Toward Personalized Therapeutics: Directed Remodeling of the Gut Microbiome to Treat Atherosclerosis

走向个性化治疗：定向重塑肠道微生物组来治疗动脉粥样硬化

• 批准号: 10600843
• 负责人: M. Reza Ghadiri
• 金额: $ 74.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-22 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600843
• 关键词: Algorithms; Animal Model; Animals; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Bile Acids; Bioinformatics; Biological; Biological Markers; Biology; Blood specimen; Cardiovascular Diseases; Categories; Cells; Chemical Agents; Chemicals; Cholesterol; Chronic; Chronic Disease; Complex; Control Animal; Data; Development; Disease; Disease Progression; Disease model; Eligibility Determination; Gene Expression; Generations; Goals; Growth; Health; Human; Immune; In Vitro; Inflammation; Inflammatory; Interdisciplinary Study; Interleukin-6; Intervention; Intestines; Lead; Maintenance; Maps; Mediating; Metagenomics; Methods; Modeling; Mus; Oral; Oral Administration; Outcome; Pathway interactions; Peptide Library; Peptides; Periodicity; Phenotype; Plasma; Population; Production; Regulatory T-Lymphocyte; Research; Series; TNF gene; Therapeutic; Time; Tissue Sample; Volatile Fatty Acids; bioinformatics tool; catalyst; chemokine; comparative; cytokine; design; efficacy study; gene network; gut bacteria; gut microbiome; host-microbe interactions; improved; in vivo; microbial; microbial community; microbiome; microbiome composition; microbiota; mouse model; novel; novel strategies; novel therapeutics; personalized therapeutic; prevent; programs; reconstruction; screening; sedentary lifestyle; self assembly; small molecule libraries; systemic inflammatory response; therapeutic target; tool; transcriptome; transcriptomics; translation to humans; western diet

PROJECT SUMMARY/ABSTRACT Gut microbiome is a dynamic and malleable microbial community vital to the maintenance of human and animal health. However, under the influence of a calorically rich Western-type diet, a healthy gut microbiome can transform into a dysfunctional state promoting the onset and progression of several non-communicable chronic diseases, including atherosclerosis. A central unresolved question had been whether and how it might be possible to remodel a dysfunctional gut microbiome within a living human or animal to treat or prevent disease progression. We now show that this indeed can be achieved. Building on our recent discoveries and advances highlighted here, the proposed multidisciplinary research program is aimed at developing novel chemical agents, advanced screening methods, and predictive bioinformatic tools to help identify and validate the biological mechanisms driven by an imbalanced gut microbiome that fuel chronic inflammation and progression of atherosclerosis. We provide Preliminary Results data to show, for the first time, that a dysfunctional gut microbiome induced by a Western diet (WD) can be selectively remodeled in vitro and in vivo to prevent the development of atherosclerosis. We disclose that self-assembling eight-residue cyclic D,L-a-peptides selected from a novel en masse in vitro screening protocol can function as bacterial growth modulators and in a targeted manner remodel a WD-induced dysfunctional gut microbiome in vivo to prevent development of atherosclerosis in LDLr-/- mice. Directed remodeling of the gut microbiome following 10-week daily oral administration of two lead peptides to mice caused diverse and beneficial biological effects in the host, including marked reductions in plasma total cholesterol levels and atherosclerotic plaques, extensive reprogramming of the microbiota and host transcriptomes, increased populations of intestinal Helios+ Treg immune cells, suppressed the production of a number of pro-inflammatory cytokines (including IL-6, TNF-a, and IL-1b), improved gut barrier integrity, and rebalanced levels of disease-relevant metabolites, such as short-chain fatty acids (SCFAs) and bile acids. Building on these advances, the proposed studies seek to improve and exploit our in vitro method for compound screening against gut microbial populations as a whole to identify molecules that can selectively modulate the overall microbiome composition without significantly reducing species diversity/richness. Complementary to the screening efforts are a host of mechanistic studies carried out in animal models of atherosclerosis. Comparative analyses of the microbial metagenomics and host transcriptomics for treated vs. control animals would provide data for developing improved compound scoring and categorization tools. Our research program focuses on characterizing and manipulating the microbiome in its entirety, and this approach could provide new tools and methods for exploring host/microbiome interactions, interrogating specific mechanistic questions, and identifying novel pathways and therapeutic targets.

项目总结/摘要 肠道微生物组是一个动态的和可塑性的微生物群落，对维持人类和 动物健康然而，在热量丰富的西式饮食的影响下，健康的肠道微生物组可以 转变为功能失调状态，促进几种非传染性慢性 疾病，包括动脉粥样硬化。一个尚未解决的核心问题是， 可以重塑活的人或动物体内的功能失调的肠道微生物组以治疗或预防疾病 进展我们现在表明，这确实可以实现。基于我们最近的发现和进展 这里强调的是，拟议的多学科研究计划旨在开发新型化学制剂， 先进的筛选方法和预测性生物信息学工具，以帮助识别和验证生物 由不平衡的肠道微生物组驱动的机制，这些微生物组助长慢性炎症和 动脉粥样硬化 我们提供的初步结果数据首次表明，功能失调的肠道微生物组诱导了 通过西方饮食（WD）可以在体外和体内选择性地重塑，以防止 动脉粥样硬化我们公开了自组装的八残基环状D，L-a-肽，其选自新的环D，L-a-肽， 体外筛选方案可以作为细菌生长调节剂并以靶向的方式重塑 WD诱导的体内肠道微生物组功能失调，以预防LDLr-/-小鼠中动脉粥样硬化的发展。 在10周每日口服施用两种先导肽以 小鼠在宿主中引起多种有益的生物学效应，包括血浆总 胆固醇水平和动脉粥样硬化斑块，微生物群和宿主的广泛重编程 转录组，增加肠道Helios+ Treg免疫细胞的数量，抑制了 大量促炎细胞因子（包括IL-6、TNF-α和IL-1b），改善肠道屏障完整性，以及 重新平衡疾病相关代谢物的水平，如短链脂肪酸（SCFA）和胆汁酸。 在这些进展的基础上，提出的研究试图改进和利用我们的体外方法， 针对肠道微生物群体作为一个整体进行化合物筛选，以鉴定可以选择性地 调节整体微生物组组成，而不显著降低物种多样性/丰富度。 作为筛选工作的补充，在动物模型中进行了大量的机制研究， 动脉粥样硬化处理与对照的微生物宏基因组学和宿主转录组学的比较分析。 对照动物将为开发改进的化合物评分和分类工具提供数据。我们 研究计划的重点是表征和操纵整个微生物组，这种方法 可以为探索宿主/微生物组相互作用提供新的工具和方法， 机制问题，并确定新的途径和治疗靶点。