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: 10412366
• 负责人: Thomas E. Sharp
• 金额: $ 42.96万
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412366
• 关键词: Adoptive Transfer; Alcohol abuse; Alcohol consumption; Alcohols; American; 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; Lead; Link; Liver; Measurement; Meat; Mediating; Metabolic syndrome; Metagenomics; Mixed Function Oxygenases; Modeling; Morbidity - disease rate; Mus; Myocardial Ischemia; Neurons; Nitric Oxide; Outcome; Oxides; 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; cardiogenesis; 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.

项目摘要 危险饮酒（HAU）导致曼联数百万个人的巨大发病率和死亡率 国家和全球每年。酒精使用的认知，神经元和心理社会方面已经 良好。最近，临床和基础研究已经开始了解HAU的作用 有助于肠道营养不良，这在一个人的整体健康状况中起着重要作用。此外，一个大 与饮酒有关的部分死亡与消化疾病有关。 hau倾向于和贡献 表现出几种合并症，例如高血压，代谢综合征和糖尿病 驱动和恶化的血管功能障碍和心血管疾病（CVD）。先前的研究已有 证明肠道微生物组在 建立的CVD。循环三甲胺-N-氧化物（TMAO）的水平增加，一种肠道衍生的代谢产物，具有 我们被证明可以推动动脉粥样硬化心脏病的发展。但是，hau-之间的关系 诱导的肠道营养不良及其对血管和简历功能的代谢物的定义不明确。我们假设 Hau诱导的肠道营养不良导致内皮功能障碍，并通过肠道造成CVD的风险增加 衍生的代谢产物（即tmao）。此外，我们认为Hau引起的肠道营养不良加剧了 心力衰竭的进展和肠道菌群靶向疗法（MBTT）将恢复血管 功能，从而在HAU的情况下改善了简历健康。通过利用hau的鼠标模型 和微生物群自适应转移我们计划执行一系列研究，以证明HAU诱导的营养不良 与CV相关的病理学相关；此外，不植物微生物组足以引起血管 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，肠道微生物组和CVD之间的因果关系。我们 然后将研究先前的肠肠癌对鼠模型中心力衰竭进展的影响 心肌缺血 - 重新灌注（MI/R）。这将回答有关个人倾向的问题 参加HAU的人及其在MI/R引起的心力衰竭后担心CV结果的风险。同时 我们将在MI/R诱导心力失败之前和之后检查连续的HAU，以了解Hau是否导致 在CVD存在下增加发病率或死亡率。这些研究成功完成将大大完成 促进我们对酒精引起的肠道营养不良的病理及其对血管和血管的影响 心脏功能。