Cholesterol-lowering activity of protocatechuic acid is mediated by increasing the excretion of bile acids and modulating gut microbiota and producing short-chain fatty acids.

The present study aimed to investigate the effects of protocatechuic acid (PCA) on plasma lipid profiles and associated mechanisms with a focus on reshaping gut microbiota. Twenty-four male hamsters were randomly divided into three groups receiving a high-cholesterol diet (HCD) and two HCD diets containing 0.5% (PL) and 1% (PH) PCA, respectively. Feeding PL and PH diets for six weeks significantly reduced plasma total cholesterol by 18% and 24%, respectively. PL and PH diets also significantly lowered plasma non-HDL cholesterol by 37% and 44%, respectively. This was accompanied by an increase in fecal short-chain fatty acids (SCFAs) and fecal bile acids with up-regulation on gene of cholesterol 7α-hydroxylase and down-regulation of 3-hydroxy-3-methylglutaryl-CoA reductase in the liver. Dietary PCA supplementation decreased hepatic lipid accumulation, whereas it increased fecal excretion of lipids. The 16S rRNA analysis found that dietary PCA significantly reduced the ratio of Firmicutes to Bacteroidetes and increased the relative abundance of Bacteroidales S24-7, whereas it reduced the abundance of Lactobacillaceae. It was concluded that dietary PCA favorably modulated plasma lipid profiles and prevented the accumulation of hepatic cholesterol and lipid disposition. Such effect was mediated at least partially by increasing gut production of SCFAs and fecal excretion of bile acids via modulating the gut microbiome.