The Role of Phytochemicals and Gut Microbiome in Atherosclerosis in Preclinical Mouse Models.

Gut microbiome alterations have recently been linked to many chronic conditions including cardiovascular disease (CVD). There is an interplay between diet and the resident gut microbiome, where the food eaten affects populations of certain microbes. This is important, as different microbes are associated with various pathologies, as they can produce compounds that are disease-promoting or disease-protecting. The Western diet negatively affects the host gut microbiome, ultimately resulting in heightened arterial inflammation and cell phenotype changes as well as plaque accumulation in the arteries. Nutritional interventions including whole foods rich in fiber and phytochemicals as well as isolated compounds including polyphenols and traditional medicinal plants show promise in positively influencing the host gut microbiome to alleviate atherosclerosis. This review investigates the efficacy of a vast array of foods and phytochemicals on host gut microbes and atherosclerotic burden in mice. Reduction in plaque by interventions was associated with increases in bacterial diversity, reduction in the Firmicutes/Bacteroidetes (F/B) ratio, and upregulation of Akkermansia. Upregulation in CYP7 isoform in the liver, ABC transporters, bile acid excretion, and the level of acetic acid, propionic acid, and butyric acid were also noted in several studies reducing plaque. These changes were also associated with attenuated inflammation and oxidative stress. In conclusion, an increase in the abundance of Akkermansia with diets rich in polyphenols, fiber, and grains is likely to reduce plaque burden in patients suffering from CVD.

The Duality of Adiponectin: The Role of Sex in Atherosclerosis.

The hormone adiponectin has many beneficial effects in atherosclerosis, as gene deficiency in adiponectin or its receptor has shown detrimental effects on plaque burden in mice. Our objective was to understand the potential roles adiponectin deficiency has on aortic plaque content, inflammation, and markers of cardiovascular disease according to sex and age. To study the influence of adiponectin status on sex and atherosclerosis, we used young male and female adipoq-/-apoe-/-, adipoq+/-apoe-/-, and apoe-/- mice, which were given a high-fat diet (HFD). Even a 50% reduction in the expression of adiponectin led to a plaque reduction in males and an increase in females compared with apoe-/- controls. Changes in plaque were not attributed to changes in cholesterol or cardiovascular disease markers but correlated with inflammatory markers. Plaque reduction in males was associated with reduced monocyte chemoattractant protein 1 (MCP1) and increased colony stimulating factor 3 (CSF3), while the increase in plaque in females correlated with the opposite effect in these markers. In old mice, both adiponectin-deficient genotypes and sexes accumulated more plaque than their respective apoe-/- controls. The increase in plaque with adiponectin deficiency according to age was not explained by a worsening lipid profile but correlated with increased levels of C-C motif chemokine ligand 5 (CCL5). Overall, our study uncovered genotype-specific effects that differed by sex and age of adiponectin deficiency in atherosclerosis.

Gallic acid ameliorates atherosclerosis and vascular senescence and remodels the microbiome in a sex-dependent manner in ApoE-/- mice.

Polyphenols found in fruits and vegetables are associated with a reduced incidence of cardiovascular disease (CVD), the leading cause of death in the USA. Our lab demonstrated that blackberry supplementation reduces atherosclerosis in male, but not in female mice. The current study investigates whether gallic acid (GA), a polyphenol abundant in blackberry, decreases plaque and whether its effect is also sex-dependent. In vitro work using vascular smooth muscle cells (VSMCs) demonstrated that GA reduced cell signaling associated with proliferation, migration, and senescence. ApoE-/- male and female mice were treated with and without 0.2% GA in drinking water and fed a chow diet (2 weeks), then switched to high-fat diet (HFD) (5 weeks) with the same GA regimen. Similar to the blackberry study, GA reduced atherosclerosis only in males. This GA-induced plaque reduction was independent of plasma cholesterol, triglycerides (TG), LDL, or HDL but corresponded with indices of lower inflammation. Males showed reduced spleen weight and serum IL3 and IL12 levels, and gut health improvement. In females, GA increased anti-atherogenic (HDL and IL10) molecules, while upregulating several pro-inflammatory cytokines and chemokines, including tumor necrosis factor α (TNFα). A major sex-dependent effect of GA was the almost complete disappearance of Eubacterium fissicatena and Turicibacter induced by HFD in males, a finding not seen in females. This study provides novel insights into how GA can improve gut microbiota alterations associated with CVD and suggests that males suffering from atherosclerosis may benefit from GA supplementation, as this polyphenol partially restored microbiome dysbiosis.