IL-22-STAT3-Nos2 axis in alcohol-mediated exacerbation of UC pathology - Project Summary/Abstract
Alcohol use is a risk factor in multiple disease conditions including gastrointestinal related diseases. Recent
findings from our laboratory show that alcohol use in patients with ulcerative colitis (UC) leads to increased
intestinal infections and antibiotic usage. Similarly, we observed that binge alcohol administration in mice
treated with dextran sulfate sodium (DSS) exacerbates the symptoms associated with UC. However, the
mechanisms by which alcohol exacerbates UC symptoms are not known. In our recent studies, we found that
alcohol administration increased the pathogenic Enterobacteriaceae and decreased beneficial Lactobacillus
bacteria in feces of mice receiving DSS. This was accompanied by increased nitric oxide synthase 2 (Nos2)
levels in colonic epithelial cells. We also observed a decrease in interleukin (IL)-22 and phosphorylated STAT3
in colons of mice treated with DSS and ethanol. An increase in Nos2 during inflammation can alter the colonic
microenvironment causing tissue damage. Furthermore, nitric oxide produced by Nos2 interacts with reactive
oxygen species to generate nitrates, which the pathogenic Enterobacteriaceae can competitively utilize as an
energy source. Conversely, IL-22, is a cytokine that utilizes STAT3 activation to promote the gut mucosal
barrier and plays a significant role in protection against pathogenic gut bacteria. STAT3 activation is also
shown to inhibit Nos2 transcription. Thus, decreases in IL-22-STAT3 signaling not only could impair the repair
process and defense mechanisms required for maintenance of intestinal barrier integrity, but also results in
increased Nos2 activity, which can cause bacterial dysbiosis and open specific niches for pathogenic
Enterobacteriaceae to infiltrate the mucosal layer of the intestine perpetuating UC flare/pathology. Therefore,
the goal of our proposed studies is to assess the role of Nos2 and IL-22-STAT3 signaling in alcohol-mediated
exacerbation of colitis pathology. Our hypothesis is that alcohol increases Nos2 expression which
combined with a decrease in IL-22-STAT3 signaling in intestinal epithelial cells following DSS-induced
colitis results in bacterial dysbiosis and exacerbation of symptoms associated with colitis. The
hypothesis will be tested in two aims using a model of DSS-induced colitis and binge alcohol exposure. Studies
in Aim 1 are designed to determine whether alcohol-mediated increase in Nos2 expression exacerbates the
pathology associated with UC directly or via bacterial dysbiosis. Aim 2 will focus on whether IL-22 utilizes
STAT3 to mitigate the upregulation of the Nos2 pathway thus preventing alcohol-induced exacerbation of
pathology/flare in mice treated with DSS. These studies will provide valuable insights into the mechanism by
which alcohol exacerbates UC flare periods, and thus will help in developing effective therapy for the treatment
of these patients.
