Associations between host gene expression, the mucosal microbiome, and clinical outcome in the pelvic pouch of patients with inflammatory bowel disease

Authors

Xochitl C. Morgan, Harvard University
Boyko Kabakchiev, Mount Sinai Hospital
Levi Waldron, CUNY School of Public HealthFollow
Andrea D. Tyler, University of Toronto
Timothy L. Tickle, Harvard University
Raquel Milgrom, University of Toronto
Joanne M. Stempak, University of Toronto
Dirk Gevers, The Broad Institute of MIT and Harvard
Ramnik J. Xavier, The Broad Institute of MIT and Harvard
Mark S. Silverberg, University of Toronto
Curtis Huttenhower, Harvard University

Document Type

Article

Publication Date

4-8-2015

Abstract

Background: Pouchitis is common after ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC). Similar to inflammatory bowel disease (IBD), both host genetics and the microbiota are implicated in its pathogenesis. We use the IPAA model of IBD to associate mucosal host gene expression with mucosal microbiomes and clinical outcomes. We analyze host transcriptomic data and 16S rRNA gene sequencing data from paired biopsies from IPAA patients with UC and familial adenomatous polyposis. To achieve power for a genome-wide microbiome-transcriptome association study, we use principal component analysis for transcript and clade reduction, and identify significant co-variation between clades and transcripts.

Results: Host transcripts co-vary primarily with biopsy location and inflammation, while microbes co-vary primarily with antibiotic use. Transcript-microbe associations are surprisingly modest, but the most strongly microbially-associated host transcript pattern is enriched for complement cascade genes and for the interleukin-12 pathway. Activation of these host processes is inversely correlated with Sutterella, Akkermansia, Bifidobacteria, and Roseburia abundance, and positively correlated with Escherichia abundance.

Conclusions: This study quantifies the effects of inflammation, antibiotic use, and biopsy location upon the microbiome and host transcriptome during pouchitis. Understanding these effects is essential for basic biological insights as well as for well-designed and adequately-powered studies. Additionally, our study provides a method for profiling host-microbe interactions with appropriate statistical power using high-throughput sequencing, and suggests that cross-sectional changes in gut epithelial transcription are not a major component of the host-microbiome regulatory interface during pouchitis.

Comments

This article was originally published in Genome Biology, available at DOI: 10.1186/s13059-015-0637-x.

This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (CC BY 4.0).