Biological signatures of blueberry derived microbial metabolites

蓝莓来源的微生物代谢物的生物特征

• 批准号: 10229449
• 负责人: Anandh Babu Pon Velayutham
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229449
• 关键词: Anthocyanins; Attenuated; Bacteria; Berry; Bifidobacterium; Biological; Biological Availability; Blood Vessels; Blueberries; Cardiovascular Diseases; Data; Dependence; Development; Diabetic mouse; Dietary Component; Dietary intake; Dose; Dyslipidemias; Endothelial Cells; Endothelium; Epidemic; Family; Flavonoids; Fruit; Functional disorder; Germ-Free; Glycocalyx; Glycosaminoglycans; Goals; Growth; Health; Heparan Sulfate Proteoglycan; High Fat Diet; Human; Hyperglycemia; Hypertension; Ii-Key; Individual; Inflammation; Inflammatory; Intake; Link; Mediating; Medical Care Costs; Metabolic Diseases; Metabolic syndrome; Metagenomics; Methods; Microbe; Modeling; Molecular; Molecular Target; Mus; Nitric Oxide; Nutritional; Organism; Palmitates; Pathway interactions; Permeability; Physiological; Plasma; Play; Population; Production; Public Health; Research; Role; Serum; Side; Stimulus; Supplementation; Surface; Techniques; Time; Tissues; Ursidae Family; Vascular Diseases; Vascular Endothelium; Vasodilation; Work; atherogenesis; base; blood pressure reduction; cardiovascular risk factor; cost; cost effective; cytokine; db/db mouse; diabetic; diabetic patient; dietary; endothelial dysfunction; gut bacteria; gut microbiome; gut microbiota; heparin proteoglycan; improved; innovation; men; metabolomics; microbial; microbiota; mortality; multiple omics; novel; novel strategies; preservation; pressure; prevent; proteoglycan core protein; restoration; traditional therapy; transcriptome sequencing; vascular inflammation

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.

项目概要/摘要 本研究的目的是确定蓝莓衍生微生物的分子机制 代谢产物可改善代谢综合征 (MetS) 期间的内皮功能障碍。我们将采用多组学 确定蓝莓代谢物血管效应的方法。 MetS 是一个重要的危险因素 心血管死亡率和内皮功能障碍在血管疾病的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有助于内皮细胞 MetS 功能障碍。血管内皮覆盖有由蛋白聚糖组成的糖萼 [具有糖胺聚糖（GAG）的核心蛋白]。健康脉管系统的完整糖萼起到保护作用 屏障并防止内皮功能障碍。糖萼，重要的是硫酸乙酰肝素蛋白多糖 (HSPG)，是 MetS 严重受损。因此，保存和恢复 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。花青素被人类肠道微生物群广泛代谢，这表明 它们对血管的益处可能是由微生物代谢产物介导的。肠道微生物代谢花青素 和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 初步数据表明：(i) 蓝莓补充剂可改善血管炎症和功能障碍，以及 增加糖尿病小鼠的有益细菌； (ii) 蓝莓的关键代谢物可减弱棕榈酸诱导的 内皮炎症和血管功能障碍，并增加内皮细胞 (EC) 中 GAG 的产生 与糖尿病患者隔离。然而，缺乏研究来确定（i）微生物代谢物 蓝莓（目标 1），(ii) 蓝莓来源的微生物代谢物改善内皮细胞的机制 MetS 功能障碍（目标 2），以及 (iii) 负责血管效应的最活跃代谢物 蓝莓（目标 3）。根据我们的初步研究，我们假设蓝莓会减弱内皮细胞 通过改善 HSPG 和/或作用于通过微生物介导的多个靶标来改善 MetS 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 使用两种已建立的模型（糖尿病 db/db 小鼠和高脂小鼠）研究 MetS 小鼠的炎症和功能障碍 饮食（HFD）喂养的小鼠]。目标 1B：鉴定蓝莓来源的“微生物代谢物”。 (2) 目标 2：确定 蓝莓来源的微生物代谢物改善 MetS 内皮功能障碍的机制。 (3) 目标 3A：确定循环代谢物对内皮功能障碍的影响。瞄准3B。确定最活跃的 微生物代谢产物。我们将使用生理相关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、组织水平和有机体水平的机制作用。 我们的研究将为建议膳食摄入蓝莓以改善健康状况提供强有力的科学依据。 美国人口和全世界的血管健康。

项目成果

Breaking bugs: gut microbes metabolize dietary components and modulate vascular health.

• DOI: 10.1080/10408398.2023.2251616
• 发表时间: 2023-08
• 期刊: Critical reviews in food science and nutrition
• 影响因子: 10.2
• 作者: Adhini Kuppuswamy Satheesh Babu;Harini Srinivasan;Pon Velayutham Anandh Babu

Scientific Evidence for the Beneficial Effects of Dietary Blueberries on Gut Health: A Systematic Review.

• DOI: 10.1002/mnfr.202300096
• 发表时间: 2023-07
• 期刊: Molecular nutrition & food research
• 影响因子: 5.2
• 作者: C. M. Della Lucia;L. Oliveira;K. A. Dias;S. Pereira;Aline Rosignoli da Conceição;Pon Velayutham Anandh Babu

Microbial taxonomic and functional shifts in adolescents with type 1 diabetes are associated with clinical and dietary factors.

• DOI: 10.1016/j.ebiom.2023.104641
• 发表时间: 2023-07
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Mokhtari, Pari;Jambal, Puujee;Metos, Julie M.;Shankar, Kartik;Babu, Pon Velayutham Anandh
• 通讯作者: Babu, Pon Velayutham Anandh

Methods to Analyze the Effect of Diet-Derived Metabolites on Endothelial Inflammation and Cell Surface Glycosaminoglycans.

• DOI: 10.1007/978-1-0716-1398-6_37
• 发表时间: 2022-01-01
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Cutler, Brett Ronald;Chua, Jie Shi;Anandh Babu, Pon Velayutham
• 通讯作者: Anandh Babu, Pon Velayutham

Dose and Time Dependent Effect of Dietary Blueberries on Diabetic Vasculature is Associated with Gut Microbes.

膳食蓝莓对糖尿病脉管系统的剂量和时间依赖性影响与肠道微生物有关。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: SatheeshBabu,AdhiniKuppuswamy;Petersen,Chrissa;Wankhade,Umesh;Paz,Henry;Benedict,Kai;Nguyen,Miley;Putich,Madison;Saldivar-Gonzalez,Miguel;Larsen,Sydney;PonVelayutham,AnandhBabu
• 通讯作者: PonVelayutham,AnandhBabu