Abstract
Objectives: Postbiotics have been shown to significantly attenuate atherosclerosis development. This study aimed to elucidate the mechanisms underlying this protective effect, focusing on gut microbiota remodeling, reduction of trimethylamine N-oxide (TMAO), and suppression of the TMAO-activated inflammatory pathway. Methods: A high-fat diet (HFD) combined with choline was used to establish an atherosclerosis mouse model. Mice were divided into four groups: control, model, JA845, and Post-JA845 groups. Histological analysis, immunofluorescence staining, inflammatory cytokine detection, 16S rRNA sequencing, metabolomics, and proteomics were used to evaluate the regulatory effects of JA845 postbiotics on gut microbiota composition, TMAO metabolism, and the JAK/STAT3 signaling pathway. Results: Histopathological examination revealed that JA845 postbiotics markedly attenuated atherosclerotic plaque formation in the aorta and improved overall vascular pathology. The treatment effectively regulated lipid metabolism, demonstrating significant reductions in atherogenic LDL and total cholesterol levels, while promoting beneficial HDL elevation. JA845 postbiotics demonstrated potent anti-inflammatory effects by significantly lowering circulating levels of IL-6, IL-33, IL-1β, and TNF-α. Gut microbiota analysis showed substantial compositional changes, with increased abundance of beneficial Bacteroides and Parabacteroides alongside decreased pro-atherogenic Ruminococcus and Akkermansia. At the molecular level, the postbiotics inhibited TMAO generation, suppressed JAK/STAT3 signaling pathway activation, and enhanced endothelial function through upregulated eNOS-mediated nitric oxide production. These coordinated effects collectively contribute to the observed cardiovascular protection. Conclusions: JA845 postbiotics exhibit superior efficacy in reducing TMAO levels, modulating gut microbiota, alleviating inflammation, and improving vascular function, offering a novel strategy for atherosclerosis prevention and treatment.