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

最近的人体研究报告了肠道微生物区系及其代谢物与 动脉粥样硬化性疾病的发展和不良心血管事件。然而，批判性知识 必须弥合差距，将这些基础性工作转化为针对肠道微生物区系的具体干预措施 以降低简历风险。这些措施包括1)确定选定的干预措施对 血管内皮细胞功能和动脉粥样硬化形成的介质以及2)确定影响的差异 对肠道菌群存在已知差异(包括性别和肥胖)的关键人群进行选定的干预 状态差异)。这项提案将解决植物乳杆菌299v(Lp299v)补充的这些问题。 我们在20名男性冠心病患者中的初步数据表明，益生菌补充剂 Lp299v对血管内皮细胞有强烈而有利的影响，具有较强的抗炎作用 炎性细胞在内皮功能障碍和动脉粥样硬化的发展中起关键作用。我们的 初步数据显示，肥胖的冠心病患者获益最大，但是否对 Lp299v补充剂在女性或患有冠心病的肥胖者中存在系统性差异，目前尚不清楚 将是AIMS 1和AIMS 2的焦点。我们的初步数据还显示，内皮依赖性血管扩张得到改善 全身性炎症的减少伴随着循环中浓度的变化 短链脂肪酸(SCFAs)-已知的肠道微生物区系的全身性代谢产物。在动物模型中， 单链脂肪酸通过激活G蛋白偶联受体41(FFAR3)引起内皮依赖性血管扩张。 目前尚不清楚这一新机制是否与患有CAD的人类相关。我们的初步数据显示 补充Lp299v可增加循环中的丙酸，这是一种三碳的SCFA。此外，邮寄- 补充血浆逆转大鼠阻力动脉内皮依赖性血管扩张功能受损 冠心病患者eNOS和FFAR3依赖。FFAR3‘S在内皮依赖中的作用 Lp299v的血管扩张反应是目标2的焦点。在目标3，我们将测试Lp299v 补充剂减少人类单个核细胞中已知的促炎信号 动脉粥样硬化的形成和疾病的活动性，以及FFAR3活性是否参与了这一效应。这个 应用程序采用了翻译调查的创新组合。我们结合了一项随机临床试验来 应用危重患者肱动脉超声研究Lp299v对血管功能的性别和BMI特异性影响 靶向FFAR3在完整血管和血管中表达和活性的分子和药理学研究 单个核细胞。此外，我们将采用创新的等离子体诱导转录研究和途径 补充剂对人单核细胞全基因组转录影响的分析 细胞[淋巴细胞(T细胞、B细胞和NK细胞)和单核细胞]，以确定Lp299v如何影响Key 参与人类血管炎症、动脉粥样硬化形成和斑块稳定性的调节通路。

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.