Akkermansia Muciniphila Protects Against Atherosclerosis by Preventing Metabolic Endotoxemia-Induced Inflammation in Apoe-/- Mice

Abstract

Background—Altered composition of the gut microbiota is involved in both onset and progression of obesity and diabetes. However, the link between gut microbiota and obesity-related cardiovascular complications has not been explored. The present study was designed to investigate the role of Akkermansia muciniphila, a mucin-degrading bacterium with beneficial effects on metabolism, in the pathogenesis of atherosclerosis in apolipoprotein E-deficient (Apoe-/-) mice. Methods and Results—Apoe-/- mice on normal chow diet or Western diet were treated with A. muciniphila by daily oral gavage for eight weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time PCR analysis demonstrated that the fecal abundance of A. muciniphila was significantly reduced by Western diet. Replenishment with A. muciniphila reversed Western diet-induced exacerbation of atherosclerotic lesion formation without affecting hypercholesterolemia. A. muciniphila prevented Western diet-induced inflammation in both circulation and local atherosclerotic lesion, as evidenced by reduced macrophage infiltration and expression of proinflammatory cytokines and chemokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia. A. muciniphila-mediated reduction in circulating endotoxin level could be attributed to induction of intestinal expression of the tight junction proteins (ZO-1 and occludin), thereby reversing Western diet-induced increases in gut permeability. Chronic infusion of endotoxin to Apoe-/- mice reversed the protective effect of A. muciniphila against atherosclerosis. Conclusions—A. muciniphila attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.