Gut microbiome of a porcine model of metabolic syndrome and HF-pEF

Abstract

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. NEW & NOTEWORTHY 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.

Gut Microbiota in Heart Failure Patients With Preserved Ejection Fraction (GUMPTION Study)

“…In spite of current medical treatment approaches, mortality of HFpEF remains high and novel treatment concepts are thus urgently required ( 2 ). A theory proposed recently showed a possible impact of gut microbiota on the incidence and progression of HFpEF ( 3 ).…”

Recent Progress in Metabolic Syndrome Research and Therapeutics

“…Interestingly, the landscape of gut microbiota was transiently reshaped with diet and steroid-induced imprint of inflammation, hepatic steatosis, and insulin sensitivity in the porcine model. The alteration was recognized to recapitulate the human MetS signature, particularly bile and fatty acid [67]. The peri-implant dental sample harvested from subjects with MetS exhibited remarkably higher level of Aggregatibacter Actinomycetemcomitans, Prevotella intermedia, and Staphylococcus aureus [68], highlighting the systematic significance of metabolic disorder.…”

Toward a porcine in vivo model to analyze the pathogenesis of TLR5-dependent enteropathies

“…IBD and MetS). Thus, as recently proposed by the Caplice group that established a porcine model of diet-and mineralocorticoidinduced MetS, 39 the pig might represent an interesting model to study the link between an altered gut microbiota, its influence on the immune system and potential consequences on the mucosal host-microbial homeostasis in more detail. Since…”

“…IBD and MetS). Thus, as recently proposed by the Caplice group that established a porcine model of diet- and mineralocorticoid-induced MetS, 39 the pig might represent an interesting model to study the link between an altered gut microbiota, its influence on the immune system and potential consequences on the mucosal host-microbial homeostasis in more detail. Since TLR5 impairment or deficiency is an established genetic risk factor for the development of MetS or IBD, the porcine animal model might open new avenues for the biomedical research of non-communicable diseases associated with TLR5.…”