Hatahet Jomana, Cook Tyler M, Bonomo Raiza R, Elshareif Nadia, Gavini Chaitanya K, White Chelsea R, Jesse Jason, Mansuy-Aubert Virginie, Aubert Gregory
Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, United States.
Department of Biomedical Science, University of Lausanne, Lausanne, Switzerland.
Front Cardiovasc Med. 2023 Feb 8;10:1105581. doi: 10.3389/fcvm.2023.1105581. eCollection 2023.
More than 50% of patients with heart failure present with heart failure with preserved ejection fraction (HFpEF), and 80% of them are overweight or obese. In this study we developed an obesity associated pre-HFpEF mouse model and showed an improvement in both systolic and diastolic early dysfunction following fecal microbiome transplant (FMT). Our study suggests that the gut microbiome-derived short-chain fatty acid butyrate plays a significant role in this improvement. Cardiac RNAseq analysis showed butyrate to significantly upregulate gene that encodes protein phosphatase 2Cm (PP2Cm) which dephosphorylates and activates branched-chain α-keto acid dehydrogenase (BCKDH) enzyme, and in turn increases the catabolism of branched chain amino acids (BCAAs). Following both FMT and butyrate treatment, the level of inactive p-BCKDH in the heart was reduced. These findings show that gut microbiome modulation can alleviate early cardiac mechanics dysfunction seen in the development of obesity associated HFpEF.
超过50%的心力衰竭患者表现为射血分数保留的心力衰竭（HFpEF），其中80%超重或肥胖。在本研究中，我们建立了一种肥胖相关的HFpEF前期小鼠模型，并表明粪便微生物群移植（FMT）后收缩期和舒张期早期功能障碍均有改善。我们的研究表明，肠道微生物群衍生的短链脂肪酸丁酸在这种改善中起重要作用。心脏RNA测序分析显示，丁酸可显著上调编码蛋白磷酸酶2Cm（PP2Cm）的基因，该基因使支链α-酮酸脱氢酶（BCKDH）酶去磷酸化并激活，进而增加支链氨基酸（BCAAs）的分解代谢。FMT和丁酸治疗后，心脏中无活性的p-BCKDH水平均降低。这些发现表明，调节肠道微生物群可缓解肥胖相关HFpEF发展过程中出现的早期心脏力学功能障碍。
