Liu Xiang, Cui Jianli, Tan Xiaona, Yu Yaozong, Niu Junfang, Wang Qiujun
Department of Anesthesiology, Hebei Children's Hospital, NO. 133, Jian Hua South Road, Shijiazhuang, Hebei Province, China.
Department of Anesthesiology, Hebei Medical University Third Hospital, NO. 139, Ziqiang Road, Shijiazhuang, Hebei Province, China.
Mol Neurobiol. 2025 Apr 29. doi: 10.1007/s12035-025-04964-9.
Perioperative neurocognitive disorders (PND), characterized by persistent cognitive impairment lasting from days to years, present substantial clinical challenges in elderly surgical populations, profoundly compromising functional independence, quality of life, and long-term prognosis. We aimed to investigate the effects of short-chain fatty acids (SCFAs) treatment on PND via mediating Brain-derived neurotrophic factor (BDNF)/Phosphatidylinositol3-kinase (PI3K)/Protein kinase B (Akt) pathway. Using 16S rDNA sequencing targeting the V3-V4 hypervariable regions, we first demonstrated significant gut microbiota dysbiosis in PND model rats, accompanied by altered SCFAs profiles. Subsequent fecal microbiota transplantation (FMT) experiments established causal relationships between PND-associated microbial alterations and spatial cognitive deficits. Mechanistically, SCFAs supplementation attenuated neuronal damage and restored synaptic plasticity, as evidenced by Nissl staining quantification (reduced chromatolysis), TUNEL assay (decreased apoptosis rate), and immunohistochemical analysis (upregulated NeuN expression). Molecular investigations revealed that SCFAs-mediated cognitive improvement involved BDNF upregulation and subsequent PI3K/Akt pathway activation, ultimately enhancing neuronal survival and synaptic integrity. Notably, PND animals exhibited characteristic neuropathological features including synaptic density reduction (PSD-95 downregulation), neuroinflammation amplification (IL-6 elevation), and apoptosis activation-all significantly reversed by SCFA intervention. Our findings establish a novel gut-brain axis mechanism wherein microbiota-derived SCFAs may exert neuroprotection through BDNF-dependent PI3K/Akt signaling, and offer potential therapeutic strategies for PND management.
围手术期神经认知障碍（PND）的特征是持续数天至数年的认知障碍，这给老年手术人群带来了重大的临床挑战，严重损害了功能独立性、生活质量和长期预后。我们旨在研究短链脂肪酸（SCFAs）治疗通过介导脑源性神经营养因子（BDNF）/磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）通路对PND的影响。通过靶向V3-V4高变区的16S rDNA测序，我们首先证明了PND模型大鼠存在明显的肠道微生物群失调，并伴有SCFAs谱的改变。随后的粪便微生物群移植（FMT）实验建立了PND相关微生物改变与空间认知缺陷之间的因果关系。从机制上讲，补充SCFAs可减轻神经元损伤并恢复突触可塑性，尼氏染色定量（减少染色质溶解）、TUNEL检测（降低凋亡率）和免疫组织化学分析（上调NeuN表达）证明了这一点。分子研究表明，SCFAs介导的认知改善涉及BDNF上调以及随后的PI3K/Akt通路激活，最终增强了神经元存活和突触完整性。值得注意的是，PND动物表现出特征性的神经病理学特征，包括突触密度降低（PSD-95下调）、神经炎症放大（IL-6升高）和凋亡激活，所有这些都被SCFA干预显著逆转。我们的研究结果建立了一种新的肠-脑轴机制，其中微生物群衍生的SCFAs可能通过BDNF依赖的PI3K/Akt信号发挥神经保护作用，并为PND管理提供了潜在的治疗策略。
