Abstract

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

Howell KJ1, Kraiczy J2, Nayak KM2, Gasparetto M3, Ross A4, Lee C3, Mak TN2, Koo BK5, Kumar N6, Lawley T6, Sinha A7, Rosenstiel P7, Heuschkel R8, Stegle O9, Zilbauer M10. Gastroenterology. 2017 Oct 11. pii: S0016-5085(17)36241-8. doi: 10.1053/j.gastro.2017.10.007. [Epub ahead of print]
 
     
Author information

1 University Department of Paediatrics, University of Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom. 2 University Department of Paediatrics, University of Cambridge, UK. 3 University Department of Paediatrics, University of Cambridge, UK; Department of Paediatric Gastroenterology, University of Cambridge & Addenbrooke's Hospital, Cambridge, UK. 4 University Department of Paediatrics, University of Cambridge, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK. 5 Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK. 6 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, United Kingdom. 7 Institute of Clinical Molecular Biology (IKMB), Kiel University, Kiel, Germany. 8 Department of Paediatric Gastroenterology, University of Cambridge & Addenbrooke's Hospital, Cambridge, UK. 9 European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom. Electronic address: stegle@ebi.ac.uk. 10 University Department of Paediatrics, University of Cambridge, UK; Department of Paediatric Gastroenterology, University of Cambridge & Addenbrooke's Hospital, Cambridge, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK. Electronic address: mz304@medschl.cam.ac.uk.

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) 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 due 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 UC 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 to 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.

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