Akkermansia muciniphila attenuates high-fat diet-induced atherosclerosis through regulation of the endocannabinoid system

Atherosclerosis is influenced by gut microbiota, with Akkermansia muciniphila ( A. muciniphila ) emerging as a key modulator of host metabolism. This study aimed to evaluate the protective effects of A. muciniphila on high-fat diet-induced atherosclerosis in ApoE −/− mice and to elucidate the underlying mechanisms via the endocannabinoid system (ECS)-CB2 receptor pathway. Live A. muciniphila supplementation significantly reduced aortic plaque burden and systemic inflammation in high-fat diet (HFD)-fed mice compared with HFD controls. Mechanistically, A. muciniphila reshaped the host endocannabinoid profile, markedly elevating serum levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Importantly, the anti-atherosclerotic benefits of A. muciniphila were functionally dependent on CB2 signaling. CB2 agonist administration sustained the protective effects of A. muciniphila , whereas CB2 antagonism abolished these protections, leading to increased plaque areas and elevated expression of vascular adhesion molecules (MCP-1, VCAM-1, and ICAM-1). Furthermore, A. muciniphila administration reinforced intestinal barrier integrity, likely by modulating local ECS tone. These findings establish a novel gut-vascular therapeutic axis, positioning A. muciniphila as a potent functional food ingredient for the prevention of atherosclerosis through ECS-CB2-dependent signaling.