High-resolution gene expression profiling using RNA sequencing in patients with inflammatory bowel disease and in mouse models of colitis.

Abstract

BACKGROUND AND AIMS:

Proper interpretation of data from preclinical animal studies requires thorough knowledge of the pathophysiology of both the human disease and animal models. In this study, the expression of inflammatory bowel disease [IBD]-associated genes was characterised in mouse models of colitis to examine the underlying molecular pathways and assess the similarity between the experimental models and human disease.

METHODS:

RNA sequencing was performed on colon biopsies from Crohn's disease [CD] patients, ulcerative colitis [UC] patients and non-IBD controls. Genes shown to be significantly dysregulated in human IBD were used to study gene expression in colons from a piroxicam-accelerated colitis interleukin-10 knockout [PAC IL-10 k.o.], an adoptive transfer [AdTr] and a dextran sulfate sodium [DSS] colitis mouse model.

RESULTS:

Of 115 literature-defined genes linked to IBD, 92 were significantly differentially expressed in inflamed mucosa of CD and/or UC patients compared with non-IBD controls. The most upregulated genes were shared by both diseases, including REG1A, LCN2, NOS2, CXCL1-2, and S100A9. Of those 92 IBD-associated genes, 71 [77%] were significantly dysregulated in PAC IL-10 k.o. mice, whereas 59 [64%] were significantly dysregulated in AdTr mice compared with wild-type controls. Some of the most upregulated genes, including S100a8-9, Nos2, and Lcn2, were shared by the colitis models and correlated with disease activity.

CONCLUSIONS:

IBD and experimental murine colitis have a high degree of similarity in the colonic transcriptional profile, probably secondary to non-specific inflammatory processes. However, differences do exist between models, emphasising the need for careful selection and interpretation of qualified animal models in preclinical research.

• Authors: Kristine Holgersen, Burak Kutlu, Brian Fox, Kyle Serikawa, James Lord, Axel Kornerup Hansen, Thomas Lindebo Holm
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 9 Issue 6 Pg. 492-506 (Jun 2015) ISSN: 1876-4479 [Electronic] England
• PMID: 25795566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Interleukin-10
• Piroxicam
• RNA
• Dextran Sulfate

Topics

• Adoptive Transfer
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Case-Control Studies
• Colitis (chemically induced, drug therapy, genetics, immunology)
• Colitis, Ulcerative (genetics)
• Crohn Disease (genetics)
• Dextran Sulfate
• Disease Models, Animal
• Female
• Gene Expression Profiling (methods)
• Humans
• Interleukin-10 (genetics)
• Intestinal Mucosa (chemistry, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, SCID
• Piroxicam (therapeutic use)
• RNA (analysis)
• Sequence Analysis, RNA
• T-Lymphocytes, Helper-Inducer
• Transcriptome