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

Xochitl C. Morgan, Harvard University
Boyko Kabakchiev, Harvard University
Levi Waldron, CUNY School of Public Health
Andrea D. Tyler, University of Toronto
Timothy L. Tickle, Harvard University
Raquel Milgrom, University of Toronto
Joanne M. Stempak, University of Toronto
Dirk Gevers, Harvard University
Ramnik J. Xavier, Harvard University
Mark S. Silverberg, University of Toronto
Curtis Huttenhower, Harvard University

Creative Commons Attribution License 4.0

Abstract

Background

Pouchitis is common after ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC). Similarly 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 covariation between clades and transcripts.

Results

Host transcripts covary primarily with biopsy location and inflammation, while microbes covary 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 crosssectional changes in gut epithelial transcription are not a major component of the hostmicrobiome regulatory interface during pouchitis.