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.
KeywordsGallic acid
Turicibacter
Atherosclerosis
VSMC
Eubacterium fissicatena
Abbreviations3-CQA3-O-caffeoylquinic acid
ANOVAanalysis of variance
ASVamplicon sequence variants
CCLC-C motif chemokine ligand
CVDcardiovascular disease
CSFcolony stimulating factor
CXCLC-X-C motif chemokine ligand
DPBSDulbecco's phosphate buffered saline
FDGFluorescein di‐β‐d‐galactopyranoside
GPxglutathione peroxidase
HDLhigh-density lipoprotein
LDAlinear discriminatory analysis
LEfSelinear discriminatory analysis effect size
LDLlow-density lipoprotein
NADPHnicotinamide adenine dinucleotide phosphate
NF-κBnuclear factor kappa B
OTUoperational taxonomic unit
PCAprincipal coordinate analysis
PERMANOVApermutational analysis of variance
RNSreactive nitrogen species
ROSreactive oxygen species
SA-β-Galsenescence associated beta galactosidase
SASPsenescence associated secretory phenotype
SDstandard deviation of mean
SIPSstress induced premature senescence
TMAOtrimethylamine-N-oxide
VCAMvascular cell adhesion molecule
VLDLvery low-density lipoprotein
VSMCvascular smooth muscle cell
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