n-3 PUFAs与维生素B1联合补充对酒精性脑损伤的改善效果及机制研究

Long-term excessive alcohol consumption can cause chronic damage to brain memory and mental function, which has attracted more and more attention and become a research hotspot of public health. N-3 polyunsaturated fatty acids (PUFAs) and vitamin B1 play an important role in maintenance of brain development and homeostasis and prevention of brain damage. However, there are few reports on the improvement effect of n-3 PUFAs combined with vitamin B1 on alcoholic brain injury and its potential mechanism. In the present randomized double-blind controlled intervention trial,400 patients with alcoholic brain damage are randomly divided into four groups, including placebo group, n-3 PUFAs group, vitamin B1 group, and n-3 PUFAs + vitamin B1 group. At the same time, a rat model of alcoholic brain injury is established. Then nutritional intervention is conducted for three months. The effects of n-3 PUFAs and vitamin B1 intervention on cognitive function of alcohol brain injury are measured. To explore the cellular and molecular biological mechanisms for the improvement effect of n-3 PUFAs and vitamin B1 on alcoholic brain injury, oxidative stress, inflammatory response, neuroendocrine, brain development and intestinal flora are analyzed. Comprehensive analysis and evaluation of the synergistic effect of n-3 PUFAs and vitamin B1 on alcoholic brain injury can guide the reasonable supplement of n-3 PUFAs and vitamin B1 in the population of alcoholic brain injury, and provide new targets and treatment strategies for the prevention and treatment of alcoholic brain injury.

长期过量酒精摄入会造成大脑记忆及精神功能损害，其危害的严重性日渐引起社会广泛关注，并成为公共卫生领域研究热点。n-3PUFAs和维生素B1是维持大脑发育和稳态重要营养素，对功能性神经损害防治具有重要生物学作用；但两者联合补充对酒精性脑损伤改善效果及机制研究鲜有报道。本课题拟采用随机双盲对照干预试验，选择400名酒精性脑损伤患者，随机分为安慰剂对照组、n-3PUFAs、维生素B1、n-3PUFAs与维生素B1联合干预组；同时建立酒精性脑损伤大鼠模型，进行3个月营养干预。探讨n-3PUFAs与维生素B1对酒精性脑损伤人群认知功能改善效果，研究其对机体氧化应激、炎性反应、神经内分泌、大脑发育及肠道菌群的影响，阐明其改善酒精性脑损伤分子生物学机制，分析评价其协同效应。该研究成果对指导酒精性脑损伤人群合理补充n-3PUFAs及维生素B1具有重要意义，并为酒精性脑损伤防治提供新靶点和治疗策略。

本研究成功建立酒精性脑损伤动物模型，分别给与n-3 PUFAs（300mg/kg）、维生素B1（15.0 mg /kg）干预或联合干预，结果发现n-3 PUFAs和维生素B1干预可有效改善酒精性脑损伤小鼠抑郁样行为，升高血清及脑组织内5-HT和DA的表达水平，抑制脑细胞凋亡，减少酒精诱导的炎性细胞因子TNF-α、IL-1β、IL-6等的释放，并上调海马内BDNF和TrkB的表达，调节肠道菌群。说明n-3PUFAs与维生素B1对酒精性脑损伤的抑郁样行为具有改善效果，其对酒精性脑损伤保护作用机制可能与其调节5-HT和DA水平、靶向BDNF/TrkB通路、改善神经炎症、调节肠道菌群失调有关，且n-3PUFAs与维生素B1联合补充具有协同效应。.本研究还探讨了烟酰胺核糖、蜂胶对酒精或高果糖暴露小鼠机体的改善作用，发现烟酰胺核糖或蜂胶补充可以有效预防和缓解酒精暴露小鼠抑郁样行为及相关病理生理学损伤，通过肠道微生物-肠-脑轴上的多种途径抑制小胶质细胞激活和BDNF/TrkB/AKT信号通路。烟酰胺核糖还能调节胆汁酸代谢紊乱，改善酒精暴露小鼠的脂质代谢，并且还能改善由高果糖暴露引起的炎症，调节脂质代谢紊乱。.同时，项目组通过人群干预试验发现干酪乳杆菌的适量补充对酒精性肝损伤患者的肝功能、脂质代谢以及肠道屏障功能具有改善作用，能够增加肠道内乳杆菌和双歧杆菌的数量，促进肠道微生态平衡。而补充干酪乳杆菌还可对酒精和铁共同暴露可引起大鼠肝损伤与脂质代谢紊乱起到改善作用，调节肠道菌群数量和比例，缓解肠源性内毒素介导的炎症反应。项目组对酒精性肝损伤动物模型进行了叶酸或岩藻多糖补充，发现叶酸或岩藻多糖对酒精暴露机体的肝脏损伤及肠道微生态具有改善作用。岩藻多糖还能调节肠道-微生物-脑轴，减少小胶质细胞活化，抑制酒精性抑郁障碍的发生和发展。.本研究结果揭示了酒精暴露机体的肝、脑等损伤可能与脂质代谢、炎症反应、肠道菌群失调等有关，而合理补充n3 PUFAs、维生素B1、烟酰胺核糖、叶酸等营养素或岩藻多糖、蜂胶等生物活性物质或益生菌制剂，可促进酒精暴露机体健康，防治酒精性脑损伤或肝损伤，具有良好的应用前景。