Berberine attenuates choline-induced atherosclerosis by inhibiting trimethylamine and trimethylamine-N-oxide production via manipulating the gut microbiome

Abstract

Trimethylamine-N-oxide (TMAO), a derivative from the gut microbiota metabolite trimethylamine (TMA), has been identified to be an independent risk factor for promoting atherosclerosis. Evidences suggest that berberine (BBR) could be used to treat obesity, diabetes and atherosclerosis, however, its mechanism is not clear mainly because of its poor oral bioavailability. Here, we show that BBR attenuated TMA/TMAO production in the C57BL/6J and ApoE KO mice fed with choline-supplemented chow diet, and mitigated atherosclerotic lesion areas in ApoE KO mice. Inhibition of TMA/TMAO production by BBR-modulated gut microbiota was proved by a single-dose administration of d9-choline in vivo. Metagenomic analysis of cecal contents demonstrated that BBR altered gut microbiota composition, microbiome functionality, and cutC/cntA gene abundance. Furthermore, BBR was shown to inhibit choline-to-TMA conversion in TMA-producing bacteria in vitro and in gut microbial consortium from fecal samples of choline-fed mice and human volunteers, and the result was confirmed by transplantation of TMA-producing bacteria in mice. These results offer new insights into the mechanisms responsible for the anti-atherosclerosis effects of BBR, which inhibits commensal microbial TMA production via gut microbiota remodeling.

Multi-Pharmacology of Berberine in Atherosclerosis and Metabolic Diseases: Potential Contribution of Gut Microbiota

“…This was accompanied by alterations in gut microbiota composition and function as well as altered cutC/cntA gene abundance. Data obtained from in vitro and fecal samples of choline-fed mice and human volunteers indicated that BBR inhibited the conversion of choline to TMA, and this conclusion was confirmed via transplantation of TMAproducing bacteria (including Anaerococcus hydrogenalis, Clostridium asparagiforme, Clostridium sporogenes, and Escherichia fergusonii) in mice (Li et al, 2021). These findings are also similar to those of our previous study on the effect of BBR on AS and gut microbiota regulation in HFD-fed ApoE −/− mice.…”

“…Wang et al first demonstrated that 3,3-dimethyl-1-butanol (DMB, a choline structural analog), and its modified product could attenuate TMA formation non-lethally by inhibiting microbial TMA lyase (cutC and cutD), significantly reducing plasma TMAO levels and alleviating atherosclerotic lesions in diet-induced animal models (Wang et al, 2015;Roberts et al, 2018). A recent study published by Li et al (2021) further confirmed these results, as BBR was found to reduce TMA/TMAO production in choline-fed C57BL/6J and ApoE knockout mice and attenuate atherosclerotic lesion areas in the latter. This was accompanied by alterations in gut microbiota composition and function as well as altered cutC/cntA gene abundance.…”

Gut Microbiota and Atherosclerosis—Focusing on the Plaque Stability

“…Some studies have demonstrated that knockdown of the FMO3 gene can significantly reduce the production of TMAO ( 67 , 68 ). In recent years, several new approaches have been found to inhibit the TMAO formation to alleviate the development of atherosclerosis ( 69 , 70 ). However, most researches conducted in vivo studies are in murine models, with few in humans.…”

Gut Microbiome, Functional Food, Atherosclerosis, and Vascular Calcifications—Is There a Missing Link?

“…A hypothesis regarding the potential capacity of berberine to modify gut microbiota and treat diabetes, obesity, and atherosclerosis was raised, based on the inhibition of TMA/TMAO production by gut microbiota mediated by berberine. According to the work of Li Xingxing et al, berberine proved to attenuate TMA/TMAO production, so it diminished atherosclerotic lesions in animal subjects fed with cereal-based diets, supplemented with choline [ 186 ].…”