Alcohol and Intestinal Inflammatory Response: The Role of Intestinal Microbiota

 描述（由申请人提供）：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有有害影响，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是美国五种最流行的胃肠道疾病之一，每年的整体医疗费用超过17亿美元。仅IBD就导致超过700，000次医生就诊，100，000次住院，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的发病机制中起关键作用。此外，最近的一项研究表明，酒精消费会加重疾病的症状，然而，酒精导致IBD发作的机制在很大程度上尚未探索。几条证据表明，酒精消费导致肠道细菌生态失调。肠道微生物群的这种变化可能会扰乱细菌和宿主之间的相互作用，导致肠上皮细胞损伤和渗漏，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酗酒暴露后肠道细菌的变化是否在改变肠道上皮屏障功能中发挥作用，以及这如何影响肠道炎症对葡聚糖硫酸钠（DSS）的反应。DSS诱导的肠道炎症通常用于临床前模型来研究IBD发病机制。我们的假设是，酒精中毒结合DSS治疗破坏了正常的微生物群，导致肠道内的革兰氏阴性细菌积累。这反过来又扰乱了微生物群/肠道上皮的相互作用，导致肠道炎症加剧和屏障破坏加剧。将在2个目标中，在已建立的酒精过量暴露和肠道炎症小鼠模型中检验该假设。AIM 1中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/渗漏是否与肠道菌群的改变有关，以及益生菌治疗是否重建肠道菌群和上皮屏障完整性。AIM 2中的研究将描述乙醇中毒和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，并可能有助于开发新的治疗策略以维持肠道屏障完整性。总的来说，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。

 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.