Alcohol-induced Gut Dysbiosis and Cardiovascular Disease

酒精引起的肠道菌群失调和心血管疾病

• 批准号: 10616789
• 负责人: Thomas E. Sharp
• 金额: --
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2023-06-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10616789
• 关键词: Adoptive Transfer; Alcohol abuse; Alcohol consumption; Alcohols; American; Atherosclerosis; Attenuated; Basic Science; Biochemical; Biological Availability; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Carnitine; Cessation of life; Choline; Chronic; Clinical Research; Cognitive; Coronary heart disease; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Digestive System Disorders; Disease; Disease Progression; FMO3; Fishes; Flavins; Functional disorder; Goals; Health; Health Care Costs; Health Status; Heart; Heart failure; Hepatic; Homeostasis; Hour; Hypertension; Individual; Inflammation; Intestinal permeability; Link; Liver; Measurement; Meat; Mediating; Metabolic syndrome; Metagenomics; Mixed Function Oxygenases; Modeling; Morbidity - disease rate; Mus; Myocardial Ischemia; Neurons; Nitric Oxide; Outcome; Pathology; Patients; Physiological; Play; Predisposition; Production; Prognosis; Reperfusion Therapy; Research; Risk; Role; Series; Severities; Severity of illness; Techniques; Therapeutic; Thrombus; Treatment Efficacy; United States; Vascular Diseases; alcohol effect; alcohol use disorder; cardiovascular disorder risk; cardiovascular health; chronic alcohol ingestion; comorbidity; cost; dietary; dysbiosis; egg; endothelial dysfunction; gut dysbiosis; gut microbiome; gut microbiota; heart function; improved; inflammatory milieu; inhibitor; insight; metabolome; metabolomics; microbiome; microbiota; mortality; mouse model; myocardial infarct sizing; novel; novel therapeutic intervention; oxidation; prognostic indicator; psychosocial; sex; targeted treatment; trimethylamine; trimethyloxamine

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.

项目概要 有害酒精使用 (HAU) 导致美国数百万人发病率和死亡率极高 每年各州和全球。饮酒对认知、神经和心理社会方面的影响已被研究 建立良好。最近，临床和基础研究已经开始了解 HAU 在其中的作用 导致肠道菌群失调，这对一个人的整体健康状况起着重要作用。此外，一个大 与饮酒相关的部分死亡与消化系统疾病有关。 HAU 促成并贡献 多种合并症的表现，如高血压、代谢综合征和糖尿病， 驱动并加剧血管功能障碍和心血管疾病（CVD）。先前的研究有 表明肠道微生物组在患有此类疾病的个体的诊断和预后中也发挥着关键作用 建立了CVD。循环三甲胺-N-氧化物（TMAO）（一种肠道来源的代谢物）水平升高， 已被证明可促进动脉粥样硬化性心脏病的发展。然而，HAU-之间的关系 引起的肠道菌群失调及其对血管和心血管功能的代谢物尚不明确。我们假设 HAU 诱导的肠道菌群失调会导致内皮功能障碍，并通过肠道菌群增加 CVD 风险 衍生代谢物（即TMAO）。此外，我们认为 HAU 诱导的肠道菌群失调会加剧 心力衰竭的进展以及肠道微生物群靶向疗法（MBTT）将恢复血管 功能，从而改善 HAU 情况下的 CV 健康状况。通过利用 HAU 小鼠模型 和微生物群过继转移，我们计划进行一系列研究来证明 HAU 引起的菌群失调 与CV相关的病理学相关；此外，失调的微生物群足以引起血管 功能障碍和 CVD 风险增加。我们计划利用宏基因组学、代谢组学和心血管 功能评估以证明 HAU、肠道微生物组与 CVD 之间的因果关系。我们 然后将在小鼠模型中研究先前 HAU 肠道菌群失调对心力衰竭进展的影响 心肌缺血再灌注（MI/R）。这将回答有关个人倾向的问题 参加 HAU 的人以及 MI/R 诱发的心力衰竭后心血管结局恶化的风险。同时， 我们将在 MI/R 诱发的心力衰竭之前和之后检查持续的 HAU，以了解 HAU 是否会导致 CVD 存在时会增加发病率或死亡率。成功完成这些研究将显着 增进我们对酒精引起的肠道菌群失调的病理学及其对血管和肠道菌群的影响的理解 心脏功能。