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

• 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
• 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

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.

项目总结

项目成果

Diet in Food Insecurity: A Mediator of Metabolic Health?

• DOI: 10.1210/jendso/bvae062
• 发表时间: 2024-04-06
• 期刊: JOURNAL OF THE ENDOCRINE SOCIETY
• 影响因子: 4.1
• 作者: Morselli，Lisa L.;Amjad，Rabia;Kidambi，Srividya
• 通讯作者: Kidambi，Srividya

The role of weight control in the management of type 2 diabetes mellitus: Bariatric surgery.

体重控制在 2 型糖尿病治疗中的作用：减肥手术。

• DOI: 10.1016/j.diabres.2023.110667
• 发表时间: 2023
• 期刊: Diabetes research and clinical practice
• 影响因子: 5.1
• 作者: Xu,ThomasQ;Kindel,TammyLyn
• 通讯作者: Kindel,TammyLyn