Metformin intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation.

Ning Yan,Ru Yan,Lijuan Wang,Hao Wang,Libo Yang,Shaobin Jia,Ting Wang,Yiwei Li,Michael Bader

doi:10.1371/journal.pone.0254321

Abstract

Atherosclerosis (AS) is closely associated with chronic low-grade inflammation and gut dysbiosis. Metformin (MET) presents pleiotropic benefits in the control of chronic metabolic diseases, but the impacts of MET intervention on gut microbiota and inflammation in AS remain largely unclear. In this study, ApoE-/- mice with a high-fat diet (HFD) were adopted to assess the MET treatment. After 12 weeks of MET intervention (100mg·kg-1·d-1), relevant indications were investigated. As indicated by the pathological measurements, the atherosclerotic lesion was alleviated with MET intervention. Moreover, parameters in AS including body weights (BWs), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC) and malondialdehyde (MDA) were elevated; whereas high-density lipoprotein (HDL) and total superoxide dismutase (T-SOD) levels were decreased, which could be reversed by MET intervention. Elevated pro-inflammatory interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and lipopolysaccaride (LPS) in AS were decreased after MET administration. However, anti-inflammatory IL-10 showed no significant difference between AS group and AS+MET group. Consistently, accumulated macrophages in the aorta of AS were conversely lowered with MET treatment. The results of 16S rRNA sequencing and analysis displayed that the overall community of gut microbiota in AS was notably changed with MET treatment mainly through decreasing Firmicutes, Proteobacteria, Romboutsia, Firmicutes/Bacteroidetes, as well as increasing Akkermansia, Bacteroidetes, Bifidobacterium. Additionally, we found that microbiota-derived short-chain fatty acids (SCFAs) including acetic acid, propionic acid, butyric acid and valeric acid in AS were decreased, which were significantly up-regulated with MET intervention. Consistent with the attenuation of MET on gut dysbiosis, decreased intestinal tight junction protein zonula occludens-1 (ZO)-1 in AS was restored after MET supplementation. Correlation analysis showed close relationships among gut bacteria, microbial metabolites SCFAs and inflammation. Collectively, MET intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation, thus can potentially serve as an inexpensive and effective intervention for the control of the atherosclerotic cardiovascular disease.

Highlights

Atherosclerosis (AS) maintains a leading cause of death worldwide despite considerable advances in prevention, diagnosis and therapy [1, 2]
There was no significant difference in initial body weights (BWs) among three groups
We found that BWs in AS group was significantly elevated compared to the control group (CON) group in week 5 and 6, whereas BWs of AS mice were obvious decreased after MET intervention from week 8 to week 12, demonstrating that MET intervention could attenuate weight gain in AS (p

Summary

Introduction

Atherosclerosis (AS) maintains a leading cause of death worldwide despite considerable advances in prevention, diagnosis and therapy [1, 2]. Patients with AS were characterized by angina, peripheral arterial disease, lipid metabolism disorders, inflammatory response and endothelial dysfunction [3, 4]. A study indicates that the relative abundance of Collinsella genus in the intestinal of AS patients are increased, while Roseburia and Eubacterium are decreased compared to healthy individuals [8]. Regulation of the composition of the overall gut microbiota by increasing Bacteroidetes and Akkermensia abundance, as well as reducing Firmicutes and Proteobacteria abundance can prevent AS in ApoE-/- mice [9]. The modulation of the gut microbiome may contribute to improving the disease

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