TITLE:
Gut sterilization in experimental colitis leukocyte mediated colon injury, and effects on angiogenesis/lymphangiogenesis
AUTHORS:
Mihir Patel, Justin Olinde, Allison Tatum, Chaitanya V. Ganta, Walter E. Cromer, Ankur R. Sheth, Merilyn H. Jennings, J. Michael Mathis, Traci Testerman, Paul A. Jordan, Kenneth Manas, Christopher P. Monceaux, J. Steven Alexander
KEYWORDS:
Crohn’s Disease; Antibiotics; Myeloperoxidase; Lymphatics; Angiogenesis
JOURNAL NAME:
Open Journal of Gastroenterology,
Vol.3 No.1,
February
17,
2013
ABSTRACT:
Inappropriate responses to normal commensal bacteria trigger
immune activation in both inflammatory bowel disease and experimental colitis.
How gut flora contribute to the pathogenesis of inflammatory bowel disease is
unclear, but may involve entrapment of leukocytes and remodeling of the
vascular system. Here we evaluated how the progression and tissue remodeling in
experimental colitis differ in a germ- free model of mouse colitis. Four
treatment groups were used: control, antibiotic-treated (ABX), dextran sulfate
colitis (DSS) and DSS pre- and co-treated with antibiotics (DSS + ABX). In days
0 - 3 of the study, germ-free
mice received antibiotics (vancomycin, neomycin,
and metronidazole). During the next 11 days, antibiotics were continued and DSS
(3%) added to “colitis” groups. Disease activity, weight, stool form and blood
were monitored daily. Mice were sacrificed and
tissue samples harvested. Histopathological scores
in controls (0.00) and in ABX (1.0+/–0.81) were significantly
(p –0). Extents of injury, inflammation and crypt damage were all
improved in DSS + ABX. The Disease Activity Index score (day 11) was
significantly worse in the DSS group compared to the DSS + ABX group. Stool
blood and form scores were also significantly improved among these groups.
Importantly, myeloper- oxidase was significantly reduced in DSS + ABX, indicating
that neutrophil infiltration was blocked. Colitis was associated with an
increase in blood and lymphatic vessels; both of these events were also
significantly reduced by gut sterilization. Our experiment shows that clinical
and histopathological severity of colitis was significantly worse in the DSS
colitis group compared to the DSS + ABX group, supporting the hypothesis that
development of IBD is likely to be less severe with appropriate antibiotic
treatment. In particular, gut sterilization effectively reduces leuko-
cyte-dependent (PMN) injury to improve outcomes and may be an important target
for therapy.