Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature
Yael Haberman, … , Dirk Gevers, Lee A. Denson
Yael Haberman, … , Dirk Gevers, Lee A. Denson
Published July 8, 2014
Citation Information: J Clin Invest. 2014;124(8):3617-3633. https://doi.org/10.1172/JCI75436.
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Research Article

Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

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.

Authors

Yael Haberman, Timothy L. Tickle, Phillip J. Dexheimer, Mi-Ok Kim, Dora Tang, Rebekah Karns, Robert N. Baldassano, Joshua D. Noe, Joel Rosh, James Markowitz, Melvin B. Heyman, Anne M. Griffiths, Wallace V. Crandall, David R. Mack, Susan S. Baker, Curtis Huttenhower, David J. Keljo, Jeffrey S. Hyams, Subra Kugathasan, Thomas D. Walters, Bruce Aronow, Ramnik J. Xavier, Dirk Gevers, Lee A. Denson

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Figure 3

The ileal APOA1 gene coexpression signature is specific to all forms of CD.

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The ileal APOA1 gene coexpression signature is specific to all forms of ...
(A) The Venn diagram shows the overlap of 179 genes differentially expressed 2-fold between patients with cCD and UC and genes within the DUOX2 and APOA1 coexpression modules. (B) A heat map of 93 of the above-mentioned 179 genes after averaging and hierarchical clustering of gene expression, with a fold change of 2.5 between the cCD and UC training cohorts for the indicated clinical subgroups. The training cohort included 17 cCD with abnormal histological features, 17 cCD with normal histology, and 45 UC. The independent validation cohort included 14 cCD with abnormal histological features, 11 cCD with normal histology, and 28 UC. The blue arrow indicates APOA1, and the red arrow indicates DUOX2. (C) The results of functional annotation enrichment analyses (IPA, Ingenuity Systems) using the DUOX2 and APOA1 gene coexpression signatures. Upregulated transcription factors and target genes are shown in orange and red, respectively, while downregulated transcription factors and target genes are shown in blue and green, respectively. Biologic functions associated with these groups of genes are also shown.