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。项目摘要/摘要 在美国，超过一百万的人患有炎症性肠病（IBD）。溃疡性结肠炎 （UC）是IBD最常见的形式之一，是一种终身疾病，其特征是缓解时期和 活性疾病耀斑。此外，UC在三十岁以下的人中更为普遍，该小组是 从事最暴饮暴食的情节。已经提出饮酒来诱导耀斑时期 但是，在IBD患者中，酒精诱导这些耀斑时期的机制完全保持 未探索。通过体重减轻，结肠注射，直肠出血和 脱水，在小鼠模型中可能导致结肠缩短。我们的初步发现表明 暴饮饮酒中的醉酒引起体重减轻的增加，并在鼠模型中缩短结肠 硫酸葡萄糖钠（DSS）诱导的结肠炎。此外，促炎细胞因子的水平，IL-18 在DSS治疗后接受酒精的小鼠的结肠中，IL-1β进一步升高。另外，IL-22，a 在小鼠的结肠中发现对UC缓解周期至关重要的细胞因子显着降低 与仅接受DSS的小鼠相比，接受DSS和酒精。此外，用鼠标饲养 病原体柠檬杆菌啮齿动物，在DSS之后，在给定暴饮的小鼠中观察到约50％的死亡率 与没有暴饮暴食的DSS无死亡率相比。这些数据表明酒精可能加剧UC 通过防止进入进入的IL-22介导的维修响应的上调，进入 缓解。此外，IL-22的减少可能会损害肠道防御机制，导致 结肠感染和对细菌病原体的敏感性增加。众所周知IL-18可以促进 炎症以及IL-18水平升高可能会进一步增加疾病的严重程度。所以， 拟议研究的总体目标是检查酒精增强UC的机制 我们的假设是，酒精通过防止上调IL-22--加剧了UC耀斑时期 进入缓解所需的介导的维修响应。该假设将在以下检验 使用DSS诱导的结肠炎的小鼠模型，并具有新颖的暴饮暴食范例。研究 在AIM 1中，旨在表征固有椎板T细胞和ILC3s，用于在DSS-之后释放IL-22 诱发结肠炎和暴饮暴食。 AIM 2将确定在此之后的暴饮暴食 DSS肺炎抑制肠道防御机制，从而增加对细菌的敏感性 殖民化。最终AIM 3研究旨在评估IL-22的体内恢复是单独的还是在 结合抑制IL-18可以改善肠道防御机制，并保护酒精 - 在经DSS处理的小鼠中诱导的UC耀斑。这些研究将通过 哪种酒精毒基加剧了UC耀斑期，因此将有助于开发有效的治疗 这些患者的治疗。