动脉粥样硬化（AS）是一种慢性炎症性血管疾病，肠道菌群失调与AS炎症密切相关，但调控AS的具体肠道菌及相关机制所知甚少。课题组发现AS患者粪便中肠道细菌Akkermansia muciniphila（AKK）量明显减少，而apoE-/-小鼠在高脂饮食基础上灌胃给予AKK可促进内源性大麻素2-arachidonoylglycerol（2-AG）在肠粘膜中的表达，抑制血管周围脂肪组织（PVAT）炎症，促进其棕色化，并抑制AS发展。基于此，本项目拟：1.研究AKK对apoE-/-小鼠AS进展和炎症浸润的调控作用；2.研究AKK对PVAT形态、棕色化、炎症浸润和功能的调控作用，应用PVAT移植技术明确AKK是否通过调控PVAT炎症和棕色化保护AS；3.通过体内和体外过表达和抑制2-AG表达，阐明2-AG在AKK保护肠道屏障功能，阻断LPS进入体内，抑制AS发展中发挥限速功能，为AS防治提供新方向。

Atherosclerosis (AS) is a low-grade chronic inflammatory vascular disease. Gut microbiota dysbiosis tightly correlated with chronic inflammation of AS, but little is known about the specific gut bacterium that regulates AS development and the mechanism involved. In previous work, we found that the levels of Akkermansia muciniphila (AKK) in fecal samples of AS patients and high fat diet-fed apoE-/- mice were obviously lower than those in normal subjects and normal chow diet-fed apoE-/- mice. While in high fat diet-fed apoE-/- mice, AKK given by daily oral gavage induced 2-arachidonoylglycerol (2-AG) expression in intestinal mucosa, inhibited perivascular adipose tissue (PVAT) inflammation, accelerated PVAT browning, and attenuated AS lesion. Based on these, this project tries to: 1. Study whether AKK inhibits high fat diet-fed apoE-/- mice AS development, and whether it regulates plaque inflammation. 2. Demonstrate how AKK regulates PVAT differentiation, inflammatory cells infiltration, adipokine and cytokine secretion. And detect whether AKK protects against AS by regulating PVAT inflammation and paracrine function using PVAT implantation technique. 3. Clarify the rate-limiting role of 2-AG in AKK protecting intestinal barrier function, inhibiting LPS enters into the body, and inhibiting AS development by up-regulating and down-regulating 2-AG in vivo and in vitro. This project is trying to disclose the role of AKK in inhibiting AS development and the mechanism involved, which might uncover a new target for AS prevention and treatment.