Abstract
Although a high-fat diet (HFD) induces gut dysbiosis and cardiovascular system remodeling, the precise mechanism is unclear. We hypothesize that HFD instigates dysbiosis and cardiac muscle remodeling by inducing matrix metalloproteinases (MMPs), which leads to an increase in white adipose tissue, and treatment with lactobacillus (a ketone body donor from lactate; the substrate for the mitochondria) reverses dysbiosis-induced cardiac injury, in part, by increasing lipolysis (PGC-1α, and UCP1) and adipose tissue browning and decreasing lipogenesis. To test this hypothesis, we used wild type (WT) mice fed with HFD for 16 weeks with/without a probiotic (PB) in water. Cardiac injury was measured by CKMB activity which was found to be robust in HFD-fed mice. Interestingly, CKMB activity was normalized post PB treatment. Levels of free fatty acids (FFAs) and methylation were increased but butyrate was decreased in HFD mice, suggesting an epigenetically governed 1-carbon metabolism along with dysbiosis. Levels of PGC-1α and UCP1 were measured by Western blot analysis, and MMP activity was scored via zymography. Collagen histology was also performed. Contraction of the isolated myocytes was measured employing the ion-optic system, and functions of the heart were estimated by echocardiography. Our results suggest that mice on HFD gained weight and exhibited an increase in blood pressure. These effects were normalized by PB. Levels of fibrosis and MMP-2 activity were robust in HFD mice, and treatment with PB mitigated the fibrosis. Myocyte calcium-dependent contraction was disrupted by HFD, and treatment with PB could restore its function. We conclude that HFD induces dysbiosis, and treatment with PB creates eubiosis and browning of the adipose tissue.
Highlights
Metabolic syndrome is associated, in part, with a high-fat diet (HFD), the mechanistic aspect(s) of this dysregulation, and the governing of the intimate relationship or fine balance between gut eubiosis and dysbiosis, are poorly understood
The results suggested an increase in 5-methylcytidine levels in mice on a HFD and the treatment with PB mitigated the increase in 1-carbon metabolism in mice on a HFD (Figure 3C)
The results suggested an increase in DNA methyltransferase (DNMT) and decrease in betaine-Hcy S−methyltransferase (BHMT) in HFD
Summary
Metabolic syndrome is associated, in part, with a high-fat diet (HFD), the mechanistic aspect(s) of this dysregulation, and the governing of the intimate relationship or fine balance between gut eubiosis and dysbiosis, are poorly understood. During eubiosis, the epigenetically controlled reversible DNA methylation by DNA methyltransferase (DNMT) and phosphatidylethanolamine methyltransferase (PEMT) allows normal gene regulation activity, during dysbiosis the irreversible DNA methylation causes hyperhomocysteinemia (HHcy) This is responsible for cardiovascular complications, most likely as a result of the gut dysbiotic environment, leading to metabolic syndromes (Chaturvedi et al, 2014). In our opinion, the mechanism of methionine-homocysteinebetaine-cycle during eubiosis versus dysbiosis favors the epigenetically reversible and irreversible DNA methylation patterns (eubiosis versus dysbiosis) that are responsible for HHcy. The effects of a HFD dysbiotic diet on cardiac structural and functional remodeling, and its mitigation by probiotics, is central to our hypothesis in this work wherein the effects on fatty acid oxidation/lipogenesis and lipolysis might reveal the beneficial effect(s) of probiotics that could increase lipolysis and bioenergetics (Chao and Zeisel, 1990; Benakanakere et al, 2015; Bjørndal et al, 2015; Reizel et al, 2015, 2018).
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