characterized previously on the basis of homology or experiment. To validate prioritized microbial proteins, we used a combination of metagenomics, metatranscriptomics and metaproteomics to provide evidence of bioactivity for a subset of proteins that are involved in host and microbial cell–cell communication in the microbiome; for example, proteins associated with adherence or invasion processes, and extracellular von Willebrand-like factors. Predictions from high-throughput data were validated using targeted experiments that revealed the differential immunogenicity of prioritized Enterobacteriaceae pilins and the contribution of homologues of von Willebrand factors to the formation of Bacteroides biofilms in a manner dependent on mucin levels. This methodology, which we term MetaWIBELE (workflow to identify novel bioactive elements in the microbiome), is generalizable to other environmental communities and human phenotypes. The prioritized results provide thousands of candidate microbial proteins that are likely to interact with the host immune system in IBD, thus expanding our understanding of potentially bioactive gene products in chronic disease states and offering a rational compendium of possible therapeutic compounds and targets.

Date: 2022
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DOI: 10.1038/s41586-022-04648-7

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