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DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome.

Published version
Peer-reviewed

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Authors

Howell, Kate Joanne 
Nayak, Komal M 
Ross, Alexander 

Abstract

BACKGROUND & AIMS: We analyzed DNA methylation patterns and transcriptomes of primary intestinal epithelial cells (IEC) of children newly diagnosed with inflammatory bowel diseases (IBD) to learn more about pathogenesis. METHODS: We obtained mucosal biopsies (N = 236) collected from terminal ileum and ascending and sigmoid colons of children (median age 13 years) newly diagnosed with IBD (43 with Crohn's disease [CD], 23 with ulcerative colitis [UC]), and 30 children without IBD (controls). Patients were recruited and managed at a hospital in the United Kingdom from 2013 through 2016. We also obtained biopsies collected at later stages from a subset of patients. IECs were purified and analyzed for genome-wide DNA methylation patterns and gene expression profiles. Adjacent microbiota were isolated from biopsies and analyzed by 16S gene sequencing. We generated intestinal organoid cultures from a subset of samples and genome-wide DNA methylation analysis was performed. RESULTS: We found gut segment-specific differences in DNA methylation and transcription profiles of IECs from children with IBD vs controls; some were independent of mucosal inflammation. Changes in gut microbiota between IBD and control groups were not as large and were difficult to assess because of large amounts of intra-individual variation. Only IECs from patients with CD had changes in DNA methylation and transcription patterns in terminal ileum epithelium, compared with controls. Colon epithelium from patients with CD and from patients with ulcerative colitis had distinct changes in DNA methylation and transcription patterns, compared with controls. In IECs from patients with IBD, changes in DNA methylation, compared with controls, were stable over time and were partially retained in ex-vivo organoid cultures. Statistical analyses of epithelial cell profiles allowed us to distinguish children with CD or UC from controls; profiles correlated with disease outcome parameters, such as the requirement for treatment with biologic agents. CONCLUSIONS: We identified specific changes in DNA methylation and transcriptome patterns in IECs from pediatric patients with IBD compared with controls. These data indicate that IECs undergo changes during IBD development and could be involved in pathogenesis. Further analyses of primary IECs from patients with IBD could improve our understanding of the large variations in disease progression and outcomes.

Description

Keywords

Epigenetics, Gut Microbiota, Human Intestinal Organoids, Intestinal Epithelium, Adolescent, Age Factors, Biopsy, Case-Control Studies, Colitis, Ulcerative, Colon, Sigmoid, Crohn Disease, DNA Methylation, Diagnosis, Differential, England, Epigenesis, Genetic, Epithelial Cells, Female, Gastrointestinal Microbiome, Gene Expression Profiling, Genome-Wide Association Study, Humans, Ileum, Intestinal Mucosa, Male, Organoids, Predictive Value of Tests, Prognosis, Prospective Studies, Ribotyping, Time Factors, Tissue Culture Techniques, Transcription, Genetic, Transcriptome

Journal Title

Gastroenterology

Conference Name

Journal ISSN

0016-5085
1528-0012

Volume Title

154

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_PC_12009)
European Commission Horizon 2020 (H2020) Societal Challenges (733100)