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：
10626829
负责人：
Tammy Lyn Kindel
金额：
$ 44.06万
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/10626829
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 Feces Functional disorder Gastrectomy Gene Expression Genetic Goals Heart Heart failure Human Impairment In Vitro Inflammation Intervention Knockout Mice Lead Measures Mediating Medical Metabolic Metabolic stress Metagenomics 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 Ventricular bariatric surgery beta diversity dietary restriction dieting 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.

项目摘要袖子胃切除术（SG）是一种减肥手术，可改善与肥胖相关的舒张功能障碍，A 标志性地发现心力衰竭，并保留了射血分数（HFPEF）。通过节食减轻体重热量限制无法改善心脏功能，这表明了舒张功能的机制 SG后胃肠道解剖学的改变引发了改善。广泛的长期目标这个项目的是探索肠道微生物是否在SG后发生变化，导致富含Farnesoid X受体的胆汁酸池（FXR）激动剂，介导舒张功能的改善。在特定目标1中，我们将检验以下假设。 SG后肠道微生物组增加了血浆胆汁酸FXR激动剂作为心脏功能的机制改进。研究将利用SG小鼠的粪便材料转移以及宏基因组进行研究从啮齿动物和人类的SG粪便进行序列分析以确定肠道的可转移效果血浆BA池和舒张功能的微生物组。在特定目标2中，我们将确定SG是否血浆通过FXR激活减少心肌细胞代谢应激。人和啮齿动物心肌细胞细胞线条将用于调节的FXR表达，以确定SG等离子体是否减少心脏通过FXR激动剂的代谢压力。在特定目标3中，我们将确定SG是否改善舒张期通过心肌细胞FXR信号在体内通过手术和评估心脏功能的功能心肌细胞特异性FXR敲除小鼠模型。我们假设SG通过微生物衍生的产品可改善心脏功能。这些发现将增强我们对减肥手术后舒张期恢复的机制，以开发新的外科手术和非手术疗法舒张功能障碍和HFPEF复制由SG产生的代谢机制。