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

Background-Altered composition of the gut microbiota is involved in both the onset and progression of obesity and diabetes mellitus. 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 a Western diet were treated with A muciniphila by daily oral gavage for 8 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time polymerase chain reaction 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 the 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 the induction of intestinal expression of the tight junction proteins (zona occuldens protein-1 and occludin), thereby reversing Western diet-induced increases in gut permeability. Long-term infusion of endotoxin to Apoe(-/-) mice reversed the protective effect of A muciniphila against atherosclerosis. Conclusion-A muciniphila attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier.