Liu Huan, Ma Xiaofeng, Yang Xuefeng, Xiao Sujun, Ouyang Shao, Hu Zhihao, Zhou Zhixiang, Jiang Zhisheng
Insititute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, Hunan 421001, China; Department of Cardiology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Department of Cardiology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Int J Med Microbiol. 2025 Mar;318:151642. doi: 10.1016/j.ijmm.2024.151642. Epub 2024 Dec 26.
The probiotic E. coli Nissle 1917 (EcN) alleviates the progression of various diseases, including colitis and tumors. However, EcN has not been studied in atherosclerosis. The study investigated the effects of EcN on atherosclerosis model mice and the potential mechanisms.
Mice in the high-fat diet (HFD) model were given EcN (1 × 10 CFU/g) or homocitrulline (150 mg/L) by oral administration for 12 weeks. The EcN + antibiotic group was set up to investigate the effects of EcN combined with antibiotics on gut microbiota. The control group was utilized as the negative control. Atherosclerosis status, pyroptosis, gut microbiota, and serum metabolites of mice were examined.
EcN treatment alleviated HFD-caused atherosclerotic plaque and lipid droplet production. EcN treatment reversed HFD-induced increases in total cholesterol, triglycerides, and low-density lipoprotein levels and decreases in high-density lipoprotein levels. EcN inhibited the HFD-caused rise in the expression of pyroptosis-related indicators (cleaved Caspase 1, GSDMD-N, NLRP3, IL-18, and IL-1β). The antibiotics partially reversed the effects of EcN on the model mice, suggesting that EcN regulated pyroptosis in the model mice through gut microbiota. Probiotic bacteria, such as Lactobacillus and Muribaculum, were mainly enriched in the EcN and EcN + antibiotic groups, while Helicobacter, Alistipes, and Rikenella were depleted, suggesting that EcN and EcN + antibiotics could alleviate disorders of gut microbiota in the model mice. EcN reversed the trend of HFD-induced decrease of some metabolites, such as 2-methyl-5-nitroimidazole-1-ethanol, methionine sulfoxide, and shikimate 3-phosphate, and inhibited the increase of some metabolites, such as kynurenine, oxoadipate, and homocitrulline. In addition, homocitrulline showed the opposite effects of EcN in the model mice. Homocitrulline could bind to pyroptosis-related proteins to aggravate ox-LDL-induced endothelial cell pyroptosis.
EcN could alleviate atherosclerosis development by ameliorating HFD-induced disorders of gut microbiota and serum metabolites (such as homocitrulline) to alleviate pyroptosis, which may be associated with homocitrulline/Caspase 1/NLRP3/GSDMD axis. Our study lays the foundation for the development of promising drugs for atherosclerosis in the future.
益生菌大肠杆菌Nissle 1917（EcN）可缓解包括结肠炎和肿瘤在内的多种疾病的进展。然而，EcN尚未在动脉粥样硬化方面进行研究。本研究调查了EcN对动脉粥样硬化模型小鼠的影响及其潜在机制。
对高脂饮食（HFD）模型小鼠口服给予EcN（1×10⁸CFU/g）或高瓜氨酸（150mg/L），持续12周。设立EcN +抗生素组以研究EcN与抗生素联合对肠道微生物群的影响。将对照组用作阴性对照。检测小鼠的动脉粥样硬化状态、细胞焦亡、肠道微生物群和血清代谢物。
EcN治疗减轻了HFD引起的动脉粥样硬化斑块和脂滴产生。EcN治疗逆转了HFD诱导的总胆固醇、甘油三酯和低密度脂蛋白水平升高以及高密度脂蛋白水平降低。EcN抑制了HFD引起的细胞焦亡相关指标（裂解的半胱天冬酶1、Gasdermin D-N、NLRP3、IL-18和IL-1β）表达的升高。抗生素部分逆转了EcN对模型小鼠的影响，表明EcN通过肠道微生物群调节模型小鼠的细胞焦亡。益生菌，如乳酸杆菌和穆里杆菌，主要在EcN组和EcN +抗生素组中富集，而幽门螺杆菌、阿里斯杆菌和理研菌属减少，表明EcN和EcN +抗生素可缓解模型小鼠肠道微生物群的紊乱。EcN逆转了HFD诱导的一些代谢物（如2-甲基-5-硝基咪唑-1-乙醇、甲硫氨酸亚砜和3-磷酸莽草酸）减少的趋势，并抑制了一些代谢物（如犬尿氨酸、草酰己二酸和高瓜氨酸）的增加。此外，高瓜氨酸在模型小鼠中表现出与EcN相反的作用。高瓜氨酸可与细胞焦亡相关蛋白结合，加重氧化型低密度脂蛋白诱导的内皮细胞焦亡。
EcN可通过改善HFD诱导的肠道微生物群和血清代谢物（如高瓜氨酸）紊乱来减轻细胞焦亡，从而缓解动脉粥样硬化的发展，这可能与高瓜氨酸/半胱天冬酶1/NLRP3/Gasdermin D轴有关。我们的研究为未来开发有前景的动脉粥样硬化药物奠定了基础。
