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

项目总结

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.