Abstract

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

Morgan XC1,2, Kabakchiev B3, Waldron L4,5, Tyler AD6, Tickle TL7,8, Milgrom R9, Stempak JM10, Gevers D11, Xavier RJ12, Silverberg MS13, Huttenhower C14,15. Genome Biol. 2015 Apr 8;16(1):67. doi: 10.1186/s13059-015-0637-x.
 
     
Author information

1Department of Biostatistics, Harvard T. H. Chan School of Public Health, 655 Huntington Ave, Boston, MA, 02115, USA. xmorgan@hsph.harvard.edu. 2The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA. xmorgan@hsph.harvard.edu. 3Mount Sinai Hospital, Zane Cohen Centre for Digestive Diseases, University of Toronto, 600 University Ave, Toronto, ON, M5G 1X5, Canada. btk2102@gmail.com. 4Department of Biostatistics, Harvard T. H. Chan School of Public Health, 655 Huntington Ave, Boston, MA, 02115, USA. levi.waldron@hunter.cuny.edu. 5City University of New York School of Public Health, Hunter College, 2180 3rd Ave Rm 538, New York, NY, 10035-4003, USA. levi.waldron@hunter.cuny.edu. 6Mount Sinai Hospital, Zane Cohen Centre for Digestive Diseases, University of Toronto, 600 University Ave, Toronto, ON, M5G 1X5, Canada. atyler@mtsinai.on.ca. 7Department of Biostatistics, Harvard T. H. Chan School of Public Health, 655 Huntington Ave, Boston, MA, 02115, USA. timothyltickle@gmail.com. 8The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA. timothyltickle@gmail.com. 9Mount Sinai Hospital, Zane Cohen Centre for Digestive Diseases, University of Toronto, 600 University Ave, Toronto, ON, M5G 1X5, Canada. rmilgrom@mtsinai.on.ca. 10Mount Sinai Hospital, Zane Cohen Centre for Digestive Diseases, University of Toronto, 600 University Ave, Toronto, ON, M5G 1X5, Canada. jstempak@mtsinai.on.ca. 11The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA. dgevers@broadinstitute.org. 12The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA. xavier@molbio.mgh.harvard.edu. 13Mount Sinai Hospital, Zane Cohen Centre for Digestive Diseases, University of Toronto, 600 University Ave, Toronto, ON, M5G 1X5, Canada. msilverberg@mtsinai.on.ca. 14Department of Biostatistics, Harvard T. H. Chan School of Public Health, 655 Huntington Ave, Boston, MA, 02115, USA. chuttenh@hsph.harvard.edu. 15The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA. chuttenh@hsph.harvard.edu.

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.

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