Impact of L. plantarum 299v Supplementation on Endothelial Function and Systemic Inflammation

补充植物乳杆菌 299v 对内皮功能和全身炎症的影响

• 批准号: 10339353
• 负责人: Michael E Widlansky
• 金额: $ 75.18万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-22 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339353
• 关键词: Address; Animal Model; Antiinflammatory Effect; Arterial Fatty Streak; Atherosclerosis; B-Lymphocytes; Biological Availability; Blood Vessels; Body mass index; Carbon; Cardiovascular system; Cells; Controlled Clinical Trials; Coronary Arteriosclerosis; Coronary artery; Data; Dependence; Development; Disease; Double-Blind Method; Endothelium; Event; FFAR3 gene; Foundations; Genetic Transcription; Grant; Human; Human Activities; Impairment; Inflammation; Inflammatory; Intervention; Investigation; Knowledge; Lactobacillus plantarum; Lymphocyte; Measures; Mediating; Mediator of activation protein; Metabolic; Molecular; Mononuclear; Myocardial Infarction; Natural Killer Cells; Nitric Oxide; Non obese; Obesity; Oral; Pathway Analysis; Patients; Pharmacology Study; Placebo Control; Plasma; Population; Propionates; Protocols documentation; Randomized; Randomized Clinical Trials; Recommendation; Regulatory Pathway; Reporting; Resistance; Role; Sampling; Signal Transduction; Stroke; Supplementation; T-Lymphocyte; Testing; Translating; Vascular Endothelium; Vasodilation; Volatile Fatty Acids; Woman; Work; brachial artery; cardiogenesis; cardiovascular health; cardiovascular risk factor; endothelial dysfunction; gut microbiome; gut microbiota; improved; in vivo; innovation; men; monocyte; novel; personalized therapeutic; probiotic supplementation; receptor; response; sex; systemic inflammatory response; ultrasound; vascular inflammation; whole genome

Recent human studies report an emerging relationship between the gut microbiota and its metabolites with the development of atherosclerotic disease and adverse cardiovascular (CV) events. However, critical knowledge gaps must be bridged to translate these foundational works into specific, gut microbiota-targeted interventions to reduce CV risk. These include 1) identifying mechanisms by which a selected intervention impacts the vascular endothelial function and mediators of atheroma formation and 2) identifying differences in the impact of a selected intervention on key populations with known differences in gut flora (including sex and obesity status differences). This proposal will address these issues for L. plantarum 299v (Lp299v) supplementation. Our preliminary data in 20 men with coronary artery disease (CAD) suggest that probiotic supplementation with Lp299v has a strong and favorable impact on the vascular endothelium and a strong anti-inflammatory effect on inflammatory cells critical to the development of endothelial dysfunction and atherosclerosis. Our preliminary data suggest obese CAD patients derive the greatest benefit, but whether the favorable impact of Lp299v supplementation systematically differs in women or in obese humans with CAD remains unknown and will be the foci of Aims 1 and 2. Our preliminary data also show improved endothelium dependent vasodilation and reduced systemic inflammation occur concomitantly with changes in the concentrations of circulating short-chain fatty acid (SCFAs)– known systemic metabolic products of the gut microbiota. In animal models, SCFAs cause endothelium-dependent vasodilation by activating G protein-coupled receptor 41 (FFAR3). Whether this novel mechanism is relevant in humans with CAD remains unknown. Our preliminary data shows Lp299v supplementation increases circulating propionate, a three-carbon SCFA. Additionally, post- supplementation plasma reversed impaired endothelium-dependent vasodilation in resistance arteries from CAD patients in an eNOS- and FFAR3-dependent manner. FFAR3's role in endothelium-dependent vasodilation responses to Lp299v is a focus of in Aim 2. In Aim 3, we will test whether Lp299v supplementation reduces pro-inflammatory signaling in human mononuclear cells known to contribute to atherosclerosis formation and disease activity and whether FFAR3 activity is involved in this effect. The application employs an innovative mix of translational investigations. We combine a randomized clinical trial to study sex- and BMI-specific effects of Lp299v on vascular function using brachial artery ultrasound with critical molecular and pharmacological studies targeting FFAR3 expression and activity in intact human vessels and mononuclear cells. Additionally, we will employ innovative plasma-induced transcription studies and pathway analyses to determine the impact of supplementation on whole genome transcription in human mononuclear cells [lymphocytes (T-cell, B-cell, and NK cells) and monocytes] to determine how Lp299v impacts key regulatory pathways involved in human vascular inflammation, atheroma formation, and plaque stability.

最近的人类研究报告了肠道微生物群及其代谢物与肠道微生物群之间的新关系。 发生动脉粥样硬化疾病和不良心血管（CV）事件。然而，批判性知识 必须弥合差距，将这些基础工作转化为针对肠道微生物的具体干预措施 降低CV风险。这些措施包括：（1）确定选定的干预措施影响 血管内皮功能和动脉粥样硬化形成的介质和2）确定影响的差异 对已知肠道植物群差异（包括性别和肥胖）的关键人群进行选定干预 地位差异）。该提案将解决L. plantarum 299 v（Lp 299 v）补充。 我们在20名冠心病患者中的初步数据表明， Lp 299 v对血管内皮有较强的有利影响，具有较强的抗炎作用 对内皮功能障碍和动脉粥样硬化的发展至关重要的炎症细胞。我们 初步数据表明，肥胖的CAD患者获得最大的好处，但是否有利的影响， Lp 299 v补充剂在患有CAD的女性或肥胖人群中的系统性差异仍然未知， 将是目标1和2的重点。我们的初步数据还显示， 和减少的全身炎症伴随着循环中的 短链脂肪酸（SCFAs）-肠道微生物群的已知全身代谢产物。在动物模型中， SCFA通过激活G蛋白偶联受体41（FFAR 3）引起内皮依赖性血管舒张。 这种新的机制是否与CAD患者相关仍不清楚。我们的初步数据显示 补充Lp 299 v增加循环丙酸盐，一种三碳SCFA。此外，后 补充血浆逆转了来自动脉粥样硬化性心脏病患者的阻力动脉中受损的内皮依赖性血管舒张 CAD患者中eNOS和FFAR 3依赖的方式。FFAR 3在内皮依赖性 对Lp 299 v的血管舒张反应是目的2的焦点。在目标3中，我们将测试Lp 299 v是否 补充剂可减少已知有助于促进炎症的人类单核细胞中的促炎信号传导 动脉粥样硬化形成和疾病活动以及FFAR 3活性是否参与这种作用。的 应用程序采用了翻译研究的创新组合。我们将联合收割机与一项随机临床试验相结合， 使用肱动脉超声研究Lp 299 v对血管功能的性别和BMI特异性影响， 靶向完整人血管中FFAR 3表达和活性的分子和药理学研究， 单核细胞此外，我们将采用创新的等离子体诱导的转录研究和途径， 分析以确定补充剂对人单核细胞中全基因组转录的影响 细胞[淋巴细胞（T细胞，B细胞和NK细胞）和单核细胞]，以确定Lp 299 v如何影响关键 参与人血管炎症、动脉粥样硬化形成和斑块稳定性的调节途径。