Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy.
Dipartimento di Medicina e Chirurgia, Università di Milano-Bicocca, 20126 Milan, Italy.
Biomolecules. 2023 Aug 29;13(9):1325. doi: 10.3390/biom13091325.
The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography-tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dysfunction were reported. Interestingly, our analysis highlighted a small group of taxa strictly related to both memory impairment and neuroactive steroid levels. Overall, the data underline an interesting role for allopregnanolone and microbiota that may represent candidates for the development of therapeutic strategies.
2 型糖尿病（T2DM）的病理后果也涉及中枢神经系统；事实上，T2DM 患者存在学习和记忆障碍，并且痴呆的风险更高。尽管已经提出了几种可能的因素，但神经活性甾体和肠道微生物组如何影响 T2DM 中的大脑病理生理学仍未得到探索。在此基础上，我们在雄性 Zucker 糖尿病肥胖（ZDF）大鼠中研究了 T2DM 是否通过新型物体识别测试、液相色谱-串联质谱法测定神经活性甾体水平、分子评估测定海马参数以及 16S 下一代测序测定肠道微生物组组成来改变记忆能力。结果表明，T2DM 会恶化记忆能力，并且这些与血浆中皮质酮水平升高以及海马中异孕烯醇酮水平降低有关，在海马中报告了神经炎症、氧化应激和线粒体功能障碍。有趣的是，我们的分析突出了一小群与记忆障碍和神经活性甾体水平都密切相关的分类群。总的来说，这些数据强调了异孕烯醇酮和微生物组的有趣作用，它们可能是治疗策略开发的候选物。
