Alcohol, bacterial dysbiosis, and inflammation during colitis

项目总结/摘要 该项目的目标是更好地了解肠道上皮细胞和细菌种群如何 在肠道炎症的情况下被酒精改变。有两种主要形式的炎症性肠病 疾病：克罗恩病（CD）和溃疡性结肠炎（UC）。UC是一种大肠炎性疾病 其病因不明，影响全球超过三百万人。这些患者经历 以严重腹部不适和血性腹泻为特征的疾病复发周期性发作， 经常需要住院治疗。耀斑的触发似乎是多因素的，但可以由某些因素促成。 食品目前的指南建议医生警告UC患者不要饮酒，但只有 很少有研究检查酒精对UC的影响。一项研究发现， 另一项研究发现，饮酒增加了UC疾病的复发率，而另一项研究发现， 与UC相关的胃肠道症状增加。尽管这些研究的影响， 酒精介导的UC复发或胃肠道症状加重的机制尚未确定。 肠道细菌变化在UC患者和饮酒者中很常见。肠道改变 持续存在的细菌种群可导致肠组织损伤，并使肠道循环永久化。 炎症在我们的实验室中，我们开发了一个模型来研究UC和酒精使用。用右旋糖酐处理小鼠 硫酸钠（DSS），它概括了UC疾病的方面，然后是酒精治疗。 与小鼠相比，接受DSS和乙醇治疗的小鼠肠组织损伤增加 只接受了DSS。这伴随着细菌种群的改变，即，增加 肠杆菌科，在UC中观察到。此外，我们发现Nos 2的表达增加， 其产生可被肠杆菌科利用的代谢物。这使我们假设，在 在DSS诱导的结肠炎的背景下，酒精促进肠中Nos 2的表达，其提供底物 使肠杆菌科细菌过度生长。肠杆菌科细菌的增加加剧了 损害在目标1中，我们将确定Nos 2表达的增加是否会导致肠杆菌科细菌的增加， DSS和乙醇处理。在目标2中，我们将确定Nos 2介导的肠杆菌科细菌的增加是否 导致肠道病理学增加。总的来说，这项研究将有助于我们了解炎症 以及UC中酒精引起的细菌变化。

Project Summary/Abstract 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.