Identifying Gut Microbiome Mediated Mechanisms for Diastolic Dysfunction Improvement After Bariatric Surgery

确定肠道微生物介导的减肥手术后改善舒张功能障碍的机制

基本信息

批准号：
10442822
负责人：
Tammy Lyn Kindel
金额：
$ 44.66万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442822
关键词：
Affect Agonist Anatomy Animal Model Anti-Inflammatory Agents Antioxidants Bacteria Bile Acids Body Weight decreased Caloric Restriction Cardiac Cardiac Myocytes Cardiovascular system Cell Line Data Development Disease EFRAC Engineering Failure Feces Functional disorder Gastrectomy Gene Expression Goals Heart Heart failure Human Impairment In Vitro Inflammation Intervention Knockout Mice Lead Measures Mediating Medical Metabolic Metabolic stress Metagenomics Microbial Genetics Molecular Morbidity - disease rate Mus Muscle Cells Nuclear Obese Mice Obesity Operative Surgical Procedures Physiological Plasma Pluripotent Stem Cells Postoperative Period Receptor Activation Receptor Gene Receptor Signaling Recovery Rodent Sequence Analysis Signal Transduction Techniques Testing Treatment Failure Ventricular bariatric surgery beta diversity dietary restriction dieting functional improvement gastrointestinal gut microbes gut microbiome gut microbiota heart function improved in vivo microbial mortality mouse model novel obese patients obesity treatment preservation receptor receptor expression

项目摘要

Project Summary Sleeve gastrectomy (SG), is a type of bariatric surgery, which improves obesity-related diastolic dysfunction, a hallmark finding of heart failure with preserved ejection fraction (HFpEF). As weight reduction through dieting and caloric restriction fails to improve cardiac function, this suggests a mechanism for diastolic function improvement initiated from the alteration in gastrointestinal anatomy after SG. The broad, long-term objective of this project is to explore if gut microbial changes after SG, lead to a bile acid pool rich in farnesoid X receptor (FXR) agonists, that mediate diastolic function improvements. In Specific Aim 1, we will test the hypothesis that the post-SG gut microbiome increases plasma bile acid FXR agonists as a mechanism for cardiac function improvement. Studies will be conducted utilizing fecal material transfer of SG mice as well as metagenomic sequence analysis of SG stool from rodents and humans to determine the transferable effect of the gut microbiome on the plasma BA pool and diastolic function. In Specific Aim 2, we will determine whether SG plasma decreases cardiomyocyte metabolic stress via FXR activation. Human and rodent cardiomyocyte cell lines will be engineered for regulated FXR expression to determine whether SG plasma reduces cardiac metabolic stress through FXR agonism. In Specific Aim 3, we will determine whether SG improves diastolic function through cardiomyocyte FXR signaling in vivo by performing surgery and assessing cardiac function in a cardiomyocyte-specific FXR knockout mouse model. We hypothesize that SG enhances FXR signaling through microbial-derived products to improve cardiac function. These findings will enhance our understanding of the mechanisms for diastolic recovery after bariatric surgery to develop novel surgical and non-surgical therapies for diastolic dysfunction and HFpEF which replicate the metabolic mechanisms generated by a SG.

项目概要袖状胃切除术（SG）是一种减肥手术，可改善肥胖相关的舒张功能障碍，射血分数保留的心力衰竭（HFpEF）的标志性发现。通过节食减肥并且热量限制无法改善心脏功能，这表明舒张功能的机制 SG 后胃肠道解剖结构的改变引发了改善。广泛、长期的目标该项目的目的是探索 SG 后肠道微生物的变化是否会导致胆汁酸库富含法尼醇 X 受体 (FXR) 激动剂，可调节舒张功能的改善。在具体目标 1 中，我们将检验以下假设： SG 后肠道微生物组增加血浆胆汁酸 FXR 激动剂作为心脏功能的机制改进。将利用 SG 小鼠的粪便物质转移以及宏基因组进行研究对啮齿动物和人类的 SG 粪便进行序列分析，以确定肠道的可转移效应微生物组对血浆 BA 池和舒张功能的影响。在具体目标 2 中，我们将确定 SG 是否血浆通过 FXR 激活降低心肌细胞代谢应激。人和啮齿动物心肌细胞细胞系将被设计用于调节 FXR 表达，以确定 SG 血浆是否会降低心脏功能通过 FXR 激动作用缓解代谢应激。在具体目标 3 中，我们将确定 SG 是否改善舒张压通过在体内进行手术和评估心脏功能，通过心肌细胞 FXR 信号发挥功能心肌细胞特异性 FXR 基因敲除小鼠模型。我们假设 SG 通过以下方式增强 FXR 信号传导：微生物衍生产品可改善心脏功能。这些发现将加深我们对减肥手术后舒张恢复的机制，以开发新的手术和非手术疗法舒张功能障碍和 HFpEF 复制了 SG 产生的代谢机制。