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

Xingxing Li,Chunyan Su,Mengxia Yang,Yue Zhang,Jiandong Jiang,Yu Du,Zhibo Jiang,Jin Zhang,Xiumin Zhang,Li Wang,Bin Hong,Yuxin Yang

doi:10.1038/s41522-021-00205-8

Xingxing Li, Chunyan Su + Show 10 more

Open Access

https://doi.org/10.1038/s41522-021-00205-8

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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.

Highlights

Atherosclerosis is the main pathological basis for cardiovascular disease, which is one of the leading causes of death worldwide[1]
Given the close association among BBR, gut microbiota, TMAO and pathogenesis of atherosclerosis, the goal of this study is to examine the role of BBR in gut microbiota remodeling and TMA/ TMAO generation in C57BL/6J and ApoE KO mice with atherosclerosis induced by choline-supplemented chow diet
BBR decreased TMA and TMAO levels and atherosclerosis via remodeling microbiota in ApoE KO mice To determine the role of the gut microbiota in the BBR-induced decrease of TMA and TMAO, we explored bacterial populations in the cecal contents of four groups ApoE KO mice by 16S ribosomal RNA (rRNA) gene sequence analysis (Supplementary Fig. 4a)

Summary

Introduction

Atherosclerosis is the main pathological basis for cardiovascular disease, which is one of the leading causes of death worldwide[1]. Gut microbiota that reside in the intestinal tract has been linked to numerous pathologies, including cardiovascular disease and metabolic syndrome[4,5,6]. With well-characterized anti-inflammatory and anti-oxidative properties[12,13], butyrate was recently found to be anti-atherosclerosis by increasing ABCA1mediated cholesterol efflux in peripheral macrophages[14]. Secondary bile acids, another kind of important gut microbiota metabolites, have been linked to lipid and glucose metabolism and prevention of atherosclerosis by functioning as signaling molecules[15,16,17]

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