Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Qingyang District, Chengdu, 610072, Sichuan Province, People's Republic of China.
Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, No. 32, West Second Section, First Ring Road, Qingyang District, Chengdu, 610072, Sichuan Province, People's Republic of China.
Mol Neurobiol. 2021 Jul;58(7):3457-3470. doi: 10.1007/s12035-021-02330-z. Epub 2021 Mar 16.
It has been reported that the gut microbiome modulates postoperative cognitive dysfunction (POCD), and that administration of probiotics (VSL#3) may effectively relieve POCD. In this study, we aimed to identify the underlying mechanism of VSL#3 in POCD. A mouse model of POCD was constructed in adult male C57BL/6 mice, which were then treated with VSL#3. VSL#3 exerted a protective role against POCD and resultant neuronal apoptosis. The expression of miR-146a was found to be downregulated in hippocampal tissues of POCD mice, while VSL#3 could restore its expression. Loss- and gain-function approaches were conducted to determine the roles of microRNA (miR)-146a, B-cell translocation gene 2 (BTG2), and Bcl-2-associated X protein (Bax) in post-operative effects on cognitive function and neuronal apoptosis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured to determine oxidative stress in brain tissue. The dual-luciferase reporter gene assay identified that miR-146a could target BTG2 and negatively regulate its expression. BTG2 knockdown suppressed neuronal apoptosis and contributed to shortened time of latency, prolonged time of mice spent in the target quadrant, and reduced oxidative stress through downregulating Bax expression. Finally, VSL#3 treatment upregulated the expression of miR-146a to block BTG2/Bax axis and consequently inhibited neuronal apoptosis and reduced oxidative stress in POCD mice. Taken together, the study suggested that miR-146a-mediated suppression of BTG2/Bax contributed to the protective role of probiotics treatment against POCD.
据报道，肠道微生物群可调节术后认知功能障碍（POCD），而益生菌（VSL#3）的给药可能有效缓解 POCD。在这项研究中，我们旨在确定 VSL#3 在 POCD 中的潜在机制。通过成年雄性 C57BL/6 小鼠构建 POCD 模型，然后用 VSL#3 进行处理。VSL#3 对 POCD 及其导致的神经元凋亡发挥保护作用。研究发现，POCD 小鼠海马组织中 miR-146a 的表达下调，而 VSL#3 可恢复其表达。通过缺失和获得功能的方法来确定 microRNA (miR)-146a、B 细胞易位基因 2 (BTG2) 和 Bcl-2 相关 X 蛋白 (Bax) 在术后对认知功能和神经元凋亡的影响中的作用。通过测量脑组织中活性氧（ROS）、丙二醛（MDA）和超氧化物歧化酶（SOD）的水平来确定氧化应激。双荧光素酶报告基因检测表明，miR-146a 可以靶向 BTG2 并负调控其表达。BTG2 敲低抑制神经元凋亡，通过下调 Bax 表达，缩短潜伏期，延长小鼠在目标象限的时间，减少氧化应激。最后，VSL#3 治疗可上调 miR-146a 的表达，阻断 BTG2/Bax 轴，从而抑制 POCD 小鼠的神经元凋亡和减轻氧化应激。总之，该研究表明，miR-146a 介导的 BTG2/Bax 抑制作用有助于益生菌治疗对 POCD 的保护作用。
