Alcohol and Intestinal Inflammatory Response: The Role of Intestinal Microbiota

酒精和肠道炎症反应：肠道微生物群的作用

• 批准号: 8663017
• 负责人: Mashkoor A Choudhry
• 金额: $ 21.71万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-10 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663017
• 关键词: Adult; Adverse effects; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcoholism; Alcohols; American; Animals; Bacteria; Bacterial Translocation; Bacteroides fragilis; Burn injury; Cause of Death; Centers for Disease Control and Prevention (U.S.); Critical Illness; Disease; Dose; Economic Burden; Economics; Epithelial; Escherichia coli; Ethanol; Flare; Functional disorder; Funding Opportunities; Gastrointestinal Diseases; Goals; Gram-Negative Bacteria; Growth; Health Care Costs; Health Resources; Homeostasis; Hospitalization; Host Defense; Hour; Immune; Impaired wound healing; Impairment; Infection; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Injury; Interleukin-18; Intestines; Klebsiella; Laboratories; Length of Stay; Lipopolysaccharides; Minor; National Institute on Alcohol Abuse and Alcoholism; Obesity; Organ; Outcome; Pathogenesis; Patients; Physicians; Play; Pre-Clinical Model; Predisposition; Probiotics; Production; Pseudomonas; Public Health; Reporting; Risk Factors; Role; Sepsis; Societies; Sodium Dextran Sulfate; Symptoms; Testing; Tight Junctions; Time; Tissues; Trauma; United States; Visit; alcohol exposure; body system; claudin-1 protein; cost; cytokine; disability; effective therapy; gastrointestinal epithelium; gut microbiota; gut microflora; health economics; human disease; immune function; injured; insight; intestinal epithelium; mouse model; neglect; novel; novel therapeutics; occludin; pathogen; public health relevance; response

 DESCRIPTION (provided by applicant): Alcohol remains a considerable health and economic burden to American society. The consumption of alcohol is well known for its deleterious effects on gut barrier function and is a potential trigger for inflammatory bowel disease (IBD) flare. According to a recent Center for Disease Control report, IBD is one of the five most prevalent gastrointestinal diseases in the United States, with annual overall health care cost of more than $1.7 billion. IBD alone results in more than 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients (http://www.cdc.gov/ibd/). Excessive production of inflammatory cytokines plays a critical role in the pathogenesis of IBD. Additionally, a recent study suggests that alcohol consumption worsens the symptoms of the disease, however, the mechanism by which alcohol contributes to IBD flares remains largely unexplored. Several lines of evidence suggest that alcohol consumption results in gut bacterial dysbiosis. Such changes in gut microbiota may perturb interactions between bacteria and the host leading to damage of the intestinal epithelium and leakiness, which may exacerbate the symptoms associated with IBD. Therefore, the overall goal of our proposed studies is to determine whether changes in gut bacteria following binge alcohol exposure play a role in altered gut epithelial barrier function, and how this influences intestinal inflammation in response to dextran sodium sulphate (DSS). DSS-induced intestinal inflammation is commonly used in preclinical model to study IBD pathogenesis. Our hypothesis is that binge ethanol intoxication combined with DSS treatment disrupts the normal microbiota resulting in Gram-negative bacterial accumulation within the intestine. This in turn perturbs the microbiota/gut epithelial interactions leading to heightened gut inflammation and exaggerated barrier disruption. The hypothesis will be tested in 2 Aims in a well-established mouse model of binge ethanol exposure and intestinal inflammation. Studies in AIM 1 will determine whether gut inflammation and mucosal damage/leakiness following ethanol intoxication and DSS treatment are related to alterations in gut microflora, and whether treatment with probiotics re-establishes gut microbiota and epithelial barrier integrity. The studies in AIM 2 will delineate the mechanism by which changes in gut bacteria influence epithelial barrier function following ethanol intoxication and DSS exposure. The findings from these studies will reveal a novel role for the gut microbiota in intestinal inflammation and altered intestinal epithelial barrier function following ethanol and DSS exposure, and may help in developing new therapeutic strategies to maintain the gut barrier integrity. Overall, these findings will have wider implications as intestinal barrier dysfunction is often implicated in multiple inflammatory conditions as well as in the pathogenesis associated with alcoholic liver disease and other organ dysfunction.

 描述（由申请人提供）：众所周知，饮酒对美国社会的健康和经济造成了相当大的负担，并且是炎症性肠病（IBD）发作的潜在诱因。美国疾病控制中心最近的一份报告显示，IBD 是美国最常见的五种胃肠道疾病之一，仅 IBD 一项就导致超过 70 万名医生每年的总体医疗费用超过 17 亿美元。就诊次数、100,000 次住院和 119,000 名患者残疾 (http://www.cdc.gov/ibd/)。此外，最近的一项研究表明，饮酒会加剧炎症细胞因子的发病机制。然而，酒精导致 IBD 发作的机制在很大程度上尚未被探索，一些证据表明饮酒会导致肠道细菌失调。肠道微生物群中的细菌可能会扰乱细菌与宿主之间的相互作用，导致肠上皮损伤和渗漏，从而可能恶化与 IBD 相关的症状。因此，我们提出的研究的总体目标是确定酗酒后肠道细菌是否发生变化。暴露在肠道上皮屏障功能改变中发挥作用，以及它如何影响右旋糖酐硫酸钠 (DSS) 诱导的肠道炎症反应，我们的假设通常用于临床前模型来研究 IBD 发病机制。暴饮暴食乙醇中毒与 DSS 治疗相结合会破坏正常的微生物群，导致革兰氏阴性细菌在肠道内积聚，这反过来又会扰乱微生物群/肠道上皮相互作用，导致胃部肠道炎症和过度的屏障破坏。 2 针对已建立的暴食乙醇暴露和肠道炎症小鼠模型，AIM 1 的研究将确定乙醇后是否会出现肠道炎症和粘膜损伤/渗漏。中毒和 DSS 治疗与肠道微生物群的改变有关，以及益生菌治疗是否可以重建肠道微生物群和上皮屏障完整性。AIM 2 中的研究将阐明乙醇中毒和 DSS 后肠道细菌的变化影响上皮屏障功能的机制。这些研究的结果将揭示肠道微生物群在乙醇和 DSS 暴露后肠道炎症和肠上皮屏障功能改变中的新作用，并可能有助于总体而言，这些发现将具有更广泛的影响，因为肠道屏障功能障碍通常与多种炎症性疾病以及与酒精性肝病和其他器官功能障碍相关的发病机制有关。