Alcohol-induced Gut Dysbiosis and Cardiovascular Disease

项目总结 在美国，危险酒精使用(HAU)导致数百万人的巨大发病率和死亡率 每年在美国和世界各地举行。酒精使用的认知、神经和心理社会方面是 久负盛名。最近，临床和基础研究开始了解Hau在其中的作用 导致肠道生物失调，这对一个人的整体健康状况起着重要作用。此外，一个大型的 与饮酒有关的部分死亡与消化系统疾病有关。Hau预先部署并做出贡献 几种并发症的表现，如高血压、代谢综合征和糖尿病 推动和加剧血管功能障碍和心血管疾病(CVD)。之前的研究已经 表明肠道微生物群在诊断和预后中也起着关键作用。 已经建立了心血管疾病。循环中的三甲胺-N-氧化物(TMAO)水平升高，这是一种来自肠道的代谢物，已 已被证明推动动脉粥样硬化性心脏病的发展。然而，Hau和Hau之间的关系- 诱导的肠道代谢失调及其代谢产物对血管和心血管功能的影响尚不清楚。我们假设 HAU诱导的肠道生物失调导致内皮功能障碍，并通过肠道增加心血管疾病的风险。 衍生代谢物(即TMAO)。此外，我们认为Hau诱导的肠道生物失调会加剧 心力衰竭进展和肠道微生物区系靶向治疗(MBTT)将恢复血管 从而改善HAU环境下的简历健康状况。通过利用Hau小鼠模型 和微生物区系的采用转移，我们计划进行一系列研究，证明Hau诱导的生物失调 和心血管相关的病理是相关的；此外，非生物微生物群足以引起血管 功能障碍和心血管疾病风险增加。我们计划利用元基因组学、代谢组学和心血管 功能评估，以证明HAU、肠道微生物群和CVD之间的因果关系。我们 然后将在一种小鼠模型中研究先前的Hau肠道生物失调对心力衰竭进展的影响 心肌缺血再灌注(MI/R)。这将回答有关个人易感性的问题 在MI/R诱导的心力衰竭后，谁参与了HAU以及他们的心血管结局恶化的风险。同时， 我们将检查MI/R诱导的心力衰竭前后持续的HAU，以了解HAU是否会导致 在存在心血管疾病的情况下增加发病率或死亡率。成功完成这些研究将极大地 加深对酒精性肠道菌群失调的发病机制及其对血管和血液系统影响的认识 心脏功能。

PROJECT SUMMARY Hazardous alcohol use (HAU) leads to tremendous morbidity and mortality in millions of individuals in the United States and worldwide annually. The cognitive, neuronal, and psycho-social aspects of alcohol use have been well established. More recently, clinical, and basic research has begun to understand the role in which HAU contributes to gut dysbiosis, which plays a significant role in one’s overall health status. Furthermore, a large portion of deaths associated with alcohol use are related to digestive diseases. HAU predisposes and contributes to the manifestation of several comorbidities, like hypertension, metabolic syndrome, and diabetes mellitus which drive and exacerbate vascular dysfunction and cardiovascular disease (CVD). Previous research has demonstrated that the gut microbiome too plays a critical role in the diagnosis and prognosis of individuals with established CVD. Increased levels of circulating trimethylamine-N-oxide (TMAO), a gut derived metabolite, has been shown to drive the development of atherosclerotic heart disease. However, the relationship between HAU- induced gut dysbiosis and its’ metabolites towards vascular and CV function is not well-defined. We hypothesize that HAU-induced gut dysbiosis leads to endothelial dysfunction and increased risk of CVD via gut- derived metabolites (i.e., TMAO). Furthermore, we believe that HAU-induced gut dysbiosis exacerbates the progression of heart failure and that gut microbiota-targeted therapies (MBTT) will restore vascular function thereby improving CV health in the setting of HAU. Through utilization of mouse models of HAU and microbiota adoptive transfer we plan to execute a series of studies that demonstrate HAU-induced dysbiosis and CV-related pathology are related; moreover, that the dysbiotic microbiome is sufficient to cause the vascular dysfunction and increased risk of CVD. We plan to utilize metagenomics, metabolomics, and cardiovascular function assessment to demonstrate the causal relationship between HAU, the gut microbiome and CVD. We will then investigate the effects of prior HAU gut dysbiosis on the progression of heart failure in a murine model of myocardial ischemia-reperfusion (MI/R). This will answer questions regarding the predisposition of individuals who participate in HAU and their risk for worsening CV outcomes after MI/R-induced heart failure. Concurrently, we will examine continuous HAU prior to and after MI/R-induced heart failure to understand if HAU leads to increase morbidity or mortality in the presence of CVD. Successful completion of these studies will significantly advance our understanding of the pathology of alcohol-induced gut dysbiosis and its’ effects on vascular and cardiac function.