Temporal gut microbiota dysbiosis links metabolic impairment, LDL desialylation, and accelerated atherosclerosis in LDLR

Introduction: This study used low-density lipoprotein receptor-deficient (LDLR-/-) mice fed a high-cholesterol diet (HCD) to establish an accelerated atherosclerosis model and to characterize the temporal dynamics of gut microbiota remodeling during disease progression. Methods: Male C57BL/6J wild-type and LDLR-/- mice were fed either a normal diet (ND) or HCD for 12 weeks, with gut microbiota profiled at weeks 0, 8, and 12. HCD markedly accelerated atherogenesis in genetically susceptible mice, as evidenced by increased body weight, visceral adiposity, aggravated atherosclerotic lesions, and dyslipidemia. Results: Time-resolved microbiota analysis revealed progressive community reorganization, characterized by expansion of Bacillota and Actinomycetota and depletion of Bacteroidota, with the most pronounced alterations observed in the HCD group. These microbial shifts were closely associated with reduced sialic acid content on LDL particles, suggesting a potential link between gut microbial dysbiosis and LDL desialylation. Functional profiling further showed a dynamic transition in microbial metabolic capacity. At week 8, the HCD group exhibited a compensatory enhancement of selected metabolic pathways, whereas by week 12, broad functional deterioration emerged, involving energy metabolism, cellular structural biosynthesis, and genetic information-processing pathways. These findings indicate a progressive loss of microbial functional resilience under sustained high-cholesterol exposure. Metabolomic analysis revealed suppression of cholesterol metabolism and bile acid biosynthesis pathways, activation of insulin resistance-related signaling, and accumulation of candidate pathogenic metabolites, including specific diglycerides and 25-hydroxycholecalciferol. These metabolites were associated with enhanced inflammatory activation and reduced LDL sialylation, suggesting that diet-induced microbial and metabolic perturbations may converge to amplify systemic chronic inflammation and accelerate atherogenesis. Discussion: HCD promotes atherosclerosis progression in the context of LDLR deficiency by inducing time-dependent gut microbiota dysbiosis, characterized by structural reorganization and progressive functional impairment. This dysbiotic trajectory promotes pathogenic metabolite accumulation, systemic inflammatory activation, and LDL desialylation through a microbiota-metabolism-immune axis. These findings provide mechanistic insight into the gut microbial regulation of atherosclerosis and support the development of microecology-based strategies for cardiovascular disease prevention and intervention.