Impact of the gut microbiome on response to lipid lowering therapy

项目摘要 尽管提供了循证策略，如大剂量他汀类药物，但心血管疾病(CVD) 仍然是世界范围内的主要死亡原因。他汀类药物有效降低血浆低密度脂蛋白 胆固醇(LDL-C)浓度和预防心血管事件；然而，有大量的 对他汀类药物的可变性和反应不足。此外，易感人群继续经历 即使在积极的他汀类药物治疗期间也会发生心脏事件，称为残余风险。因此，我们需要 提高我们对他汀类药物药理可变性的因素的理解。 了解药物治疗的可变性和解决残留风险的最佳策略将 加强我们在降低与心血管疾病相关的发病率和死亡率方面的努力。越来越多的证据表明 肠道微生物区系影响心血管疾病的发展，宿主的血脂水平，外来生物的代谢，以及 已被证明是药物可变性的一个促成因素。重要的是，目前尚不清楚肠道微生物群 影响他汀类药物的疗效。这项建议的目标是了解 利用16S rRNA测序在肠道微生物群和宿主药物对他汀类药物治疗的反应之间， 元基因组测序和胆汁酸代谢组学，以及为申请者提供以患者为导向的 有指导的培训计划，以获得元基因组学和代谢组学数据解释和 分析。在目标1中，将对90名健康受试者进行安慰剂对照干预研究，以 确定瑞舒伐他汀是否影响肠道微生物区系组成。治疗前后的大便标本 将通过16S rRNA和元基因组测序进行分析。在目标2中，肠源性胆汁的贡献 酸性代谢产物和成纤维细胞生长因子-19对瑞舒伐他汀降低密度脂蛋白的作用 下定决心。粪便样本将通过目标代谢组学分析进行分析。职业发展和 概述了申请者的培训计划，包括元基因组学和代谢组学方法学方面的培训 完成这个项目所需的。宾夕法尼亚大学是世界级的研究机构，也是 这是进行培训和研究的绝佳环境。这一建议具有创新性和独特性，因为它结合了 药物诱导的元基因组学和代谢组学特征与药物反应的人体模型。更好的 了解肠道微生物群与宿主药物对他汀类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，识别 对治疗的反应不佳，并通知开发新的治疗方法，以针对 心血管疾病。最重要的是，这项研究和培训将为申请者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点，将改善心血管疾病患者的预后。

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.