Over a million people suffer from Inflammatory Bowel Disease (IBD) within the United States. Ulcerative colitis (UC), one of the most common forms of IBD, is a lifelong disease characterized by periods of remission and active disease flares. Additionally, UC is more prevalent in people under the age of thirty, the group that engages in the most binge drinking episodes. Alcohol consumption has been proposed to induce flare periods in IBD patients, however, the mechanism by which alcohol induces these flare periods remains completely unexplored. Periods of UC flares are identified by weight loss, colonic inflammation, rectal bleeding, and dehydration, which in mouse models can result in colon shortening. Our preliminary findings demonstrate that binge alcohol intoxication induces increased body weight loss and colon shortening in a murine model of dextran sulfate sodium (DSS)-induced colitis. Furthermore, the levels of the pro-inflammatory cytokines, IL-18 and IL-1?, are further elevated in the colon of mice receiving alcohol after DSS treatment. Additionally, IL-22, a cytokine critical to UC remission periods, was found to be significantly decreased in the colons of mice receiving DSS and alcohol compared to mice receiving DSS alone. Furthermore, upon gavage with a mouse pathogen Citrobacter rodentium, an ~50% mortality was observed in mice given binge alcohol following DSS compared to no mortality in DSS without binge alcohol. These data suggest that alcohol may exacerbate UC flare periods by preventing upregulation of the IL-22 mediated repair response needed for entrance into remission. Additionally, diminished IL-22 could compromise intestinal defense mechanisms resulting in increased colonic inflammation and susceptibility to bacterial pathogens. IL-18 is known to promote inflammation and thus the elevated levels of IL-18 could further increase the severity of the disease. Therefore, the overall goal of the proposed studies is to examine the mechanism by which alcohol potentiates the UC flare. Our hypothesis is that alcohol exacerbates UC flare periods by preventing upregulation of the IL-22- mediated repair response needed for entrance into remission. The hypothesis will be tested in the following aims using a mouse model of DSS-induced colitis with a novel adaptation of a binge alcohol paradigm. Studies in Aim 1 are designed to characterize the lamina propria T cells and ILC3s for their release of IL-22 after DSS- induced colitis and binge alcohol intoxication.
Aim 2 will determine whether binge alcohol intoxication after DSS-colitis suppresses intestinal defense mechanisms, resulting in increased susceptibility to bacterial colonization. Finally Aim 3 studies are designed to evaluate whether in vivo restoration of IL-22 alone or in combination with an inhibition of IL-18 improves intestine defense mechanisms and protects from alcohol- induced UC flare in DSS-treated mice. These studies will provide valuable insights into the mechanism by which alcohol intoxication exacerbates UC flare periods, and thus will help in developing effective therapy for the treatment of these patients.
Alcohol consumption has been proposed to induce flare periods in patients suffering from Inflammatory Bowel Disease (IBD). Our studies are designed to examine the mechanisms by which alcohol use results in IBD flare. The findings from these studies are likely to help in developing therapeutic strategies to maintain gut homeostasis and protect it from the exacerbating symptoms associated with alcohol intoxication and IBD.