1型糖尿病伴认知功能损伤小鼠脑组织肠道菌群代谢物的改变  

Dysregulated microbial metabolites in brain of mice with type 1 diabetes mellitus-induced cognitive impairment

作　　者：安宇 边南南 丁小雨 常晓娜 刘佳[1] 王广[1] An Yu;Bian Nannan;Ding Xiaoyu;Chang Xiaona;Liu Jia;Wang Guang(Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China)

机构地区：[1]首都医科大学附属北京朝阳医院内分泌科,北京100020

出　　处：《首都医科大学学报》2022年第4期622-629,共8页Journal of Capital Medical University

基　　金：国家自然科学基金青年项目(82103811);首都医科大学附属北京朝阳医院金种子科研基金(CYJZ202102);中国科协第六届青年人才托举工程项目(2020QNRC001)。

摘　　要：目的探讨在发生认知功能损伤的1型糖尿病(type 1 diabetes mellitus,T1DM)小鼠脑组织中肠道菌群代谢物的变化。方法选取20只6周龄C57BL/6小鼠,适应性喂养1周后采用数字表法随机分为对照组(Control组,n=10)和1型糖尿病模型组(DM组,n=10)进行处理。采用链脲佐菌素(streptozotocin,STZ)诱导T1DM小鼠,造模成功8周后进行Morris水迷宫检测,随后收集小鼠脑组织采用宏代谢组学检测肠道菌群代谢产物,并分析差异代谢物以及代谢通路。结果STZ腹腔注射后8周DM组小鼠空间学习和记忆能力明显受损,表现为Morris水迷宫中逃避潜伏期显著增加(P<0.001),平均游泳距离显著增加(P=0.001),目的象限所在时间(P=0.043)和穿越平台次数显著减少(P=0.004)。采用宏代谢组学鉴定了脑组织中123种肠道菌群代谢物并发现了谷氨酰胺(Log_(2)FC=0.262,P=0.002)、酒石酸(Log_(2)FC=0.847,P=0.017)、乳酸(Log_(2)FC=0.326,P=0.002)和间氨基苯甲酸(Log_(2)FC=1.028,P=0.046)、3-氨基异丁酸(Log_(2)FC=-1.466,P=0.049)、葡萄糖酸内酯(Log_(2)FC=-0.796,P=0.043)和苏糖酸(Log_(2)FC=-0.310,P=0.042)、吲哚乳酸(Log_(2)FC=-1.252,P=0.030)、酮亮氨酸(Log_(2)FC=-0.922,P=0.040)、3-羟基丁酸(Log_(2)FC=-0.372,P=0.009)以及肉豆蔻酸(Log_(2)FC=-0.563,P=0.035)11种显著差异代谢物,涉及14个主要相关代谢通路,包括嘧啶代谢、氨基酸代谢、糖代谢、短链脂肪酸代谢等。结论DM小鼠脑组织中多种肠道菌群代谢物水平发生显著变化,靶向肠道菌群及其相关代谢通路有望成为治疗T1DM诱导的认知功能障碍的有效策略。Objective To investigate the changes of intestinal microflora metabolites in brain tissue of type 1 diabetes mellitus(T1DM)mice with cognitive impairment.Methods To develop a T1DM model,male C57BL/6 mice aged 6 weeks were given by intraperitoneal injection of STZ at dosage 40 mg/kg of body weight for five consecutive days.The Morris water maze test was used to assess learning and memory ability in mice.An ultra-performance liquid chromatography coupled to tandem mass spectrometry(UPLC-MS/MS)system was applied to identify and quantify microbiota-derived metabolites in brain samples collected from sacrificed mice.Results The gut microbial metabolic profiles in brains of diabetes mellitus(DM)mice differed significantly from controls.Compared with control mice,brain levels of glutamine(Log_(2)FC=0.262,P=0.002),tartaric acid(Log_(2)FC=0.847,P=0.017),lactic acid(Log_(2)FC=0.326,P=0.002)and m-aminobenzoic acid(Log_(2)FC=1.028,P=0.046)were significantly higher(all Log_(2)FC>0,P<0.05)while indolelactic acid,3-hydroxybutyric acid(Log_(2)FC=-1.466,P=0.049)and other 5 metabolites were significantly lower(all Log_(2)FC<0,P<0.05)in DM mice.Such metabolic differences encompassed pyrimidine metabolism,D-glutamine and D-glutamate metabolism,pyruvate metabolism,purine metabolism and other metabolic pathways.Conclusion Gut microbiome and its metabolites may play a crucial role in the onset and development of type 1 diabetes-induced cognitive impairment.Targeting the gut microbiome and relevant microbiota-derived metabolites would be effective therapeutic treatments for T1DM-induced cognitive impairment.

关 键 词：1型糖尿病 认知功能 肠道菌群代谢物 宏代谢组 

分 类 号：R587[医药卫生—内分泌]