Impact of the gut microbiome on response to lipid lowering therapy

肠道微生物组对降脂治疗反应的影响

• 批准号: 10418776
• 负责人: Sony Tuteja
• 金额: $ 17.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418776
• 关键词: 16S ribosomal RNA sequencing; Acids; Address; Aftercare; Agonist; Animals; Bacteria; Bacterial Genes; Bacterial Genome; Bile Acids; Bioinformatics; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cholesterol; Clinical; Complex; Data; Data Analyses; Development; Dose; Drug Modelings; Drug Targeting; Environment; Enzymes; Event; Exposure to; FGF19 gene; Fibroblast Growth Factor Receptors; Funding; Gene Cluster; Goals; Heart Diseases; Homeostasis; Human; Hydrolase; Individual; Innovative Therapy; Intervention; Intervention Studies; Knowledge; LDL Cholesterol Lipoproteins; Link; Lipids; Low-Density Lipoproteins; Mentors; Metabolism; Metagenomics; Methodology; Methods; Morbidity - disease rate; Nicotinic Acids; Nuclear Receptors; Observational Study; Pathway interactions; Patient-Focused Outcomes; Pennsylvania; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Placebo Control; Placebos; Plasma; Play; Randomized; Research; Research Infrastructure; Research Institute; Research Personnel; Research Training; Residual state; Ribosomal RNA; Risk; Role; Secondary to; Serum; Signal Transduction; Training; Training Programs; Translational Research; United States National Institutes of Health; Universities; Variant; Work; Xenobiotic Metabolism; bile acid metabolism; bile salts; cardiogenesis; career development; clinically relevant; evidence base; experience; gut bacteria; gut microbiome; gut microbiota; healthy volunteer; heart disease risk; host microbiome; human model; human subject; improved; improved outcome; innovation; lipid metabolism; metabolomics; metagenomic sequencing; microbiome; microbiome composition; microbiome research; microbiota; mortality; new technology; new therapeutic target; novel; patient oriented; prevent; receptor; response; response biomarker; rosuvastatin; small molecule; stool sample; treatment response

Project Summary Despite the availability of evidence-based strategies such as high-dose statins, cardiovascular disease (CVD) remains the leading cause of death worldwide. Statins effectively reduce plasma low-density lipoprotein cholesterol (LDL-C) concentrations and prevent cardiovascular events; however, there is a great deal of variability and inadequate response to statins. Additionally, susceptible individuals continue to experience cardiac events even while on aggressive statin therapy, referred to as residual risk. Therefore we need to improve our understanding of the factors contributing to pharmacological variability to statin therapy. Understanding the variability in pharmacologic treatment and the best strategy for addressing residual risk will enhance our efforts in decreasing CVD related morbidity and mortality. Accumulating evidence suggests that intestinal microbiota impacts the development of CVD, host plasma lipid levels, metabolism of xenobiotics, and has shown to be a contributing factor in drug variability. Importantly, is unknown whether the gut microbiome impacts the efficacy of statin medications. The objective of this proposal is to understand the interaction between the gut microbiome and host drug response to statin therapy using 16S rRNA sequencing, metagenomics sequencing and bile acid metabolomics, as well as provide the applicant with a patient-oriented mentored training program to gain expertise in metagenomics and metabolomic data interpretation and analysis. In Aim 1, a placebo-controlled interventional study will be performed in 90 healthy subjects to determine if rosuvastatin impacts the gut microbiota composition. Stool samples at before and after treatment will be analyzed by 16S rRNA and metagenomics sequencing. In Aim 2, the contribution of gut-derived bile acid metabolites and fibroblast growth factor (FGF)-19 to the LDL-C lowering effect of rosuvastatin will be determined. Stool samples will be analyzed by targeted metabolomic analysis. A career development and training plan for the applicant is outlined including training in metagenomics and metabolomics methodology required for completion of this project. The University of Pennsylvania is a world-class research institute and a wonderful environment for this training and research. This proposal is innovative and unique in that it integrates human models of drug-induced metagenomics and metabolomic signatures with drug response. A better understanding of the complex interactions of the gut microbiome with host drug response to statin therapy could advance our understanding of additional factors contributing to the variability of drug response, identify poor responders to treatment and inform the development of novel therapeutics for targeting residual risk in CVD. Most importantly, this research and training will provide the applicant with the means to discover clinically relevant drug response biomarkers and drug targets that will improve outcomes for patients with CVD.

项目摘要 尽管有基于证据的策略，例如高剂量汀类药物，心血管疾病（CVD） 仍然是全球死亡的主要原因。他汀类药物有效减少血浆低密度脂蛋白 胆固醇（LDL-C）浓度并预防心血管事件；但是，有很多 变异性和对他汀类药物的反应不足。此外，易感人士继续经历 心脏事件即使在激进的他汀类药物治疗时也被称为残留风险。因此我们需要 提高我们对导致他汀类药物治疗的药理变异性的因素的理解。 了解药理学治疗的可变性和解决剩余风险的最佳策略将 加强我们在降低CVD相关的发病率和死亡率方面的努力。积累的证据表明 肠道菌群影响CVD的发展，宿主血浆脂质水平，异种生物的代谢和 已证明是药物变异性的促成因素。重要的是，肠道微生物组是否未知 影响他汀类药物的功效。该提议的目的是了解互动 使用16S rRNA测序，肠道微生物组和宿主对他汀类药物疗法的反应， 宏基因组测序和胆汁酸代谢组学，并为申请人提供面向患者的 指导的培训计划，以获得宏基因组学和代谢组数据解释方面的专业知识以及 分析。在AIM 1中，将在90名健康受试者中进行安慰剂控制的介入研究 确定瑞明素是否影响肠道菌群组成。治疗前后的粪便样品 将通过16S rRNA和宏基因组学测序分析。在AIM 2中，肠道来源的胆汁的贡献 酸性代谢物和成纤维细胞生长因子（FGF）-19至LDL-C降低余地素的降低作用将是 决定。粪便样品将通过靶向代谢组分析进行分析。职业发展和 概述了申请人的培训计划，包括宏基因组学和代谢组学方法的培训 完成此项目所需的要求。宾夕法尼亚大学是世界一流的研究所， 这项培训和研究的奇妙环境。该建议具有创新性和独特性，因为它整合了 药物诱导的宏基因组学和代谢组学特征的人类模型具有药物反应。更好 了解肠道微生物组与他汀类药物治疗的宿主药物反应的复杂相互作用 可以促进我们对导致药物反应可变性的其他因素的理解，确定 响应者对治疗的反应人不佳，并为针对靶向残留风险的新型治疗剂提供了信息 CVD。最重要的是，这项研究和培训将为申请人提供临床发现的手段 相关的药物反应生物标志物和药物靶标将改善CVD患者的预后。

项目成果

COVID-19: Understanding Inter-Individual Variability and Implications for Precision Medicine.

• DOI: 10.1016/j.mayocp.2020.11.024
• 发表时间: 2021-03
• 期刊: Mayo Clinic proceedings
• 影响因子: 8.9
• 作者: Pereira NL;Ahmad F;Byku M;Cummins NW;Morris AA;Owens A;Tuteja S;Cresci S
• 通讯作者: Cresci S

Proton-pump inhibitor use is not associated with severe COVID-19-related outcomes: a propensity score-weighted analysis of a national veteran cohort.

• DOI: 10.1136/gutjnl-2021-325701
• 发表时间: 2022-07
• 期刊: GUT
• 影响因子: 24.5
• 作者: Shah, Shailja;Halvorson, Alese;McBay, Brandon;Dorn, Chad;Wilson, Otis;Tuteja, Sony;Chang, Kyong-Mi;Cho, Kelly;Hauger, Richard;Suzuki, Ayako;Hunt, Christine;Siew, Edward;Matheny, Michael;Hung, Adriana;Greevy, Robert;Roumie, Christianne
• 通讯作者: Roumie, Christianne