The goal of this project is to better understand how the intestinal epithelial cells and bacterial populations can be altered by alcohol in the setting of intestinal inflammation. There are two main forms of inflammatory bowel disease: Crohn's disease (CD) and ulcerative colitis (UC). UC is an inflammatory disease of the large intestine with unknown etiology that affects more than three million individuals globally. These patients experience periodic episodes of disease reactivation characterized by severe abdominal discomfort and bloody diarrhea, often requiring hospitalization. Triggers of flares appear to be multifactorial but can be precipitated by certain foods. Current guidelines recommend for physicians to caution UC patients against drinking alcohol, yet only a few studies have examined the effects of alcohol in UC. One study found that patients with increased alcohol consumption had increased rates of UC disease relapse, while another found that alcohol consumption increased gastrointestinal symptoms associated with UC. Despite the implications of these studies, a mechanism for alcohol-mediated relapse in UC or exacerbation of gastrointestinal symptoms is not defined. Intestinal bacterial changes are common in UC patients and individuals with alcohol use. Altered intestinal bacterial populations that are persistent can lead to intestinal tissue damage and perpetuate a cycle of inflammation. In our lab, we developed a model to study UC and alcohol use. Mice are treated with dextran sulfate sodium (DSS), which recapitulates aspects of the UC disease, followed by a binge ethanol treatment. Mice that received the DSS and ethanol treatment had increases in intestinal tissue damage compared to mice that received DSS only. This was accompanied by alterations in bacterial populations, i.e., increased Enterobacteriaceae, that have been observed in UC. Furthermore, we identified increased expression of Nos2 which produces metabolites that can be used by Enterobacteriaceae. This led us to hypothesize that in the setting of DSS-induced colitis, alcohol promotes expression of Nos2 in the intestine, which provides substrates that allow for Enterobacteriaceae overgrowth. The increased Enterobacteriaceae exacerbates intestinal damage.
In Aim 1 we will determine if increased Nos2 expression leads to increased Enterobacteriaceae after DSS and ethanol treatment.
In Aim 2 we will determine if Nos2-mediated increase in Enterobacteriaceae results in increased intestinal pathology. Overall, this study will aid in our understanding of the inflammatory and bacterial changes that occur due to alcohol in UC.
Research has shown that alcohol can have negative effects in the setting of IBD, but the mechanism behind this is not defined. The proposed studies will examine how alcohol induced intestinal epithelial and bacterial changes can lead to enhanced intestinal tissue damage.
