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

项目摘要 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， 射血分数保留性心力衰竭（HFpEF）的标志性发现。通过节食减肥 限制热量摄入不能改善心脏功能，这表明舒张功能的机制 改善始于SG后胃肠道解剖结构的改变。广泛的长期目标 本项目的目的是探索SG后肠道微生物的变化，是否导致富含法尼醇X受体的胆汁酸池 (FXR)激动剂，介导舒张功能改善。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学进行研究。 啮齿动物和人类SG粪便的序列分析，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活化降低心肌细胞代谢应激。人和啮齿动物心肌细胞 细胞系将被工程化以调节FXR表达，以确定SG血浆是否降低心脏功能。 代谢应激通过FXR激动。在特定目标3中，我们将确定SG是否改善舒张压 通过进行手术和评估心脏功能， 心肌细胞特异性FXR敲除小鼠模型。我们假设SG通过增强FXR信号传导， 微生物衍生产品，以改善心脏功能。这些发现将加深我们对 减肥手术后舒张期恢复的机制，以开发新的手术和非手术疗法， 舒张功能障碍和HFpEF，其复制了SG产生的代谢机制。

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.