Binge alcohol intoxication and pathobiology of ulcerative colitis

酗酒中毒与溃疡性结肠炎的病理学

• 批准号: 9548415
• 负责人: Mashkoor A Choudhry
• 金额: $ 21.4万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-10 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9548415
• 关键词: Abbreviations; Affect; Age; Alcohol consumption; Alcoholic Intoxication; Alcohols; Body Weight decreased; Citrobacter rodentium; Colitis; Colon; Colony-forming units; Crohn' s disease; Data; Defense Mechanisms; Dehydration; Disease; Disease remission; Epithelial Cells; Ethanol; Flare; Gastrointestinal Diseases; Goals; Health Care Costs; Hemorrhage; Homeostasis; Host Defense Mechanism; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Interleukin-1; Interleukin-1 beta; Interleukin-18; Intestines; Knowledge; Lamina Propria; Leukocytes; Lymphoid Cell; Mediating; Mesentery; Modeling; Mus; Natural regeneration; Patients; Polymerase Chain Reaction; Predisposition; Proteins; Quantitative Reverse Transcriptase PCR; Recommendation; Reporting; Severity of illness; Sodium Dextran Sulfate; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Ulcerative Colitis; United States; Up-Regulation; Weight Gain; alcohol abstinence; alcohol exposure; antimicrobial peptide; associated symptom; binge drinking; cytokine; design; effective therapy; experience; improved; in vivo; insight; interleukin-22; intraperitoneal; islet; lymph nodes; mortality; mouse model; novel; pathogen; pathogenic bacteria; prevent; protective effect; rectal; repaired; response; restoration

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.

7.项目总结/摘要 在美国，超过一百万人患有炎症性肠病（IBD）。溃疡性结肠炎 (UC)IBD是IBD最常见的形式之一，是一种终身疾病，其特征在于缓解期， 活动性疾病发作。此外，UC在30岁以下的人群中更为普遍， 参与了最多的酗酒事件。有人提出饮酒可诱发发作期 然而，在IBD患者中，酒精诱导这些发作期的机制仍然完全 未开发的UC发作期可通过体重减轻、结肠炎症、直肠出血和 脱水，这在小鼠模型中可导致结肠缩短。我们的初步调查结果表明， 在小鼠模型中，酒精中毒导致体重减轻和结肠缩短增加， 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DSS治疗后接受酒精的小鼠的结肠中进一步升高。此外，IL-22，a 在小鼠结肠中发现对UC缓解期至关重要的细胞因子显著减少 与单独接受DSS的小鼠相比，接受DSS和酒精的小鼠。此外，在用小鼠灌胃后， 病原体啮齿类柠檬酸杆菌，在DSS后给予酗酒的小鼠中观察到约50%的死亡率 相比之下，没有酗酒的DSS没有死亡率。这些数据表明，酒精可能会加剧UC 通过阻止IL-22介导的修复反应的上调， 缓解。此外，减少的IL-22可能会损害肠道防御机制， 增加结肠炎症和对细菌病原体的易感性。已知IL-18促进 炎症和因此升高的IL-18水平可进一步增加疾病的严重性。因此，我们认为， 这些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的上调而加重UC发作期。 介导进入缓解期所需的修复反应。该假设将在下面进行检验 目的是使用DSS诱导的结肠炎小鼠模型，并对酗酒模式进行新的调整。研究 在目的1中，设计用于表征固有层T细胞和ILC 3在DSS-1后释放IL-22。 诱发结肠炎和酗酒目标2将确定是否酗酒后 DSS-结肠炎抑制肠道防御机制，导致对细菌的易感性增加 殖民化最后，目的3研究被设计为评估单独的IL-22或IL-22联合的IL-22的体内恢复是否是在体内恢复。 联合抑制IL-18可改善肠道防御机制，并防止酒精中毒。 在DSS处理的小鼠中诱导UC发作。这些研究将提供有价值的见解， 酒精中毒加剧UC发作期，因此将有助于开发有效的治疗方法， 这些患者的治疗。