Elucidating the role of the gut metagenome in hypertension.

阐明肠道宏基因组在高血压中的作用。

• 批准号: 10271244
• 负责人: Fatima L Saravia
• 金额: $ 4.6万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271244
• 关键词: Address; Affect; Albumins; American; Attenuated; Bacteria; Bioinformatics; Biological Markers; Biomedical Research; Blood Pressure; Cardiovascular Diseases; Career Choice; Cause of Death; Consumption; DNA; Dahl Hypertensive Rats; Data; Desulfovibrio; Development; Diagnostic; Dietary Supplementation; Disease; Environment; Exhibits; Family; Family suidae; Future; Generations; Genes; Goals; Growth; Human; Hydrogen Sulfide; Hypertension; Immunology; In Situ; In Vitro; Intake; Laboratories; Lactobacillus helveticus; Latina; Lead; Machine Learning; Measurement; Measures; Metabolic; Microbiology; Milk; Mission; Modeling; Monitor; National Heart, Lung, and Blood Institute; Patients; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Positioning Attribute; Production; Rattus; Recombinant DNA; Research; Resistant Hypertension; Role; Severities; Shotguns; Sodium; Source; Supplementation; Testing; Therapeutic; Training; Wisconsin; Woman; Work; alternative treatment; animal data; base; biomedical scientist; cardiovascular disorder risk; cardiovascular risk factor; clinical biomarkers; deep sequencing; design; experimental study; gut bacteria; gut metagenome; gut microbiome; gut microbiota; hypertension treatment; medical schools; member; metagenomic sequencing; microbial; microbiome; microbiota; modifiable risk; mutant; noninvasive diagnosis; predictive marker; predictive modeling; prevent; programs; prolyl-proline; prolylisoleucine; random forest; renal damage; salt sensitive; salt sensitive hypertension; small molecule; statistics; sulfate reducing bacteria; tool; urinary

Project Summary Cardiovascular disease (CVD) is the leading cause of death world-wide. The primary modifiable risk factor for CVD is hypertension (HTN), which is exacerbated by high sodium intake. One third of Americans are hypertensive, of which half exhibit salt-sensitive HTN. Additionally, 12% of HTN patients do not respond to treatment using standard medications. Taken together, these statistics highlight the critical need to elucidate the mechanisms involved in the development of HTN for the design of alternative treatment options. The gut microbiome has been implicated in many diseases including HTN. This project is designed to identify HTN- exacerbating or protective bacteria and their associated metabolic genes to inform the design of microbiome-based therapeutics for the treatment of HTN. Our preliminary results demonstrate that severe HTN induced by salt consumption correlates with shifts in the gut microbial community of Dahl salt-sensitive (SS) rats. Therefore, we tested the potential for the gut microbiota to affect HTN by performing a fecal material transfer (FMT) from hypertensive Dahl SS into HTN-resistant rats. We demonstrated that the microbiome was sufficient to exacerbate HTN in recipients and corresponded with statistically significant shifts in the gut microbiome. These results lead us to hypothesize that the gut microbiota directly influences HTN. Aim 1 will evaluate the role of bacterial supplementation during onset of HTN in the Dahl SS rat model. Predetermined strains identified from our preliminary experiments will be grown in vitro and transferred into SS Dahl rats and the effect on blood pressure and kidney damage will be evaluated. Potential mechanisms through which the bacteria influence the severity of HTN will be explored by measuring metabolite production, evaluating gut barrier function, and identifying shifts in the gut microbiome. Aim 2 will utilize machine learning to identify specific gut bacteria and metabolic genes that serve as signatures for the severity of HTN. Experiments in this aim will exploit shotgun metagenomic sequencing and computational approaches to identify specific bacteria and metabolic genes associated with HTN. Their use as predictive biomarkers for HTN will be validated by PCR-based analysis. This work will take place in the laboratory of Dr. John Kirby in the Department of Microbiology & Immunology (M&I) at the Medical College of Wisconsin, a highly collaborative and stimulating environment that is well equipped to perform the proposed aims. The Department of M&I offers a state-of-the-art educational program and various opportunities to explore alternative career pathways. We have designed a complementary training plan for my scientific and professional growth that will position me to reach my goal of becoming an independent biomedical scientist. In all, this project is critical for my advancement as a Latina woman in biomedical research, the field of HTN research, and the generation of microbiome-based therapeutics for CVD.

项目摘要 心血管疾病（CVD）是全球范围内的主要死亡原因。主要可改变的风险因素 CVD是高血压（HTN），高钠摄入会加剧高血压。三分之一的美国人 高血压，其中一半表现出盐敏感性HTN。此外，12%的HTN患者对 使用标准药物治疗。总之，这些统计数字突出表明，迫切需要阐明 参与HTN发展的机制，用于设计替代治疗方案。肠道 微生物组与包括HTN在内的许多疾病有关。该项目旨在识别HTN- 加剧或保护细菌及其相关的代谢基因，以告知设计 用于治疗HTN的基于微生物组的疗法。我们的初步结果表明，严重的 盐消耗诱导的HTN与Dahl盐敏感（SS）肠道微生物群落的变化相关 大鼠因此，我们通过执行粪便物质转移来测试肠道微生物群影响HTN的潜力。 (FMT)从高血压Dahl SS到HTN耐药大鼠。我们证明了微生物组足够 加剧接受者的HTN，并与肠道微生物组的统计学显著变化相对应。这些 结果使我们假设肠道微生物群直接影响HTN。 目的1将评估在Dahl SS大鼠模型中HTN发作期间细菌补充的作用。 从我们的初步实验中确定的预定菌株将在体外生长并转移到SS中 将评价Dahl大鼠和对血压和肾损伤的影响。潜在机制， 细菌影响HTN的严重程度将通过测量代谢产物的产生，评估 肠道屏障功能，并确定肠道微生物组的变化。Aim 2将利用机器学习来识别 特定的肠道细菌和代谢基因作为HTN严重程度的标志。实验 在这个目标中，将利用鸟枪宏基因组测序和计算方法来鉴定特定的 与HTN相关的细菌和代谢基因。将验证它们作为HTN的预测生物标志物的用途 基于PCR的分析 这项工作将在微生物学和免疫学系的John Kirby博士的实验室进行 （M&I）在威斯康星州医学院，一个高度协作和刺激的环境，是很好的 具备实现既定目标的能力。M&I部门提供最先进的教育计划 以及探索替代职业道路的各种机会。我们设计了一个补充培训 我的科学和专业发展计划，这将使我能够实现我成为一个独立的目标 生物医学科学家总之，这个项目对我作为一个拉丁裔女性在生物医学研究中的进步至关重要， HTN研究领域，以及基于微生物组的CVD疗法的产生。

项目成果

Dietary influences on the Dahl SS rat gut microbiota and its effects on salt-sensitive hypertension and renal damage.

• DOI: 10.1111/apha.13662
• 发表时间: 2021-08
• 期刊: ACTA PHYSIOLOGICA
• 影响因子: 6.3
• 作者: Abais-Battad, Justine M.;Saravia, Fatima L.;Lund, Hayley;Dasinger, John Henry;Fehrenbach, Daniel J.;Alsheikh, Ammar J.;Zemaj, Jeylan;Kirby, John R.;Mattson, David L.
• 通讯作者: Mattson, David L.