PDF(Pubmed)
Abstract：
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here.
METHODS: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing.
RESULTS: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (- 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray-Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats.
CONCLUSIONS: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities.
METHODS: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing.
RESULTS: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (- 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray-Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats.
CONCLUSIONS: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities.
摘要：
背景：射血分数保留的心力衰竭（HFpEF）与全身性炎症有关，肥胖，代谢综合征,和肠道微生物组的变化。三甲胺-N-氧化物（TMAO）水平升高是HFpEF死亡率的预测因素。TMAO前体三甲胺（TMA）由肠道微生物组合成，穿过肠屏障，并通过含肝黄素的单加氧酶（FMO）代谢为TMAO。这里分析了微生物组改变和TMAO与HFpEF表现和进展的复杂相互作用。
方法：研究了具有HFpEF的健康瘦（L-ZSF1，n=12）和肥胖ZSF1大鼠（O-ZSF1，n=12）。经胸超声心动图证实HFpEF，侵入性血液动力学测量，并检测N末端脑钠肽前体(NT-proBNP)。TMAO,肉碱,对称二甲基精氨酸（SDMA），和氨基酸使用质谱法测量。通过免疫组织化学分析肠上皮屏障，体外阻抗测量和通过ELISA测定血浆脂多糖。通过Western印迹测定肝FMO3量。使用16srRNA扩增子测序评估8、13和20周龄的粪便微生物组。
结果：TMAO水平增加（54％），在患有HFpEF的肥胖大鼠中观察到肉碱（46％）和心脏压力标志物NT-proBNP（25％）以及明显的氨基酸失衡。O-ZSF1中的SDMA水平与L-ZSF1相当,表明肾功能稳定。肠上皮中的解剖学和小带闭塞蛋白密度保持不变，但是阻抗测量和LPS水平升高均表明上皮屏障功能受损。FMO3在扩大时降低（-20%），但组织学正常的O-ZSF1肝脏。阿尔法多样性，如香农多样性指数所示，在8周龄时相当，但下降到13周龄，当HFpEF出现在O-ZSF1中时。Bray-Curtis差异（β-多样性）在20周龄时可有效区分L-ZSF1和O-ZSF1。乳杆菌科微生物家族的成员，Ruminocycaceae,在O-ZSF1和L-ZSF1大鼠中，Erypelotrichaceae和Lachnospienceae的含量显着不同。
结论：在ZSF1HFpEF大鼠模型中，饮食摄入增加与肠道微生物组组成和细菌代谢产物的改变有关，肠屏障受损,以及促炎和健康预测代谢谱的变化。HFpEF及其最常见的合并症，肥胖和代谢综合征以及此处描述的改变是并行发展的，并且可能是相互关联和相辅相成的。饮食适应可能会对所有实体产生积极影响。
方法：研究了具有HFpEF的健康瘦（L-ZSF1，n=12）和肥胖ZSF1大鼠（O-ZSF1，n=12）。经胸超声心动图证实HFpEF，侵入性血液动力学测量，并检测N末端脑钠肽前体(NT-proBNP)。TMAO,肉碱,对称二甲基精氨酸（SDMA），和氨基酸使用质谱法测量。通过免疫组织化学分析肠上皮屏障，体外阻抗测量和通过ELISA测定血浆脂多糖。通过Western印迹测定肝FMO3量。使用16srRNA扩增子测序评估8、13和20周龄的粪便微生物组。
结果：TMAO水平增加（54％），在患有HFpEF的肥胖大鼠中观察到肉碱（46％）和心脏压力标志物NT-proBNP（25％）以及明显的氨基酸失衡。O-ZSF1中的SDMA水平与L-ZSF1相当,表明肾功能稳定。肠上皮中的解剖学和小带闭塞蛋白密度保持不变，但是阻抗测量和LPS水平升高均表明上皮屏障功能受损。FMO3在扩大时降低（-20%），但组织学正常的O-ZSF1肝脏。阿尔法多样性，如香农多样性指数所示，在8周龄时相当，但下降到13周龄，当HFpEF出现在O-ZSF1中时。Bray-Curtis差异（β-多样性）在20周龄时可有效区分L-ZSF1和O-ZSF1。乳杆菌科微生物家族的成员，Ruminocycaceae,在O-ZSF1和L-ZSF1大鼠中，Erypelotrichaceae和Lachnospienceae的含量显着不同。
结论：在ZSF1HFpEF大鼠模型中，饮食摄入增加与肠道微生物组组成和细菌代谢产物的改变有关，肠屏障受损,以及促炎和健康预测代谢谱的变化。HFpEF及其最常见的合并症，肥胖和代谢综合征以及此处描述的改变是并行发展的，并且可能是相互关联和相辅相成的。饮食适应可能会对所有实体产生积极影响。
