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 & 4 others Bruce Aronow, Ramnik J. Xavier, Dirk Gevers, Lee A. Denson

Research output: Contribution to journalArticle

180 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3617-3633
Number of pages17
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014

Fingerprint

Microbiota
Transcriptome
Crohn Disease
Ulcerative Colitis
Ileum
Gene Expression
Pediatric Crohn's disease
Proteobacteria
Lipoproteins
Oxidoreductases
Colon
Oxidative Stress
Down-Regulation
Steroids
Pediatrics
Inflammation
Wounds and Injuries
Therapeutics

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Haberman, Y., Tickle, T. L., Dexheimer, P. J., Kim, M. O., Tang, D., Karns, R., ... Denson, L. A. (2014). Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. Journal of Clinical Investigation, 124(8), 3617-3633. https://doi.org/10.1172/JCI75436
Haberman, Yael ; Tickle, Timothy L. ; Dexheimer, Phillip J. ; Kim, Mi Ok ; Tang, Dora ; Karns, Rebekah ; Baldassano, Robert N. ; Noe, Joshua D. ; Rosh, Joel ; Markowitz, James ; Heyman, Melvin B. ; Griffiths, Anne M. ; Crandall, Wallace V. ; Mack, David R. ; Baker, Susan S. ; Huttenhower, Curtis ; Keljo, David J. ; Hyams, Jeffrey S. ; Kugathasan, Subra ; Walters, Thomas D. ; Aronow, Bruce ; Xavier, Ramnik J. ; Gevers, Dirk ; Denson, Lee A. / Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 8. pp. 3617-3633.
@article{41ae3071f939405bbbf573dec721474b,
title = "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.",
author = "Yael Haberman and Tickle, {Timothy L.} and Dexheimer, {Phillip J.} and Kim, {Mi Ok} and Dora Tang and Rebekah Karns and Baldassano, {Robert N.} and Noe, {Joshua D.} and Joel Rosh and James Markowitz and Heyman, {Melvin B.} and Griffiths, {Anne M.} and Crandall, {Wallace V.} and Mack, {David R.} and Baker, {Susan S.} and Curtis Huttenhower and Keljo, {David J.} and Hyams, {Jeffrey S.} and Subra Kugathasan and Walters, {Thomas D.} and Bruce Aronow and Xavier, {Ramnik J.} and Dirk Gevers and Denson, {Lee A.}",
year = "2014",
month = "8",
day = "1",
doi = "10.1172/JCI75436",
language = "English (US)",
volume = "124",
pages = "3617--3633",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",

}

Haberman, Y, Tickle, TL, Dexheimer, PJ, Kim, MO, Tang, D, Karns, R, Baldassano, RN, Noe, JD, Rosh, J, Markowitz, J, Heyman, MB, Griffiths, AM, Crandall, WV, Mack, DR, Baker, SS, Huttenhower, C, Keljo, DJ, Hyams, JS, Kugathasan, S, Walters, TD, Aronow, B, Xavier, RJ, Gevers, D & Denson, LA 2014, 'Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature', Journal of Clinical Investigation, vol. 124, no. 8, pp. 3617-3633. https://doi.org/10.1172/JCI75436

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

In: Journal of Clinical Investigation, Vol. 124, No. 8, 01.08.2014, p. 3617-3633.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

AU - Haberman, Yael

AU - Tickle, Timothy L.

AU - Dexheimer, Phillip J.

AU - Kim, Mi Ok

AU - Tang, Dora

AU - Karns, Rebekah

AU - Baldassano, Robert N.

AU - Noe, Joshua D.

AU - Rosh, Joel

AU - Markowitz, James

AU - Heyman, Melvin B.

AU - Griffiths, Anne M.

AU - Crandall, Wallace V.

AU - Mack, David R.

AU - Baker, Susan S.

AU - Huttenhower, Curtis

AU - Keljo, David J.

AU - Hyams, Jeffrey S.

AU - Kugathasan, Subra

AU - Walters, Thomas D.

AU - Aronow, Bruce

AU - Xavier, Ramnik J.

AU - Gevers, Dirk

AU - Denson, Lee A.

PY - 2014/8/1

Y1 - 2014/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84905482236&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905482236&partnerID=8YFLogxK

U2 - 10.1172/JCI75436

DO - 10.1172/JCI75436

M3 - Article

VL - 124

SP - 3617

EP - 3633

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 8

ER -