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.
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This work was supported by the Crohn’s and Colitis Foundation, the Gene and Protein Expression and Bioinformatics cores of the National Institutes of Health (NIH)-supported Cincinnati Children’s Hospital Research Foundation Digestive Health Center (1P30DK078392-01), NIH grant U54 DE023798 and HMP2 (R.J.X., and C.H), the Leona M. and Harry B. Helmsley Charitable Trust (R.J.X., and C.H), the European Crohn’s and Colitis Organization (ECCO, Y.H), the Israel Science Foundation (grant No 908/15), the I-CORE program (Y.H), and European Research Council starting grant (grant No 758313, Y.H). We thank the Crohn’s and Colitis Foundation RISK study publication committee for critical review of this manuscript.
The authors declare no competing interests.
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Cytokine & Growth Factor Reviews (2019)