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Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis. Mucosal Immunol 2019 03;12(2):491-502

Date

12/14/2018

Pubmed ID

30542108

Pubmed Central ID

PMC6375755

DOI

10.1038/s41385-018-0114-4

Scopus ID

2-s2.0-85058468776   10 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.

Author List

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

Author

Joshua D. Noe MD Associate Dean, Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Age Factors
Aging
Child
Child, Preschool
Cohort Studies
Crohn Disease
Dysbiosis
Female
Gene Expression Regulation
Humans
Ileum
Male
Peyer's Patches
Puberty
Risk
Th1 Cells
alpha-Defensins