Oligomeric procyanidins combined with Parabacteroides distasonis ameliorate high-fat diet-induced atherosclerosis by regulating lipid metabolism, inflammation reaction and bile acid metabolism in ApoE^-/- mice

Atherosclerosis (AS) is the main pathological basis of cardiovascular diseases. Hence, the prevention and treatment strategies of AS have attracted great research attention. As a potential probiotic, Pararabacteroides distasonis has a positive regulatory effect on lipid metabolism and bile acids (BAs) profile. Oligomeric procyanidins have been confirmed to be conducive to the prevention and treatment of AS, whose antiatherosclerotic effect may be associated with the promotion of gut probiotics. However, it remains unclear whether and how oligomeric procyanidins and P. distasonis combined (PPC) treatment can effectively alleviate high-fat diet (HFD)-induced AS. In this study, PPC treatment was found to significantly decrease atherosclerotic lesion, as well as alleviate the lipid metabolism disorder, inflammation and oxidative stress injury in ApoE^-/- mice. Surprisingly, targeted metabolomics demonstrated that PPC intervention altered the BA profile in mice by regulating the ratio of secondary BAs to primary BAs, and increased fecal BAs excretion. Further, quantitative polymerase chain reaction (qPCR) analysis showed that PPC intervention facilitated reverse cholesterol transport by upregulating Srb1 expression; In addition, PPC intervention promoted BA synthesis from cholesterol in liver by upregulating Cyp7a1 expression via suppression of the farnesoid X receptor (FXR) pathway, thus exhibiting a significant serum cholesterol-lowering effect. In summary, PPC attenuated HFD-induced AS in ApoE^-/- mice, which provides new insights into the design of novel and efficient anti-atherosclerotic strategies to prevent AS based on probiotics and prebiotics.