Dietary secoisolariciresinol diglucoside ameliorates high-fat diet-induced atherosclerosis via regulating immunological inflammation and reshaping gut microbiota in ApoE-/- mice

Secoisolariciresinol diglucoside (SDG) has shown a variety of biological activities, but its impact on atherosclerosis (AS) remains poorly understood. This study investigated the potential of SDG in preventing and treating AS. Firstly, SDG administration ameliorated atherosclerotic lesion, lipid indicators and total bile acids (TBA). It also reduced chronic systemic/vascular inflammatory cytokines and in situ macrophages (Mψs). Due to the critical role of gut-vascular axis in AS, multi-omics analysis revealed that the modulation of gut microbiota and metabolism, including reductions in Firmicutes , Intestinimonas , Bilophila , Oscillibacter and Negativibacillus and increases in linoleic acid and 12,13-DHOME, may contribute to the attenuation of SDG on gut dysbiosis. Further verification exhibited that the regulation of intestinal gammadelta and regulatory T subsets, incresed intestinal tight junction proteins and lower plasma lipopolysaccharide (LPS) may attributed to this effectiveness of SDG intervenion. Collectively, dietary SDG ameliorates HFD-induced AS mice via suppressing inflammation and reshaping gut homeostasis. • Supplementary SDG can improve atherosclerotic mice by reducing plaque progression. • Protective SDG exerts an anti-inflammatory effect on AS by regulating macrophage, Treg and γδT cells. • SDG intervention restores gut homeostasis by reshaping gut microbiota and enhancing TJPs in intestinal barrier. • The ameliorative effects of SDG on AS may be mediated by increasing the metabolites linoleic acid and associated downstream products.