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

项目摘要/摘要 肠道微生物群是一种动态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，健康的肠道微生物群可以 转化为功能障碍状态促进了几种非传染性慢性疾病的发生和发展 疾病，包括动脉粥样硬化。一个核心的悬而未决的问题是，它是否以及如何可能 改造活人或动物体内失调的肠道微生物群以治疗或预防疾病的可能性 进步。我们现在表明，这确实是可以实现的。以我们最新的发现和进展为基础 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，帮助识别和验证生物 肠道微生物群失衡导致慢性炎症和疾病进展的机制 动脉硬化。 我们提供了初步结果数据，第一次表明，功能失调的肠道微生物群可以诱导 通过西方饮食(WD)可以在体外和体内选择性地重塑，以防止发展 动脉硬化。我们揭示了从一个新的EN中选择的自组装八个残基的环D，L-a-肽 MASSE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 体内WD诱导的肠道微生物群功能障碍，以防止LDLR-/-小鼠动脉粥样硬化的发展。 每日口服两种铅多肽10周后肠道微生物组的定向重塑 小鼠在宿主体内引起了各种有益的生物效应，包括显著降低了血浆总含量 胆固醇水平和动脉粥样硬化斑块，微生物区系和宿主的广泛重新编程 转录本，增加的肠道Helios+Treg免疫细胞群，抑制了a 促炎细胞因子(包括IL-6、TNF-a和IL-1b)的数量，改善肠道屏障的完整性，以及 重新平衡与疾病相关的代谢物水平，如短链脂肪酸(SCFA)和胆汁酸。 在这些进展的基础上，拟议的研究试图改进和开发我们的体外方法 针对肠道微生物群体进行化合物筛选，以确定可以选择性地 在不显著降低物种多样性/丰富度的情况下，调整整个微生物组的组成。 对筛查工作的补充是在动物模型中进行的一系列机制研究。 动脉硬化。微生物元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。我们的 研究计划的重点是描述和操纵整个微生物组，而这种方法 可以提供新的工具和方法来探索宿主/微生物组的相互作用，询问特定的 机械性问题，以及确定新的途径和治疗靶点。

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.