Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature
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
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
View: Text | PDF | Corrigendum
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

×

Figure 5

The ileal microbial community in patients with IBD and Ctls.

Options: View larger image (or click on image) Download as PowerPoint
The ileal microbial community in patients with IBD and Ctls. (A) Univari...
(A) Univariate analysis (LDA Effect Size) was performed to test for association between ileal microbial composition and disease state in 240 CD (48 cCD, 178 iCD, and 14 CD with no indicated ileal involvement), 163 non-IBD Ctl, and 56 UC subjects from the RISK cohort that had not received antibiotics prior to endoscopy. The cladogram illustrates the output of this univariate analysis by demonstrating the relationship between the different bacterial taxa and disease state. Colored nodes from the center to the periphery represent marked phylum (p), class (c), order (o), family (f), genus (g), and species (s) differences detected between groups for Ctls (green), CD (red), and UC (blue). Only phylum, class, order, and family levels are indicated on the right side of the cladogram. (B) Fold change for each taxon was calculated by dividing the mean abundance in the cases (cCD [48 patients] or iCD [178 patients]) by that of the Ctls (154 patients) and is shown for microbiota with differential abundance in CD compared with Ctl by univariate analysis. The cCD group was further subdivided to cCD with abnormal histological features (25 patients) and cCD with normal histology (18 patients).