Aucubin ameliorates atherosclerosis by modulating tryptophan metabolism and inhibiting endothelial-mesenchymal transitions via gut microbiota regulation.

BACKGROUND

The gut microbiota is believed to influence atherosclerosis (AS), and Aucubin (Au), a natural compound found in the traditional Chinese medicine Eucommia ulmoides Oliver, is being explored as a potential treatment for cardiovascular disease. Yet, the specific impact of Au on AS through the gut microbiota remains unclear.

PURPOSE

This study aimed to highlight the potential of Au in improving AS by influencing gut microbiota and investigating its potential mechanisms by which it and its metabolites of gut microbiota regulate lipid metabolism, inflammation and endothelial dysfunction.

METHODS

The impact of Au on AS in ApoE mice was examined, followed by a fecal microbiota transplantation experiment to confirm the influence of Au on AS through gut microbiota. Subsequent analysis of fecal and serum samples using 16S rRNA gene sequencing and metabolomics revealed distinct features of gut microbiota and metabolites. Identified metabolites were then utilized in vivo experiments to investigate underlying mechanisms.

RESULTS

Au treatment effectively reduced dietary-induced dyslipidemia and endothelial dysfunction in a dose-dependent manner in atherosclerotic mice. It also improved vascular plaque accumulation and inflammation, increased aortic valve fibrous cap thickness, and decreased necrotic core and collagen fiber area. Subsequently, we observed a substantial increase in indole-3-acrylic acid (IAA), a microbe-derived metabolite, in cecal contents and serum, along with a significant rise in Lactobacillus abundance responsible for IAA production. Our findings demonstrated that IAA played a crucial role in alleviating AS. Furthermore, we discovered that IAA activated the Aryl hydrocarbon receptor (AhR) and suppressed the TGF-β/Smad pathway, potentially ameliorating endothelial-mesenchymal transitions in atherosclerotic mice.

CONCLUSION

These findings suggested that Au's anti-atherosclerotic effects were primarily due to elevated Lactobacillus-derived IAA, thereby potentially contributing to alleviating AS.