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 Scopus citations

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)
JournalMucosal Immunology
DOIs
StateAccepted/In press - Jan 1 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Haberman, Y., Schirmer, M., Dexheimer, P. J., Karns, R., Braun, T., Kim, M. O., Walters, T. D., Baldassano, R. N., Noe, J. D., Rosh, J., Markowitz, J., Crandall, W. V., Mack, D. R., Griffiths, A. M., Heyman, M. B., Baker, S. S., Kellermayer, R., Moulton, D., Patel, A. S., ... Denson, L. A. (Accepted/In press). 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. https://doi.org/10.1038/s41385-018-0114-4