肠道菌群代谢物TMAO上调NLRP3炎性小体:海马相关认知障碍致病机制的研究  

Role of gut microbiota metabolite TMAO in upregulating NLRP3 inflammasome:a study on the pathogenesis of hippocampus-related cognitive impairment

作　　者：杨梅芳 陈治任 周紫璇 陈巍巍 YANG Meifang;CHEN Zhiren;ZHOU Zixuan;CHEN Weiwei(Xuzhou Clinical College of Xuzhou Medical University,Xuzhou,Jiangsu 221000,China;Department of Neurology,Xuzhou Central Hospital,Xuzhou,Jiangsu 221000;Xuzhou Medical Science Research Institute,Xuzhou,Jiangsu 221000)

机构地区：[1]徐州医科大学徐州临床学院,江苏徐州221000 [2]徐州市中心医院神经内科,江苏徐州221000 [3]徐州市医学科学研究所,江苏徐州221000

出　　处：《徐州医科大学学报》2025年第2期88-92,共5页Journal of Xuzhou Medical University

基　　金：国家自然科学基金(81501138);江苏省中医药科技发展计划项目(MS2022067);江苏省研究生科研与实践创新计划项目(SJCX23_1402,SICX241550);徐州市科技局项目(KC23072)。

摘　　要：目的探究肠道菌群代谢物三甲胺N-氧化物(TMAO)介导神经炎症反应在认知功能障碍中的潜在作用。方法将小鼠随机分为对照组、TMAO组、TMAO+DMB组。TMAO组小鼠经TMAO和高胆碱高脂饲料联合喂养6周,TMAO+DMB组在此基础上同时喂养TMAO抑制剂4,4′-二氨基-3,3′-二甲基联苯(DMB)6周。Western blot检测小鼠双侧海马中NOD样受体热蛋白结构域相关蛋白3(NLRP3)、半胱氨酸蛋白酶-1(caspase-1)、白细胞介素-1β(IL-1β)蛋白水平;焦油紫染色观察小鼠海马CA1区神经元形态及存活情况;水迷宫实验评估小鼠学习记忆能力。结果与对照组相比,TMAO组小鼠海马组织内NLRP3、caspase-1、IL-1β蛋白表达明显增加(P<0.05),CA1区神经元大量死亡,学习记忆能力受损;DMB抑制TMAO后,TMAO+DMB组小鼠海马组织中NLRP3、caspase-1、IL-1β蛋白表达水平显著降低(P<0.05),CA1区神经元死亡率下降,损伤减轻(P<0.05),学习记忆能力得到改善。结论肠道菌群代谢产物TMAO通过上调NLRP3炎性小体介导海马组织慢性炎症反应,加重CA1区神经元损伤,导致学习记忆能力减退,加剧认知功能障碍。Objective To explore the potential role of the gut microbiota metabolite trimethylamine N-oxide(TMAO)in mediating neuroinflammatory responses in cognitive impairment.Methods Mice were randomly divided into three groups:control,TMAO,and TMAO+DMB.The TMAO group was fed a high-choline,high-fat diet combined with TMAO for six weeks,while the TMAO+DMB group received the same diet along with TMAO inhibitor 4,4′-diamino-3,3′-dimethylbiphenyl(DMB)for six weeks.The levels of NOD-like receptor thermal protein domain associated protein 3(NLRP3),caspase-1,and interleukin-1β(IL-1β)in the bilateral hippocampus of the mice were detected by Western blot.The morphology and survival of neurons in hippocampal CA1 region was observed by Cresyl violet staining.The Morris water maze test was used to evaluate learning and memory abilities.Results Compared with the control group,the TMAO group showed significantly increased expression of NLRP3,caspase-1,and IL-1βproteins in the hippocampal tissues(P<0.05),and exhibited excessive neuron deaths in the CA1 region,with impaired learning and memory abilities.After TMAO inhibition with DMB,the TMAO+DMB group showed significantly reduced levels of NLRP3,caspase-1,and IL-1βproteins in the hippocampus(P<0.05),and exhibited decreases in neuron death rate,indicating alleviated damage(P<0.05),with improved learning and memory abilities.Conclusions The gut microbiota metabolite TMAO exacerbates chronic inflammatory responses in the hippocampus by upregulating the NLRP3 inflammasome,which lesds to increased neuronal damage in the CA1 region,and impaired learning and memory,ultimately worsening cognitive dysfunction.

关 键 词：肠道菌群代谢物 三甲胺N-氧化物 NOD样受体热蛋白结构域相关蛋白3 海马体 认知功能障碍 

分 类 号：R741.02[医药卫生—神经病学与精神病学]