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

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(Log₂FC=0.262,P=0.002)、酒石酸(Log₂FC=0.847,P=0.017)、乳酸(Log₂FC=0.326,P=0.002)和间氨基苯甲酸(Log₂FC=1.028,P=0.046)、3-氨基异丁酸(Log₂FC=-1.466,P=0.049)、葡萄糖酸内酯(Log₂FC=-0.796,P=0.043)和苏糖酸(Log₂FC=-0.310,P=0.042)、吲哚乳酸(Log₂FC=-1.252,P=0.030)、酮亮氨酸(Log₂FC=-0.922,P=0.040)、3-羟基丁酸(Log₂FC=-0.372,P=0.009)以及肉豆蔻酸(Log₂FC=-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。

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

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 (Log₂FC=0.262,P=0.002), tartaric acid (Log₂FC=0.847,P=0.017), lactic acid (Log₂FC=0.326,P=0.002) and m-aminobenzoic acid (Log₂FC=1.028,P=0.046) were significantly higher (all Log₂FC>0, P<0.05) while indolelactic acid, 3-hydroxybutyric acid (Log₂FC=-1.466,P=0.049) and other 5 metabolites were significantly lower (all Log₂FC<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.