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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.

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 IFN?-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 INF?, and reduced expression of antimicrobial Paneth cell ?-defensins, in older compared to younger patients. Reduced ?-defensin expression in older patients was associated with higher IFN? 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 IFN?, and positive associations between Bacteroides and ?-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial ?-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.

SUBMITTER: Haberman Y

PROVIDER: S-EPMC6375755 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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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.

Haberman Yael Y Schirmer Melanie M Dexheimer Phillip J PJ Karns Rebekah R Braun Tzipi T Kim Mi-Ok MO Walters Thomas D TD Baldassano Robert N RN Noe Joshua D JD Rosh Joel J Markowitz James J Crandall Wallace V WV Mack David R DR Griffiths Anne M AM Heyman Melvin B MB Baker Susan S SS Kellermayer Richard R Moulton Dedrick D Patel Ashish S AS Gulati Ajay S AS Steiner Steven J SJ LeLeiko Neal N Otley Anthony A Oliva-Hemker Maria M Ziring David D Kirschner Barbara S BS Keljo David J DJ Guthery Stephen L SL Cohen Stanley A SA Snapper Scott S Evans Jonathan J Dubinsky Marla M Aronow Bruce B Hyams Jeffrey S JS Kugathasan Subra S Huttenhower Curtis C Xavier Ramnik J RJ Denson Lee A LA

Mucosal immunology 20181212 2

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 patie ...[more]

PMID: 30542108

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Project description:To formulate therapy goals, we aimed to define the relationship between fecal calprotectin and health-related quality of life in inflammatory bowel diseases (IBDs). This retrospective single-center cross-sectional study included ambulatory IBD patients who had completed standardized questionnaires comprising items of health-related quality of life (Short Inflammatory Bowel Disease Questionnaire) and clinical disease activity scores, and who had provided stool samples for calprotectin determination within 30 days of questionnaire completion. Correlation analyses were performed between the indicated parameters. Post hoc analysis was conducted, taking into account only data from patients with fecal calprotectin concentrations measured within 3 days of questionnaire completion. One hundred ninety-seven patients with Crohn disease and 111 patients with ulcerative colitis were enrolled in the study. Lower fecal calprotectin concentrations were associated with better health-related quality of life. The correlations were weak, but stronger if only fecal calprotectin concentrations measured within 3 days of questionnaire completion were included (results for 3 days; Crohn disease: n?=?86, rS?=?-0.419, P?<?0.001; ulcerative colitis: n?=?43, rS?=?-0.432, P?=?0.004). In Crohn disease, a significant correlation between fecal calprotectin concentration and health-related quality of life was found in patients with colonic involvement (n?=?59, rS?=?-0.470, P?<?0.001), but not in patients with purely ileal disease (n?=?27, rS?=?-0.268, P?=?0.18). Correlations between fecal calprotectin concentrations and clinical disease activity were also only weak to moderate. Owing to its moderate correlation with fecal calprotectin concentrations in IBD patients with colonic involvement, health-related quality of life should be used in combination with other markers for IBD management. This is even more important in isolated ileal Crohn disease, where no significant correlation between fecal calprotectin concentration and health-related quality of life was found. Especially for use in research studies, care should be taken to keep the time between clinical evaluation of IBD patients and the determination of fecal calprotectin concentrations as short as possible.

Dataset Information

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

Publications

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

Similar Datasets

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