The Gut Microbiota in Metabolic Surgery: A Multi-Ethnic, Multi-Omic, Longitudinal Study

项目总结 代谢和减肥手术是治疗肥胖相关代谢性疾病的新兴选择，例如2型 糖尿病，并预防动脉粥样硬化性心血管疾病(ASCVD)。新陈代谢手术可以深刻地改变 肠道微生物区系；同时，肠道微生物区系及其代谢产物可能会影响心脏代谢结果 手术。对这些“宿主-微生物区系相互作用”的研究将提供新的机制理解。 代谢手术和开发潜在的基于微生物区系的模型/疗法以实现更好效果的证据 心脏代谢健康。然而，纵向患者研究检查了手术前后的肠道微生物区系和 它们的代谢物与心脏代谢结果相关的很少。现有的研究受到很小的限制 样本大小XVXDOO\Q，非前瞻性设计，不评估微生物功能或活性(例如， 通过多组学)，很少考虑饮食或药物使用。值得注意的是，还没有研究评估肠道 微生物区系与估计的10年ASCVD风险的关系，这反映了 根据ACC/AHA指南，代谢性外科手术被广泛应用于临床。此外，没有研究表明 包括非裔美国人(AAs)，这是一个心脏代谢性疾病发病率很高的人群。 我们的目标是通过建立一个纵向的、多种族的代谢外科队列来填补这些研究空白。 患者和应用多重组学来确定微生物特征(例如，物种、途径和代谢物) 与估计的10年ASCVD风险和/或A1C、血压和血脂的改善有关。 在一项初步研究中，我们招募了20名患者(包括AA)，收集了纵向的粪便/血液样本，进行了 调查发现，手术后微生物组和微生物代谢物发生了显著变化，表明 进行拟议全面研究的可行性和我们的能力。具体来说，我们将注册并跟踪200名 患者在术前、术后3个月和1年内收集生物标本并进行调查。 我们将评估手术前后肠道微生物群以及粪便和循环代谢物水平的变化， 尤其是微生物区系衍生的代谢物，以及术前和术后3个月的前瞻性关联 微生物群和代谢产物与ASCVD风险和术后1年的代谢结果。我们还将 探索通过饮食和药物治疗的潜在效果改变，重点是纤维摄入和二甲双胍的使用。 我们提出的研究将提供大量新颖的数据，以促进我们对肠道作用的理解 代谢手术后心脏代谢改善中的微生物区系，这可能转化为新的微生物 识别和治疗患者以获得更好的心脏代谢健康的方法。我们的团队拥有丰富的专业知识 心脏代谢性疾病，饮食-微生物-宿主相互作用，代谢组学和代谢组学 队列，以及具有患者、护理提供者和/或研究人员经验的代谢外科，以及 因此，在完成拟议的研究方面具有得天独厚的优势。

PROJECT SUMMARY Metabolic and bariatric surgery is an emerging option to treat obesity-related metabolic diseases, e.g., type 2 diabetes, and prevent atherosclerotic cardiovascular disease (ASCVD). Metabolic surgery can profoundly alter the gut microbiota; meanwhile, gut microbiota and their metabolites may affect cardiometabolic outcomes after the surgery. Investigation of these “host-microbiota interactions” will offer novel mechanistic understanding of metabolic surgery and evidence for developing potential microbiota-based models/therapies to achieve better cardiometabolic health. Yet, longitudinal patient studies that examined pre- to post-surgery gut microbiota and their metabolites in relation to cardiometabolic outcomes are scarce. Existing studies are limited by small sample sizes XVXDOO\ Q , non-prospective design, no evaluation of microbial functionality nor activity (e.g., via multi-omics), and little consideration of diet or medication use. Of note, no studies have evaluated gut microbiota in relation to estimated 10-year ASCVD risk, which reflects the overall cardiometabolic benefit of metabolic surgery and is widely used in clinical practice per ACC/AHA guideline. Furthermore, no studies have included African Americans (AAs), a population with high rates of cardiometabolic diseases. We aim to fill these research gaps by establishing a longitudinal, multi-ethnic cohort of metabolic surgery patients and applying multi-omics to identify microbial features (e.g., species, pathways, and metabolites) associated with estimated 10-year ASCVD risk and/or improvements in A1C, blood pressure, and blood lipids. In a pilot study, we enrolled 20 patients (including AAs), collected longitudinal stool/blood samples, conducted surveys, and found significant changes in microbiome and microbial metabolites after surgery, demonstrating the feasibility and our ability to carry out the proposed full-scale study. Specifically, we will enroll and follow 200 patients to collect biospecimen and conduct surveys at pre-surgery and 3-month and 1-year post-surgery visits. We will evaluate pre- to post-surgery changes in gut microbiome and fecal and circulating levels of metabolites, especially microbiota-derived metabolites, and the prospective associations of pre-surgery and 3-month microbiome and metabolites with ASCVD risk and metabolic outcomes at 1-year post-surgery. We will also explore potential effect modifications by diet and medication, focusing on fiber intake and metformin use. Our proposed research will provide substantial novel data to advance our understanding of the role of gut microbiota in cardiometabolic improvements after metabolic surgery, which may translate into novel microbial approaches to identify and treat patients for better cardiometabolic health. Our team has extensive expertise in cardiometabolic diseases, diet-microbiota-host interactions, metagenomics and metabolomics in longitudinal cohorts, as well as in metabolic surgery with experiences as patients, care providers, and/or researchers, and thus, is uniquely positioned to accomplish the proposed research.