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Author Notes:

Address correspondence to: Theresa Alenghat, 3333 Burnet Ave., MLC 7038, Cincinnati, Ohio, USA. Phone: 513.803.7498; Email: theresa.alenghat@cchmc.org

TA, DK, and LAD designed the studies. DK, VW, SJ, JW, and JM carried out experiments.

DK, MK, YH, RK, and AB assisted with computational analyses.

LAD, BJA, MCD, JSH, JFM, RNB, MCS, TDW, and SK provided patient samples and clinical expertise.

NS, MJR, and MH provided critical reagents and tools.

TA and DK analyzed the data and wrote the manuscript.

We thank the S. Way, D. Haslam, and J. Qualls labs (Infectious Disease, CCHMC) and the H. Deshmukh lab (Pulmonology, CCHMC) for useful discussions and members of the Alenghat lab for critical reading of the manuscript.

The RISK committee provided patient samples and clinical expertise.

We thank CCHMC Veterinary Services, the CCHMC DNA Sequencing Core, and the University of Cincinnati Genomics, Epigenomics, and Sequencing Core for services.

We also thank RISK investigators for patient recruitment and the Crohn’s & Colitis Foundation for RISK support.

Conflict of interest: The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

This research is supported by the National Institutes of Health (DK093784, DK114123, and DK116868 to TA; DK098231 to LAD; and T32 DK007727 to DK), and a Crohn’s & Colitis Foundation/Janssen/AGA award to TA. TA holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and is a Pew Scholar in the Biomedical Sciences, supported by the Pew Charitable Trust.

This project is supported in part by Public Health Service grant P30 DK078392 and the CCHMC Trustee Award and Procter Scholar’s Program.

Keywords:

  • Gastroenterology
  • Inflammatory bowel disease

Microbiota-sensitive epigenetic signature predicts inflammation in Crohn's disease.

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Journal Title:

JCI insight

Volume:

Volume 3, Number 18

Publisher:

, Pages e122104-e122104

Type of Work:

Article | Final Publisher PDF

Abstract:

Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients. Genes characterized by significant alterations in histone H3-lysine 4 trimethylation (H3K4me3) showed differential enrichment in pathways involving immunoregulation, cell survival and signaling, and metabolism. Interestingly, a large subset of these genes was epigenetically regulated by microbiota in mice and several microbiota-sensitive epigenetic targets demonstrated altered expression in IBD patients. Remarkably though, a substantial proportion of these genes exhibited H3K4me3 levels that correlated with the severity of intestinal inflammation in IBD, despite lacking significant differential expression. Collectively, these data uncover a previously unrecognized epigenetic profile of IBD that can be primed by commensal microbes and indicate sensitive targets in the epithelium that may underlie how microbiota predispose to subsequent intestinal inflammation and disease.

Copyright information:

© 2018, American Society for Clinical Investigation

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