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

Kelly D1,2, Kotliar M3, Woo V1, Jagannathan S3, Whitt J1, Moncivaiz J1, Aronow BJ4, Dubinsky MC5, Hyams JS6, Markowitz JF7, Baldassano RN8, Stephens MC9, Walters TD10, Kugathasan S11, Haberman Y2,12, Sundaram N13, Rosen MJ2, Helmrath M13, Karns R2, Barski A3, Denson LA2, Alenghat T1. JCI Insight. 2018 Sep 20;3(18). pii: 122104. doi: 10.1172/jci.insight.122104. [Epub ahead of print]

Author information

1 Division of Immunobiology, Center for Inflammation and Tolerance.

2 Division of Gastroenterology, Hepatology, and Nutrition.

3 Divisions of Allergy and Immunology and Human Genetics, and.

4 Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center (CCHMC) and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

5 Department of Pediatrics, Mount Sinai Hospital, New York, New York, USA.

6 Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut, USA.

7 Department of Pediatrics, Northwell Health, New York, New York, USA.

8 Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

9 Department of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA.

10 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

11 Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA.

12 Sheba Medical Center, Tel Hashomer, affiliated with the Tel-Aviv University, Israel.

13 Division of Pediatric General and Thoracic Surgery, CCHMC and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.


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.

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