Multifactorial patterns of gene expression in colonic epithelial cells predict disease phenotypes in experimental colitis.
BACKGROUND
The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five "signature" biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn's disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation.


METHODS
We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. Factor analysis was used to combine the five biomarkers into two multifactorial principal components (PCs). PC scores for individual mice were correlated with disease severity.


RESULTS
For both colitis models, PC1 was strongly weighted toward RelA, A20, and pIgR, and PC2 was strongly weighted toward TNF and MIP-2, while the contributions of other biomarkers varied depending on the etiology of inflammation. Disease severity was correlated with elevated PC2 scores in DSS colitis and reduced PC1 scores in T-cell transfer colitis. Downregulation of pIgR was a common feature observed in both colitis models and was associated with altered cellular localization of pIgR and failure to transport IgA.


CONCLUSIONS
A multifactorial analysis of epithelial gene expression may be more informative than examining single gene responses in IBD. These results provide insight into the homeostatic and proinflammatory functions of CEC in IBD pathogenesis and suggest that biomarker analysis could be useful for evaluating therapeutic options for IBD patients.
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536-0096, USA.
Aubrey L
AL
Frantz
Maria E C
ME
Bruno
Eric W
EW
Rogier
Halide
H
Tuna
Donald A
DA
Cohen
Subbarao
S
Bondada
R Lakshman
RL
Chelvarajan
J Anthony
JA
Brandon
C Darrell
CD
Jennings
Charlotte S
CS
Kaetzel
D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015415:Biomarkers; D018398:Homeodomain Proteins; D012333:RNA, Messenger; C064658:RAG-1 protein; D016264:Dextran Sulfate