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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

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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 6

Covariation of the ileal microbial community structure with ileal gene expression and clinical subgroup and severity.

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Covariation of the ileal microbial community structure with ileal gene e...
(A) The biplot depicts covariation of the ileal microbial community structure with clinical group, clinical disease activity (PCDAI), and ileal gene expression using NMDS rotated by CD and based on significant associations obtained from MaAsLin. Patients with IBD and healthy Ctls are plotted as orange circles (Ctl), green circles (UC), red circles (cCD), purple circles (iCD-noDU), or purple triangles (iCD-DU). Arrows indicate the direction of covariation for APOA1 or DUOXA2 gene expression and clinical severity (PCDAI). Microbial taxa are labeled with capitalized lettering. The stress measurement tests for the goodness of fit of the biplot 2-dimensional depiction of the multidimensional data, with stress < 0.2 regarded as a good fit. (B) The bar plot graphs show effect sizes (r coefficients) on the x axes for significant associations between microbial taxa and the indicated ileal gene expression, clinical disease activity (PCDAI), and clinical groups obtained from MaAsLin, while controlling for age, gender, BMI, antibiotic exposure, and NOD2, FUT2, and ATG16L1 risk allele carriage (P < 0.05, q < 0.25 were considered significant). Representative genes are from the APOA1 (APOA1 and CXCL9) and DUOX2 (DUOXA2, MUC4, and LCT) gene coexpression signatures. The comprehensive presentation of these data with P values, q values, and taxon abundance can be found in Supplemental Excel file 16.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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