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

Circulation. 2016 Jun 14;133(24):2434-46. doi: 10.1161/CIRCULATIONAHA.115.019645. Epub 2016 Apr 25.


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.

Keywords: atherosclerosis; endotoxemia; gut microbiota.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Atherosclerosis / microbiology
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Caco-2 Cells
  • Disease Models, Animal
  • Endotoxemia / etiology
  • Endotoxemia / microbiology
  • Endotoxemia / prevention & control*
  • Humans
  • Inflammation / etiology
  • Inflammation / microbiology
  • Inflammation / prevention & control*
  • Intestines / microbiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Treatment Outcome
  • Verrucomicrobia / physiology*