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

Kristine Holgersen; Burak Kutlu; Brian Fox; Kyle Serikawa; James Lord; Axel Kornerup Hansen; Thomas Lindebo Holm

doi:10.1093/ecco-jcc/jjv050

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

J Crohns Colitis. 2015 Jun;9(6):492-506. doi: 10.1093/ecco-jcc/jjv050. Epub 2015 Mar 20.

Authors

Kristine Holgersen¹, Burak Kutlu², Brian Fox², Kyle Serikawa², James Lord³, Axel Kornerup Hansen⁴, Thomas Lindebo Holm⁵

Affiliations

¹ Novo Nordisk-LIFE In Vivo Pharmacology Centre, Frederiksberg, Denmark Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark Department of Immunopharmacology, Novo Nordisk A/S, Maaloev, Denmark krihol@sund.ku.dk.
² NNRC-Molecular Immunology, Novo Nordisk Inc., Seattle, WA, USA.
³ Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, USA.
⁴ Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
⁵ Department of Immunopharmacology, Novo Nordisk A/S, Maaloev, Denmark.

PMID: 25795566
DOI: 10.1093/ecco-jcc/jjv050

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.

Keywords: Experimental colitis; RNA sequencing; interleukin-10 knockout mouse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adoptive Transfer
Animals
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Case-Control Studies
Colitis / chemically induced
Colitis / drug therapy
Colitis / genetics*
Colitis / immunology
Colitis, Ulcerative / genetics
Crohn Disease / genetics
Dextran Sulfate
Disease Models, Animal*
Female
Gene Expression Profiling* / methods
Humans
Interleukin-10 / genetics
Intestinal Mucosa / chemistry*
Intestinal Mucosa / 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

Substances

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