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 美国有超过一百万人患有炎症性肠病 (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 活跃的疾病发作。此外，UC 在 30 岁以下的人群中更为普遍，该群体 酗酒次数最多。有人提出饮酒会诱发发作期 然而，在 IBD 患者中，酒精诱发这些发作期的机制仍然完全保留。 未经探索。 UC 发作的时期可通过体重减轻、结肠炎症、直肠出血和 脱水，在小鼠模型中会导致结肠缩短。我们的初步研究结果表明 在小鼠模型中，酗酒会导致体重减轻和结肠缩短 葡聚糖硫酸钠（DSS）诱发的结肠炎。此外，促炎细胞因子 IL-18 的水平 DSS 治疗后接受酒精的小鼠结肠中的 IL-1β 和 IL-1β 进一步升高。此外，IL-22，一种 发现对 UC 缓解期至关重要的细胞因子在小鼠结肠中显着减少 接受 DSS 和酒精的小鼠与仅接受 DSS 的小鼠进行比较。此外，在用小鼠强饲时 病原体柠檬酸杆菌（Citrobacter rodentium），在 DSS 后酗酒的小鼠中观察到约 50% 的死亡率 与不酗酒的 DSS 中没有死亡相比。这些数据表明酒精可能会加剧 UC 通过防止进入所需的 IL-22 介导的修复反应的上调来抑制耀斑期 缓解。此外，IL-22 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。 IL-18 已知可促进 炎症以及 IL-18 水平升高可能进一步加剧疾病的严重程度。所以， 拟议研究的总体目标是检查酒精增强 UC 的机制 耀斑。我们的假设是，酒精通过阻止 IL-22- 的上调来加剧 UC 发作期。 进入缓解所需的介导修复反应。该假设将在下面进行检验 目标是使用 DSS 诱导的结肠炎小鼠模型，并采用新的酗酒范式。研究 目标 1 旨在表征固有层 T 细胞和 ILC3 在 DSS- 后释放 IL-22 诱发结肠炎和酗酒中毒。目标 2 将确定是否酗酒后中毒 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，Aim 3 研究旨在评估 IL-22 的体内恢复是否单独或在 与 IL-18 抑制相结合可改善肠道防御机制并防止酒精- 在 DSS 处理的小鼠中诱导 UC 发作。这些研究将为该机制提供有价值的见解 酒精中毒会加剧 UC 发作期，因此有助于开发有效的治疗方法 这些患者的治疗。