Project 1: Discovery of gut microbiota dependent pathways contributing to cardiovascular disease in type 2 diabetes

摘要 肠道微生物区系在人类健康和疾病过程中的作用日益得到认可。此外， 肠道微生物群现在被认为是一个能产生生物活性的大型内分泌器官。 代谢物，一旦被宿主吸收，往往有专门的受体，并影响生理 过程，和疾病的易感性。在这个项目中，我们研究了特定的肠道微生物区系途径的作用 在心血管疾病(CVD)发病机制中的作用。我们利用非靶向代谢组学作为一项发现 平台，结合细胞和动物模型研究，以确定额外/新的潜在肠道微生物区系- 依赖通路在2型糖尿病中增强，两者都与，并可能与 心血管疾病的贡献者。患有2型糖尿病的受试者发生糖尿病的风险不成比例地增加。 然而，血糖控制的总体水平并不一定与心血管疾病的风险有关。因此，有以下几个 糖尿病糖中心论以外的代谢途径在这一高危人群中导致心血管疾病。 大规模的临床研究被用于将研究注意力集中在候选代谢物上，这些代谢物 循环水平可重复地与不良心血管事件的发生相关，如 在这一高危人群中心脏病发作、中风和死亡。在确认关联之后(并且通常通常 观察候选代谢物预测糖尿病和非糖尿病患者的风险)，我们继续前进 机械论研究旨在确定观察到的关联是否与心血管疾病和代谢有关 通过细胞和动物模型研究与疾病相关的表型。初步的细胞、动物模型和 使用基因工程人类共生体的微生物移植相关研究(得与失 功能突变体)用于询问特定微生物区系衍生代谢物的作用，以及微生物 酶(S)负责它们的产生，在诱导宿主的相关表型方面有所增强 血栓形成的可能性，或动脉粥样硬化的易感性。我们提议的研究承诺发现新的 肠道微生物区系对心血管疾病的作用机制。它们还将有助于提高对 那些有心血管疾病及其不良事件风险的人，否则可能无法识别。他们还将提供 使新发现成为可能，这将促进心血管疾病新疗法的开发。

Abstract The role of gut microbiota in human health and disease processes is increasingly recognized. Moreover, the gut microbiome is now recognized as a large endocrine organ that can generate biologically active metabolites, which upon absorption into the host, often have dedicated receptors, and impact physiological processes, and disease susceptibility. In this Project, we examine the role of specific gut microbiota pathways in cardiovascular disease (CVD) pathogenesis. We have employed untargeted metabolomics as a discovery platform, coupled with cellular and animal model studies, to identify additional/new potential gut microbiota- dependent pathways enhanced in type 2 diabetes mellitus that are both associated with, and potentially a contributor to CVD. Subjects with type 2 diabetes are at a disproportionately increased risk for development of CVD, and yet, the overall level of glycemic control is not necessarily related to CVD risks. There thus are metabolic pathways beyond the glucocentric view of diabetes that contribute to CVD in this at risk population. Large-scale clinical investigations are used to focus research attention on candidate metabolites whose circulating levels are reproducibly associated with incident development of adverse cardiovascular events like heart attack, stroke and death in this at risk population. After validating the associations (and often typically observing the candidate metabolite predicts risks in diabetic and non-diabetic subject alike), we move forward with mechanistic studies aimed at defining whether observed associations are linked to CVD and metabolic disease relevant phenotypes, through cellular and animal model studies. Preliminary cell, animal model and microbial transplantation related studies using genetically engineered human commensals (gain and loss of function mutants) are used to interrogate the role of specific microbiota derived metabolites, and the microbial enzyme(s) responsible for their generation, in eliciting relevant phenotypes in the host like enhanced thrombosis potential, or susceptibility to atherosclerosis. Our proposed studies promise to identify new mechanisms through which gut microbiota may contribute to CVD. They also will help improve identification of those at risk for CVD and its adverse events who otherwise might not be identified. They also will provide enabling discoveries that will foster potential development of novel treatments for CVD.