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

Abstract

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 β-sitosterol can inhibit TMA production in ApoE–/– mice by reshaping the gut microbial structure. 16S rRNA sequencing of the gut microbiota showed that β-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, β-sitosterol effectively reduced the TMA, FMO3, and TMAO levels while ameliorating the atherosclerotic plaques of AS mice. Moreover, β-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 β-sitosterol, which targets the microbiota-metabolism-immunity axis as a possible therapy for AS.

Key ingredients in Verbena officinalis and determination of their anti-atherosclerotic effect using a computer-aided drug design approach

“…A study reported the antioxidant, anti-inflammatory, and cardioprotective effects of kaempferol and suggested its potential as a drug candidate for treating and preventing AS ( Chen et al., 2022b ). Beta-sitosterol can effectively reduce the production of the intestinal microbial metabolite trimethylamine to ameliorate atherosclerotic plaques in AS mice ( Wu et al., 2022 ). Stigmasterol activates the nuclear receptor LXR to promote cholesterol secretion via the intestinal tract and inhibits the expression of proinflammatory mediators such as IL-6, IL-1β, COX-2, and TNF-α to ameliorate AS ( Lifsey et al., 2019 ).…”

Gut–brain communication mediates the impact of dietary lipids on cognitive capacity

“…Sitosterol intervention can increase the abundance of Lactobacillus pentosus to produce SCFAs in the gut of mice, 195 contributing to alleviate cognitive impairment through the GBA. 196 Intake of β-sitosterol inhibits TMA production in the gut of mice, 197 leading to a reduction in TMAO levels in the liver, 198 and ultimately lowering the cognitive impairment caused by TMAO. Moreover, stigmasterol activates the butyrate–PPARγ axis, and re-establishes the equilibrium of Treg/Th17 cells to alleviate the damage to the cerebrovascular system caused by the massive release of Th17, and ultimately improves cognition in colitis mice.…”

More than a meat- or synthetic nitrogen fertiliser-substitute: a review of legume phytochemicals as drivers of ‘One Health’ via their influence on the functional diversity of soil- and gut-microbes

“…On the other hand, soyasaponins, which are commonly found in soybean, have been observed to reduce inflammation caused by allergies by positively impacting the composition of the intestinal flora ( Nagano et al., 2017 ). Additionally, other bioactive compounds, like β-sitosterol, a phytosterol commonly present in legume ingredients found in Mediterranean diets ( Jiménez-Escrig et al., 2006 ), have demonstrated the capability to inhibit certain bacterial genera that possess the genes responsible for a major pathway leading to atherosclerosis (the build-up of lipids in arteries) ( Wu et al., 2022 ). Plant sterols have also been associated with an increase in the abundance of Eubacterium hallii ( Cuevas-Tena et al., 2018 ), an anaerobic bacterium currently classified as Anaerobutyricum hallii , known for producing butyrate, which has positive implications for insulin sensitivity treatments in obese and diabetic mice ( Udayappan et al., 2016 ).…”