Biological signatures of blueberry derived microbial metabolites

项目摘要/摘要 这项研究的目标是确定蓝莓衍生微生物 代谢产物改善代谢综合征期间的内皮功能障碍(METS)。我们将采用多元经济学 测定蓝莓代谢物血管效应的方法。甲型肝炎是一个重要的风险因素。 心血管死亡率和内皮功能障碍在血管的发生发展中起着重要作用 并发症。高血糖、血脂异常和促炎细胞因子参与内皮细胞的形成 甲型肝炎患者的功能障碍。血管内皮细胞被一种由蛋白多糖组成的糖萼覆盖。 [含糖胺多聚糖的核心蛋白(GAG)]。健康血管系统完整的糖皮瓣起到保护作用 可防止血管内皮细胞功能障碍。糖萼，重要的是硫酸乙酰肝素蛋白多糖(HSPG)，是 在大都会队严重受损。因此，保存和修复HSPG可改善内皮功能障碍 是一种改善METS血管并发症的新策略。人体研究支持血管效应 蓝莓花青素。人类肠道微生物区系广泛代谢花青素，提示 它们的血管益处可能是通过它们的微生物代谢产物来调节的。肠道微生物区系代谢花青素 花青素支持微生物的生长，表明它们之间存在双向关系。我们的 初步数据显示：(I)补充蓝莓可以改善血管炎症和功能障碍，以及 增加糖尿病小鼠的益生菌；(Ii)蓝莓的关键代谢产物减弱棕榈酸酯诱导的 内皮炎症和血管功能障碍，并增加内皮细胞(ECs)中GAG的产生 从糖尿病患者身上分离出来的。然而，缺乏研究确定(I)微生物代谢物 蓝莓(目标1)，(Ii)蓝莓来源的微生物代谢产物改善内皮细胞的机制 蛋氨酸的功能障碍(目标2)，以及(Iii)导致血管效应的最活跃的代谢物 蓝莓(目标3)。根据我们的初步研究，我们假设蓝莓可以减弱内皮细胞。 通过改善HSPG和/或通过微生物介导的多靶点作用于蛋氨酸的功能障碍 蓝莓的代谢物。(1)目标1A：确定改善血管所需的蓝莓最佳剂量 使用两种已建立的糖尿病db/db小鼠和高脂肪模型的蛋氨酸小鼠的炎症和功能障碍 饮食(HFD)喂养的小鼠]。目的1B：鉴定蓝莓衍生的“微生物代谢产物”。(二)目标二：确定 蓝莓衍生微生物代谢物改善蛋氨酸内皮细胞功能障碍的机制。(3)目标 3A：测定循环代谢产物对内皮功能障碍的影响。目标3B。确定最活跃的 微生物代谢物(S)。我们将使用与生理相关的模型和最先进的技术来评估 蓝莓微生物代谢产物在细胞水平、组织水平和机体水平的作用机理。 我们的研究将为推荐蓝莓的饮食摄入量提供强有力的科学依据 美国人口和世界范围内的血管健康。

PROJECT SUMMARY/ ABSTRACT The goal of this study is to identify the molecular mechanisms by which blueberry-derived microbial metabolites improve endothelial dysfunction during metabolic syndrome (MetS). We will employ multiomics approaches to determine the vascular effects of blueberry metabolites. MetS is an important risk factor for cardiovascular mortality and endothelial dysfunction plays a major role in the development of vascular complications. Hyperglycemia, dyslipidemia, and pro-inflammatory cytokines contribute to endothelial dysfunction in MetS. The vascular endothelium is covered with a glycocalyx which is comprised of proteoglycans [core proteins with glycosaminoglycans (GAG)]. Intact glycocalyx of healthy vasculature acts as a protective barrier and prevents endothelial dysfunction. Glycocalyx, importantly heparan sulfate proteoglycan (HSPG), is severely compromised in MetS. Hence, preservation and restoration of HSPG to improve endothelial dysfunction is a novel strategy to ameliorate vascular complications in MetS. Human studies support the vascular effects of blueberry anthocyanins. Anthocyanins are extensively metabolized by the gut microbiota in humans, suggesting their vascular benefits might be mediated by their microbial metabolites. Gut microbiota metabolize anthocyanins and anthocyanins support the growth of microbes indicating a two-way relationship between them. Our preliminary data show that :(i) blueberry supplementation improves vascular inflammation and dysfunction, and increases the beneficial bacteria in diabetic mice; (ii) key blueberry metabolites attenuate palmitate-induced endothelial inflammation and vascular dysfunction, and increase GAG production in endothelial cells (ECs) isolated from diabetic patients. However, studies are lacking that identify (i) the microbial metabolites of blueberries (Aim 1), (ii) the mechanisms by which blueberry-derived microbial metabolites improve endothelial dysfunction in MetS (Aim 2), and (iii) the most active metabolites responsible for the vascular effects of blueberries (Aim 3). Based on our preliminary studies, we hypothesize that blueberry attenuates endothelial dysfunction in MetS by improving HSPG and/or acting on multiple targets which is mediated through the microbial metabolites of blueberries. (1) Aim 1A: Determine the optimal dose of blueberry required to improve vascular inflammation and dysfunction in mice with MetS using two established models [diabetic db/db mice and high fat diet (HFD)-fed mice]. Aim 1B: Identify blueberry-derived `microbial metabolites'. (2) Aim 2: Determine the mechanisms by which blueberry-derived microbial metabolites improve endothelial dysfunction in MetS. (3) Aim 3A: Determine the impact of circulating metabolites on endothelial dysfunction. Aim 3B. Identify the most active microbial metabolite(s). We will use physiologically relevant models and state of the art techniques to evaluate the mechanistic roles of microbial metabolites of blueberries at the cellular level, tissue level and organism level. Our study will provide strong scientific rationale for recommending dietary intake of blueberries to improve vascular health in the US population and worldwide.