β-sitosterol inhibits trimethylamine production by regulating the gut microbiota and attenuates atherosclerosis in ApoE-/- mice

The intestinal microbial metabolite trimethylamine (TMA), which is activated by flavin monooxygenase (FMO) to produce trimethylamine-N-oxide (TMAO), has been implicated in the pathogenesis of atherosclerosis (AS), leading to the development of therapeutic strategies for AS. This study aimed to investigate whether beta-sitosterol can inhibit TMA production in ApoE(-/-) mice by reshaping the gut microbial structure. 16S rRNA sequencing of the gut microbiota showed that beta-sitosterol has beneficial effects on intestinal flora function, especially the inhibition of bacteria genera that contain the gene cholintrimethylamine lyase, which is responsible for the major pathway for TMA production. In parallel, beta-sitosterol effectively reduced the TMA, FMO3, and TMAO levels while ameliorating the atherosclerotic plaques of AS mice. Moreover, beta-sitosterol could alleviate cholesterol metabolism and the inflammatory response, and improve the antioxidant defense capacity. These studies offer new insights into the mechanisms responsible for the antiatherosclerotic effects of beta-sitosterol, which targets the microbiota-metabolism-immunity axis as a possible therapy for AS.

Automated summary

This study found that beta-sitosterol has a regulatory effect on the gut microbial structure, inhibiting a key step in the development of atherosclerosis. Simultaneously, it improves plaque formation in AS mice by reducing TMA, FMO3, and TMAO levels. Additionally, beta-sitosterol improves cholesterol metabolism, reduces inflammation, and enhances antioxidant defense capacity.