Multivariate modeling identifies neutrophil- and Th17-related factors as differential serum biomarkers of chronic murine colitis.
BACKGROUND
Diagnosis of chronic intestinal inflammation, which characterizes inflammatory bowel disease (IBD), along with prediction of disease state is hindered by the availability of predictive serum biomarker. Serum biomarkers predictive of disease state will improve trials for therapeutic intervention, and disease monitoring, particularly in genetically susceptible individuals. Chronic inflammation during IBD is considered distinct from infectious intestinal inflammation thereby requiring biomarkers to provide differential diagnosis. To address whether differential serum biomarkers could be identified in murine models of colitis, immunological profiles from both chronic spontaneous and acute infectious colitis were compared and predictive serum biomarkers identified via multivariate modeling.


RESULTS
Discriminatory multivariate modeling of 23 cytokines plus chlorotyrosine and nitrotyrosine (protein adducts from reactive nitrogen species and hypochlorite) in serum and tissue from two murine models of colitis was performed to identify disease-associated biomarkers. Acute C. rodentium-induced colitis in C57BL/6J mice and chronic spontaneous Helicobacter-dependent colitis in TLR4(-/-) x IL-10(-/-) mice were utilized for evaluation. Colon profiles of both colitis models were nearly identical with chemokines, neutrophil- and Th17-related factors highly associated with intestinal disease. In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon. In contrast, the discriminatory predictive serum factors for chronic colitis were neutrophil- and Th17-related factors (KC, IL-12/23p40, IL-17, G-CSF, and chlorotyrosine) that were also elevated in colon tissue. Chronic colitis serum biomarkers were specific to chronic colitis as they were not discriminatory for acute colitis.


CONCLUSIONS
Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis. Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.
Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. mmcbee@bsd.uchicago.edu
Megan E
ME
McBee
Yu
Y
Zeng
Nicola
N
Parry
Cathryn R
CR
Nagler
Steven R
SR
Tannenbaum
David B
DB
Schauer
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002908:Chronic Disease; D003092:Colitis / Q000097:blood*; D016207:Cytokines / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D015999:Multivariate Analysis; D009504:Neutrophils / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism*
D015415:Biomarkers; D016207:Cytokines; D026361:Reactive Nitrogen Species