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

• Type of Material: Article
• Authors: Yael Haberman, Cincinnati Children's Hospital Medical Center; Melanie Schirmer, Broad Institute of MIT and Harvard; Phillip J. Dexheimer, Cincinnati Children's Hospital Medical Center; Rebekah Karns, Cincinnati Children's Hospital Medical Center; Tzipi Braun, Sheba Medical Center; Mi-Ok Kim, Cincinnati Children's Hospital Medical Center; Thomas D. Walters, University of Toronto; Robert N. Baldassano, Childrens Hospital of Philadelphia; Joshua D. Noe, Medical College of Wisconsin; Joel Rosh, Goryeb Children's Hospital; James Markowitz, Cohen Children's Medical Center; Wallace V. Crandall, Nationwide Children's Hospital; David R. Mack, University of Ottawa; Anne M. Griffiths, University of Toronto; Melvin B. Heyman, University of California San Francisco; Susan S. Baker, SUNY Buffalo; Richard Kellermayer, Texas Children's Hospital; Dedrick Moulton, Vanderbilt Children's Hospital; Ashish S. Patel, University of Texas Southwestern; Ajay S. Gulati, University of North Carolina; Steven J. Steiner, Riley Children's Hospital; Neal LeLeiko, Hasbro Children's Hospital; Anthony Otley, IWK Health Centre; Maria Oliva-Hemker, Johns Hopkins University; David Ziring, Cedars Sinai Medical Center; Barbara S. Kirschner, University of Chicago; David J. Keljo, University of Pittsburgh Medical Center; Stephen L. Guthery, University of Utah; Stanley Cohen, Emory University; Scott Snapper, Children's Hospital; Jonathan Evans, Nemours Children's Hospital; Marla Dubinsky, Mt Sinai Hospital; Bruce Aronow, Cincinnati Children's Hospital Medical Center; Jeffrey S. Hyams, Connecticut Children's Medical Center; Subramaniam Kugathasan, Emory University; Curtis Huttenhower, Broad Institute of MIT and Harvard; Ramnik J. Xavier, Broad Institute of MIT and Harvard; Lee A. Denson, Cincinnati Children's Hospital Medical Center
• Language: English
• Date: 2019-02-01
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, Society for Mucosal Immunology.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41385-018-0114-4
• Title of Journal or Parent Work: Mucosal Immunology
• ISSN: 1933-0219
• Volume: 12
• Issue: 2
• Start Page: 491
• End Page: 502
• Grant/Funding Information: 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 (1P30DK07839–201), 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).
• Keywords: Science & Technology; EXPRESSION; CHILDREN; Immunology; Life Sciences & Biomedicine; PEYERS-PATCHES; INFLAMMATORY-BOWEL-DISEASE; MICROBIOME; MUCOSA
• Research Categories: Health Sciences, Immunology

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.