J Clin Invest. doi:10.1172/JCI75436.
Copyright © 2014, The American Society for Clinical Investigation.
Research Article
Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature
Yael Haberman1, Timothy L. Tickle2,3, Phillip J. Dexheimer4, Mi-Ok Kim5, Dora Tang1, Rebekah Karns4, Robert N. Baldassano6, Joshua D. Noe7, Joel Rosh8, James Markowitz9, Melvin B. Heyman10, Anne M. Griffiths11, Wallace V. Crandall12, David R. Mack13, Susan S. Baker14, Curtis Huttenhower2,3, David J. Keljo15, Jeffrey S. Hyams16, Subra Kugathasan17, Thomas D. Walters11, Bruce Aronow4, Ramnik J. Xavier3,18,19, Dirk Gevers3 and Lee A. Denson1
1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
2Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
3Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
4Biomedical Informatics and
5Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
6The Children’s Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
7Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
8Goryeb Children’s Hospital/Atlantic Health, Morristown, New Jersey, USA.
9Division of Pediatric Gastroenterology and Nutrition, Cohen Children’s Medical Center of New York, New Hyde Park, New York, USA.
10Department of Pediatrics, UCSF, San Francisco, California, USA.
11Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
12Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children’s Hospital, Columbus, Ohio, USA.
13Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
14Digestive Diseases and Nutrition Center, Department of Pediatrics, University at Buffalo, Buffalo, New York, USA.
15Division of Pediatric Gastroenterology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
16Division of Digestive Disease and Nutrition, Connecticut Children’s Medical Center, Hartford, Connecticut, USA.
17Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
18Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease and
19Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Lee A. Denson, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, MLC 2010, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. Phone: 513.636.7575; E-mail: lee.denson@cchmc.org.
Published July 8, 2014
Received for publication January 29, 2014, and accepted in revised form May 29, 2014.
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.