Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland.
School of Microbiology, University College Cork, Cork, Ireland.
Am J Physiol Heart Circ Physiol. 2020 Mar 1;318(3):H590-H603. doi: 10.1152/ajpheart.00512.2019. Epub 2020 Feb 7.
Metabolic syndrome (MetS) is a composite of cardiometabolic risk factors, including obesity, dyslipidemia, hypertension, and insulin resistance, with a range of secondary sequelae such as nonalcoholic fatty liver disease and diastolic heart failure. This syndrome has been identified as one of the greatest global health challenges of the 21st century. Herein, we examine whether a porcine model of diet- and mineralocorticoid-induced MetS closely mimics the cardiovascular, metabolic, gut microbiota, and functional metataxonomic phenotype observed in human studies. Landrace pigs with deoxycorticosterone acetate-induced hypertension fed a diet high in fat, salt, and sugar over 12 wk were assessed for hyperlipidemia, hyperinsulinemia, and immunohistologic, echocardiographic, and hemodynamic parameters, as well as assessed for microbiome phenotype and function through 16S rRNA metataxonomic and metabolomic analysis, respectively. All MetS animals developed obesity, hyperlipidemia, insulin resistance, hypertension, fatty liver, structural cardiovascular changes including left ventricular hypertrophy and left atrial enlargement, and increased circulating saturated fatty acid levels, all in keeping with the human phenotype. A reduction in α-diversity and specific microbiota changes at phylum, family, and genus levels were also observed in this model. Specifically, this porcine model of MetS displayed increased abundances of proinflammatory bacteria coupled with increased circulating tumor necrosis factor-α and increased secondary bile acid-producing bacteria, which substantially impacted fibroblast growth factor-19 expression. Finally, a significant decrease in enteroprotective bacteria and a reduction in short-chain fatty acid-producing bacteria were also noted. Together, these data suggest that diet and mineralocorticoid-mediated development of biochemical and cardiovascular stigmata of metabolic syndrome in pigs leads to temporal gut microbiome changes that mimic key gut microbial population signatures in human cardiometabolic disease. This study extends a prior porcine model of cardiometabolic syndrome to include systemic inflammation, fatty liver, and insulin sensitivity. Gut microbiome changes during evolution of porcine cardiometabolic disease recapitulate those in human subjects with alterations in gut taxa associated with proinflammatory bacteria, bile acid, and fatty acid pathways. This clinical scale model may facilitate design of future interventional trials to test causal relationships between gut dysbiosis and cardiometabolic syndrome at a systemic and organ level.
代谢综合征（MetS）是一组心血管代谢危险因素的综合病症，包括肥胖、血脂异常、高血压和胰岛素抵抗，以及一系列继发性并发症，如非酒精性脂肪肝和舒张性心力衰竭。该综合征已被确定为 21 世纪全球最大的健康挑战之一。在此，我们研究了饮食和盐皮质激素诱导的代谢综合征的猪模型是否能很好地模拟人类研究中观察到的心血管、代谢、肠道微生物组和功能宏分类组表型。用去氧皮质酮乙酸盐诱导高血压的长白猪在 12 周内喂食高脂肪、高盐和高糖饮食，评估其高血脂、高胰岛素血症以及免疫组织化学、超声心动图和血液动力学参数，并通过 16S rRNA 宏分类组和代谢组学分析分别评估微生物组表型和功能。所有代谢综合征动物都发展为肥胖、血脂异常、胰岛素抵抗、高血压、脂肪肝、包括左心室肥厚和左心房扩大在内的结构性心血管变化，以及循环饱和脂肪酸水平升高，这些都与人类表型一致。该模型还观察到α多样性降低和特定微生物群落在门、科和属水平的变化。具体来说，该代谢综合征猪模型显示促炎细菌丰度增加，同时循环肿瘤坏死因子-α增加和次级胆汁酸产生细菌增加，这极大地影响了成纤维细胞生长因子 19 的表达。最后，还观察到肠保护性细菌显著减少和短链脂肪酸产生细菌减少。总之，这些数据表明，饮食和盐皮质激素介导的猪代谢综合征生物化学和心血管标志的发展导致肠道微生物组随时间发生变化，模拟了人类心血管代谢疾病中关键的肠道微生物种群特征。本研究将先前的猪代谢综合征心血管模型扩展到包括全身炎症、脂肪肝和胰岛素敏感性。在猪心血管代谢疾病演变过程中肠道微生物组的变化反映了人类受试者的变化，与促炎细菌、胆汁酸和脂肪酸途径相关的肠道分类群发生了改变。这种临床规模的模型可能有助于设计未来的干预试验，以在系统和器官水平上测试肠道菌群失调与代谢综合征之间的因果关系。
