학술논문
Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis
Document Type
article
Author
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
Source
Mucosal Immunology. 12(2)
Subject
Language
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.