Binge alcohol intoxication and pathobiology of ulcerative colitis

7.项目摘要/摘要 美国有100多万人患有炎症性肠病(IBD)。溃疡性结肠炎 (UC)是IBD最常见的形式之一，是一种终生疾病，其特征是缓解期和 活跃的疾病爆发。此外，UC在30岁以下的人群中更为普遍，这一群体 沉浸在最狂欢的饮酒中。饮酒被认为是导致红斑期的原因。 然而，在IBD患者中，酒精诱导这些红斑期的机制仍然完全存在。 未被开发的。UC红斑期可通过体重减轻、结肠炎、直肠出血和 脱水，在小鼠模型中会导致结肠缩短。我们的初步调查结果表明 酗酒致小鼠体重减轻和结肠缩短的实验研究 葡聚糖硫酸钠(DSS)诱导的结肠炎。此外，促炎细胞因子IL-18的水平 和IL-1β在饮酒小鼠结肠中的表达进一步升高。此外，IL-22、a 对UC缓解期至关重要的细胞因子在小鼠的结肠中显著减少 接受DSS和酒精的小鼠与只接受DSS的小鼠相比。此外，在用老鼠灌胃时 病原体轮状柠檬酸杆菌，在DSS后酗酒的小鼠中观察到50%的死亡率 相比之下，在没有酗酒的DSS中没有死亡率。这些数据表明，酒精可能会加重UC 通过阻止IL-22介导的修复反应的上调来阻止细胞进入 减刑。此外，IL-22的减少可能会损害肠道防御机制，导致 增加结肠炎症和对细菌病原体的易感性。已知IL-18可促进 炎症和IL-18水平的升高可能会进一步增加疾病的严重性。因此， 建议研究的总体目标是研究酒精增强UC的机制。 照明弹。我们的假设是，酒精通过阻止IL-22上调而加剧UC发作期。 进入缓解期所需的中介修复反应。这一假设将在以下方面得到检验 目的使用DSS诱导的结肠炎的小鼠模型，采用一种新的酗酒范例的改编。研究 目的1研究DSS后固有层T细胞和ILC3释放IL-22的特性。 诱发结肠炎和酗酒。目标2将确定狂欢酒精中毒后 DSS-结肠炎抑制肠道防御机制，导致对细菌的易感性增加 殖民主义。最后，Aim 3项研究旨在评估IL-22的体内修复是单独还是在 联合抑制IL-18可改善肠道防御机制，保护肠道免受酒精侵害。 DSS诱导小鼠溃疡性结肠炎。这些研究将通过以下方式为机制提供有价值的见解 酒精中毒会加剧UC的红斑期，因此将有助于开发有效的治疗方法 这些病人的治疗。

7. Project Summary/Abstract 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-1β, 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.