Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis

Yael Haberman, Melanie Schirmer, Phillip J. Dexheimer, Rebekah Karns, Tzipi Braun, Mi Ok Kim, Thomas D. Walters, Robert N. Baldassano, Joshua D. Noe, Joel Rosh, James Markowitz, Wallace V. Crandall, David R. Mack, Anne M. Griffiths, Melvin B. Heyman, Susan S. Baker, Richard Kellermayer, Dedrick Moulton, Ashish S. Patel, Ajay S. GulatiSteven J. Steiner, Neal LeLeiko, Anthony Otley, Maria Oliva-Hemker, David Ziring, Barbara S. Kirschner, David J. Keljo, Stephen L. Guthery, Stanley A. Cohen, Scott Snapper, Jonathan Evans, Marla Dubinsky, Bruce Aronow, Jeffrey S. Hyams, Subra Kugathasan, Curtis Huttenhower, Ramnik J. Xavier, Lee A. Denson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

Original languageEnglish (US)
Pages (from-to)491-502
Number of pages12
JournalMucosal Immunology
Volume12
Issue number2
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

Fingerprint

alpha-Defensins
Dysbiosis
Defensins
Paneth Cells
Peyer's Patches
Mucosal Immunity
Th1 Cells
Bacteroides
Enterobacteriaceae
Granulocyte-Macrophage Colony-Stimulating Factor
Crohn Disease
Genes
Multivariate Analysis
Gene Expression
Pediatric Crohn's disease
Incidence

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Haberman, Yael ; Schirmer, Melanie ; Dexheimer, Phillip J. ; Karns, Rebekah ; Braun, Tzipi ; Kim, Mi Ok ; Walters, Thomas D. ; Baldassano, Robert N. ; Noe, Joshua D. ; Rosh, Joel ; Markowitz, James ; Crandall, Wallace V. ; Mack, David R. ; Griffiths, Anne M. ; Heyman, Melvin B. ; Baker, Susan S. ; Kellermayer, Richard ; Moulton, Dedrick ; Patel, Ashish S. ; Gulati, Ajay S. ; Steiner, Steven J. ; LeLeiko, Neal ; Otley, Anthony ; Oliva-Hemker, Maria ; Ziring, David ; Kirschner, Barbara S. ; Keljo, David J. ; Guthery, Stephen L. ; Cohen, Stanley A. ; Snapper, Scott ; Evans, Jonathan ; Dubinsky, Marla ; Aronow, Bruce ; Hyams, Jeffrey S. ; Kugathasan, Subra ; Huttenhower, Curtis ; Xavier, Ramnik J. ; Denson, Lee A. / Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis. In: Mucosal Immunology. 2019 ; Vol. 12, No. 2. pp. 491-502.
@article{dbb326ebd8b7495698819253ccaff295,
title = "Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis",
abstract = "Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.",
author = "Yael Haberman and Melanie Schirmer and Dexheimer, {Phillip J.} and Rebekah Karns and Tzipi Braun and Kim, {Mi Ok} and Walters, {Thomas D.} and Baldassano, {Robert N.} and Noe, {Joshua D.} and Joel Rosh and James Markowitz and Crandall, {Wallace V.} and Mack, {David R.} and Griffiths, {Anne M.} and Heyman, {Melvin B.} and Baker, {Susan S.} and Richard Kellermayer and Dedrick Moulton and Patel, {Ashish S.} and Gulati, {Ajay S.} and Steiner, {Steven J.} and Neal LeLeiko and Anthony Otley and Maria Oliva-Hemker and David Ziring and Kirschner, {Barbara S.} and Keljo, {David J.} and Guthery, {Stephen L.} and Cohen, {Stanley A.} and Scott Snapper and Jonathan Evans and Marla Dubinsky and Bruce Aronow and Hyams, {Jeffrey S.} and Subra Kugathasan and Curtis Huttenhower and Xavier, {Ramnik J.} and Denson, {Lee A.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1038/s41385-018-0114-4",
language = "English (US)",
volume = "12",
pages = "491--502",
journal = "Mucosal Immunology",
issn = "1933-0219",
publisher = "Nature Publishing Group",
number = "2",

}

Haberman, Y, Schirmer, M, Dexheimer, PJ, Karns, R, Braun, T, Kim, MO, Walters, TD, Baldassano, RN, Noe, JD, Rosh, J, Markowitz, J, Crandall, WV, Mack, DR, Griffiths, AM, Heyman, MB, Baker, SS, Kellermayer, R, Moulton, D, Patel, AS, Gulati, AS, Steiner, SJ, LeLeiko, N, Otley, A, Oliva-Hemker, M, Ziring, D, Kirschner, BS, Keljo, DJ, Guthery, SL, Cohen, SA, Snapper, S, Evans, J, Dubinsky, M, Aronow, B, Hyams, JS, Kugathasan, S, Huttenhower, C, Xavier, RJ & Denson, LA 2019, 'Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis', Mucosal Immunology, vol. 12, no. 2, pp. 491-502. https://doi.org/10.1038/s41385-018-0114-4

Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis. / Haberman, Yael; Schirmer, Melanie; Dexheimer, Phillip J.; Karns, Rebekah; Braun, Tzipi; Kim, Mi Ok; Walters, Thomas D.; Baldassano, Robert N.; Noe, Joshua D.; Rosh, Joel; Markowitz, James; Crandall, Wallace V.; Mack, David R.; Griffiths, Anne M.; Heyman, Melvin B.; Baker, Susan S.; Kellermayer, Richard; Moulton, Dedrick; Patel, Ashish S.; Gulati, Ajay S.; Steiner, Steven J.; LeLeiko, Neal; Otley, Anthony; Oliva-Hemker, Maria; Ziring, David; Kirschner, Barbara S.; Keljo, David J.; Guthery, Stephen L.; Cohen, Stanley A.; Snapper, Scott; Evans, Jonathan; Dubinsky, Marla; Aronow, Bruce; Hyams, Jeffrey S.; Kugathasan, Subra; Huttenhower, Curtis; Xavier, Ramnik J.; Denson, Lee A.

In: Mucosal Immunology, Vol. 12, No. 2, 01.03.2019, p. 491-502.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis

AU - Haberman, Yael

AU - Schirmer, Melanie

AU - Dexheimer, Phillip J.

AU - Karns, Rebekah

AU - Braun, Tzipi

AU - Kim, Mi Ok

AU - Walters, Thomas D.

AU - Baldassano, Robert N.

AU - Noe, Joshua D.

AU - Rosh, Joel

AU - Markowitz, James

AU - Crandall, Wallace V.

AU - Mack, David R.

AU - Griffiths, Anne M.

AU - Heyman, Melvin B.

AU - Baker, Susan S.

AU - Kellermayer, Richard

AU - Moulton, Dedrick

AU - Patel, Ashish S.

AU - Gulati, Ajay S.

AU - Steiner, Steven J.

AU - LeLeiko, Neal

AU - Otley, Anthony

AU - Oliva-Hemker, Maria

AU - Ziring, David

AU - Kirschner, Barbara S.

AU - Keljo, David J.

AU - Guthery, Stephen L.

AU - Cohen, Stanley A.

AU - Snapper, Scott

AU - Evans, Jonathan

AU - Dubinsky, Marla

AU - Aronow, Bruce

AU - Hyams, Jeffrey S.

AU - Kugathasan, Subra

AU - Huttenhower, Curtis

AU - Xavier, Ramnik J.

AU - Denson, Lee A.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

AB - Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

UR - http://www.scopus.com/inward/record.url?scp=85058468776&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058468776&partnerID=8YFLogxK

U2 - 10.1038/s41385-018-0114-4

DO - 10.1038/s41385-018-0114-4

M3 - Article

C2 - 30542108

AN - SCOPUS:85058468776

VL - 12

SP - 491

EP - 502

JO - Mucosal Immunology

JF - Mucosal Immunology

SN - 1933-0219

IS - 2

ER -