Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

• Type of Material: Article
• Authors: Yael Haberman, Cincinnati Children's Hospital Medical Center; Timothy L. Tickle, Harvard University; Phillip J. Dexheimer, Cincinnati Children's Hospital Medical Center; Mi-Ok Kim, Cincinnati Children's Hospital Medical Center; Dora Tang, Cincinnati Children's Hospital Medical Center; Rebekah Karns, Cincinnati Children's Hospital Medical Center; Robert N. Baldassano, University of Pennsylvania; Joshua D. Noe, Medical College of Wisconsin; Joel Rosh, Goryeb Children's Hospital; James Markowitz, Cohen Children's Medical Center of New York; Melvin B. Heyman, University of California San Francisco; Anne M. Griffiths, University of Toronto; Wallace V. Crandall, Nationwide Children's Hospital; David R. Mack, Children's Hospital of Eastern Ontario; Susan S. Baker, University at Buffalo; Curtis Huttenhower, Harvard University; David J. Keljo, Children's Hospital of Pittsburgh; Jeffrey S. Hyams, Connecticut Children's Medical Center; Subramaniam Kugathasan, Emory University; Thomas D. Walters, University of Toronto; Bruce Aronow, Cincinnati Children's Hospital Medical Center; Ramnik J.. Xavier, Harvard University; Dirk Gevers, Harvard University; Lee A. Denson, Cincinnati Children's Hospital Medical Center
• Language: English
• Date: 2014-08-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2014, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI75436
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 124
• Issue: 8
• Start Page: 3617
• End Page: 3633
• Grant/Funding Information: This work was supported by the Crohn’s and Colitis Foundation of America, the Gene and Protein Expression and Bioinformatics cores of the NIH-supported Cincinnati Children’s Hospital Research Foundation Digestive Health Center (1P30DK078392-01), the Cincinnati Children’s Hospital Medical Center Innovation Fund (to L.A. Denson), NIH grant U54DK102557 (to R.J. Xavier, C. Huttenhower, and D. Gevers), and the Leona M. and Harry B. Helmsley Charitable Trust.
• Keywords: INFLAMMATORY-BOWEL-DISEASE; MAINTENANCE THERAPY; GUT MICROBIOTA; Research & Experimental Medicine; ULCERATIVE-COLITIS; Science & Technology; MEDICINE, RESEARCH & EXPERIMENTAL; ONSET; GENE-EXPRESSION; MICE; Life Sciences & Biomedicine; HOST; RESPONSES; INFLIXIMAB; Medicine, Research & Experimental
• Research Categories: Biology, Biostatistics; Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.