Alcohol and Intestinal Inflammatory Response: The Role of Intestinal Microbiota

 描述(申请人提供)：酒精仍然是美国社会相当大的健康和经济负担。众所周知，饮酒对肠道屏障功能的有害影响是炎症性肠病(IBD)发作的潜在触发因素。根据疾病控制中心最近的一份报告，IBD是美国最常见的五种胃肠道疾病之一，每年的总医疗费用超过17亿美元。仅炎症性肠病就导致超过700,000名医生就诊，100,000人住院，119,000名患者残疾(http://www.cdc.gov/ibd/).炎性细胞因子的过度产生在IBD的发病机制中起重要作用。此外，最近的一项研究表明，饮酒会加剧疾病的症状，然而，酒精导致IBD发作的机制在很大程度上仍不清楚。有几条证据表明，饮酒会导致肠道细菌失调。肠道微生物区系的这种变化可能扰乱细菌与宿主之间的相互作用，导致肠道上皮损伤和渗漏，这可能会加剧与IBD相关的症状。因此，我们拟议研究的总体目标是确定酗酒后肠道细菌的变化是否在肠道上皮屏障功能改变中发挥作用，以及这如何影响葡聚糖硫酸钠(DSS)引起的肠炎症。DSS诱导的肠道炎症是临床前研究IBD发病机制的常用模型。我们的假设是，狂欢酒精中毒与DSS治疗相结合，扰乱了正常的微生物区系，导致革兰氏阴性细菌在肠道内积累。这反过来扰乱了微生物区系/肠道上皮细胞的相互作用，导致肠道炎症加剧和屏障被夸大破坏。这一假设将在两个目标上进行验证，该模型是在一只公认的酗酒和肠道炎症的小鼠模型上进行的。目标1的研究将确定乙醇中毒和DSS治疗后的肠道炎症和粘膜损伤/渗漏是否与肠道微生物区系的变化有关，以及益生菌治疗是否重建肠道微生物区系和上皮屏障的完整性。AIM 2中的研究将阐明乙醇中毒和DSS暴露后肠道细菌变化影响上皮屏障功能的机制。这些研究的发现将揭示肠道微生物区系在乙醇和DSS暴露后肠道炎症和肠道上皮屏障功能改变中的新作用，并可能有助于开发新的治疗策略来维持肠道屏障的完整性。总体而言，这些发现将具有更广泛的意义，因为肠屏障功能障碍通常与多种炎症条件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。

 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.