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（由适用提供）：酒精仍然是美国社会的大量健康和经济燃烧。酒精的食用以其对肠道屏障功能的有害影响而闻名，并且是炎症性肠病（IBD）耀斑的潜在触发因素。根据最近的疾病控制中心报告，IBD是美国五种最普遍的胃肠道疾病之一，年度医疗保健成本超过17亿美元。仅IBD就会导致119,000名患者的700,000多次身体访问，100,000次住院和残疾（http://www.cdc.gov/ibd/）。炎性细胞因子的过度产生在IBD的发病机理中起着至关重要的作用。此外，最近的一项研究表明，饮酒会使疾病的症状恶化，但是，酒精对IBD耀斑的贡献的机制仍然存在。很大程度上出乎意料。几条证据表明，饮酒会导致肠道细菌营养不良。肠道微生物群的这种变化可能会在细菌与宿主之间的相互作用扰动肠上皮和泄漏的损害，这可能会加剧与IBD相关的症状。因此，我们提出的研究的总体目标是确定暴饮暴食后肠道细菌的变化是否在改变的肠道上皮屏障功能中起作用，以及这如何影响肠道感染对硫酸葡萄糖钠（DSS）的响应。 DSS诱导的肠道感染通常在临床前模型中用于研究IBD发病机理。我们的假设是，狂饮乙醇中毒与DSS治疗相结合会破坏正常的菌群，从而导致肠道阴性细菌在肠内积累。这反过来伴随着微生物群/肠上皮相互作用，导致肠道注射和夸大的屏障破坏。该假设将在2个目标中进行的2个目标进行测试，以狂暴乙醇暴露和肠道感染的良好小鼠模型。 AIM 1中的研究将确定乙醇中毒和DSS治疗后肠道注射和粘膜损伤/泄漏是否与肠道菌群的改变有关，以及使用益生菌治疗是否可以重新建立肠道肌群和上皮屏障完整性。 AIM 2中的研究将描述肠道细菌的变化影响乙醇肠毒性和DSS暴露后上皮屏障功能的机制。这些研究的发现将揭示肠道菌群在肠道感染中的新作用，并改变乙醇和DSS暴露后肠上皮屏障功能改变，并可能有助于开发新的治疗策略以维持肠道屏障完整性。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在多种炎症条件下以及与酒精性肝病和其他器官功能障碍相关的发病机理中实施。