绿原酸联合罗伊氏乳杆菌改善肥胖阿尔茨海默症小鼠的代谢紊乱和认知功能障碍

Caffeoylquinic acid and Limosilactobacillus reuteri improves metabolic disorders and cognitive dysfunction in obese Alzheimer’s disease mouse model

关键词:  阿尔茨海默症  肥胖相关代谢紊乱  益生菌  益生元  短链脂肪酸

Key words:  Alzheimer’s disease  obesity-related metabolic disorders  probiotics  prebiotics  SCFAs

摘要:

目的 研究绿原酸(Caffeoylquinic acid,CQA)联合罗伊氏乳杆菌(Limosilactobacillus reutter,L. reuteri)对肥胖阿尔茨海默症(Alzheimer’s disease,AD)小鼠代谢紊乱及认知障碍的影响及具体作用机制。方法 将5×FAD小鼠随机分为三组：正常饮食对照组(CD-V)、高脂饮食模型组(HFD-V)以及高脂饮食联合给药组(HFD-CQA + L. reuteri),连续给药8周,检测各组小鼠的血糖、血脂等代谢指标；通过新物体识别实验和Y迷宫实验评估认知功能；检测海马区神经元丢失及突触相关蛋白的表达水平；采用16S rRNA测序分析肠道菌群变化；利用LC-MS检测血清短链脂肪酸水平。结果 CQA和L. reuteri联合干预显著降低了肥胖AD小鼠的体脂含量、脂肪/瘦肉比值及血脂水平,改善了血糖水平和葡萄糖耐量,缓解了高脂饮食引起的代谢紊乱。同时,联合干预显著提高了认知指数和自发交替率,改善了肥胖AD小鼠对新物体的探索兴趣和空间记忆能力,且认知指数与和血糖血脂水平呈显著负相关；通过降低GFAP水平减少星形胶质细胞活化,并增加PSD95表达,减轻了脑组织损伤。此外,CQA显著增强L. reuteri的生长及益生菌活性；CQA和L. reuteri能够恢复肠道微生物稳态,增加有益菌丰度,显著增加血清中丙酸水平。结论 CQA和L. reuteri通过改善肥胖相关代谢紊乱、缓解海马神经元丢失和突触损伤、减少星形胶质细胞活化、恢复肠道微生物稳态,改善小鼠的认知功能障碍和脑损伤。

Abstract:

ABSTRACT: OBJECTIVE To investigate the effects and underlying mechanisms of caffeoylquinic acid (CQA) combined with Limosilactobacillus reuteri (L. reuteri) on metabolic disorders and cognitive impairment in obese Alzheimer""s disease (AD) mice. METHODS 5×FAD mice were randomly divided into three groups: normal diet control (CD-V), high-fat diet model (HFD-V), and high-fat diet with CQA + L. reuteri intervention (HFD-CQA + L. reuteri). After 8 weeks of treatment, metabolic parameters including blood glucose and lipid profiles were measured. Cognitive function was assessed using the novel object recognition test and Y-maze test. Hippocampal neuronal loss and synaptic protein expression (PSD95) were evaluated. Gut microbiota composition was analyzed via 16S rRNA sequencing, and serum short-chain fatty acid (SCFAs) levels were quantified by LC-MS. RESULTS The combined intervention of CQA and L. reuteri significantly reduced body fat content, fat/lean ratio, and serum lipid levels in AD mice, while improving glucose metabolism and ameliorating HFD-induced metabolic disorders. Meanwhile, the treatment markedly enhanced recognition index and spontaneous alternation rate, indicating improved exploration behavior and spatial memory. The recognition indices were negatively correlated with blood glucose and lipid levels. The intervention also attenuated astrocyte activation by reducing GFAP levels, while increasing PSD95 expression to alleviating brain tissue damage. Notably, CQA significantly enhanced the growth and probiotic activity of L. reuteri. Additionally, the combination of CQA and L. reuteri restored gut microbiota homeostasis, increased beneficial bacterial abundance, and elevated propionic acid levels. CONCLUSION CQA and L. reuteri synergistically ameliorated cognitive dysfunction and neuropathology by improving obesity-related metabolic disorders, reducing hippocampal neuronal loss and synaptic damage, suppressing astrocyte activation, and restoring intestinal microbiota homeostasis.