基于肠道菌群/TRP-KYN通路调控神经可塑性探讨加味温胆汤干预抑郁症情绪、胃肠动力障碍的作用机制

The pathogenesis of depression is closely related to intestinal flora regulating TRP - KYN pathway and TRP - KYN pathway metabolic changes affect neuroplasticity， In light of effects on ameliorating emotion and gastrointestinal symptoms in depression significantly, and mechanism of affecting intracellular signal transduction pathway to alter atrophy and regeneration of hippocampal neuron, which is well recognized about JiaWeiWendan Decoction in our previous research, We get the enlightenment：The mechanism of JiaWeiWendan Decoction’s therapeutic effects on ameliorating emotion and gastrointestinal symptoms in depression might involve with regulating intestinal flora to influence TRP-KYN pathway and then to affect neuroplasticity. Chronic stress induced depression model were adopted in this research, and including:Observations on changes of emotion, intestinal mobility and pathomorphological changes of brain-gastrointestinal tissue; Change Steady state of intestinal flora with antibiotics，and study the change of intestinal flora via 16SrRNA sequencing, ERIC_PCR fingerprint spectrum; Using inhibitors block the TRP - KYN pathway neural protection and toxicity of metabolic pathways to study the effect of the channel changes on neural plasticitystudy,With the comprehensive analysis to uncover the influence of intestinal flora regulating TRP - KYN pathway to change neural plasticity in the pathogenesis of emotion and gastrointestinal dysfunction in depression and the overall adjustment function of Jiawei wendan decoction and their mutual relations,it hopes to provide new scientific basis for JiaWeiWendan Decoction in clinical practice, and to to open up new approaches for studying pathogenesis of depression in the future.

抑郁症发病机制与TRP-KYN通路受肠道菌群调节及其代谢影响神经可塑性密切相关；结合前期加味温胆汤可显著改善抑郁症患者情绪及胃肠道症状，以及调节胞内信号转导通路改变海马神经元萎缩、再生的机制研究，启示：加味温胆汤治疗抑郁症情绪、胃肠动力障碍的作用机制可能与调节肠道菌群影响TRP-KYN通路代谢改变神经可塑性有关。本项目采用慢性应激抑郁模型，通过：观测情绪、胃肠动力及相关脑-胃肠组织病理形态变化；以抗生素干预肠道菌群稳态，用16SrRNA测序、ERIC_PCR指纹图谱技术等研究肠道菌群变化；以抑制剂阻断TRP-KYN通路神经保护/毒性代谢途径，研究该通路变化对神经可塑性的影响，综合分析，揭示肠道菌群影响TRP-KYN通路改变神经可塑性在抑郁症情绪、胃肠动力障碍发病机制及加味温胆汤整体调节中的作用及其相互关系，以期为加味温胆汤有效临床实践提供新的科学依据，为抑郁症发病机制研究开辟新途径。

本项目在中医理论指导下，以调理脾胃立法组方，采用孤养结合慢性不可预见性温和应激法复制抑郁大鼠模型，综合应用了中医学、心理学、生物科学等多学科方法和技术，从肠道菌群影响TRP-KYN 通路改变神经可塑性的新视角，通过：观测情绪、胃肠动力及相关脑-胃肠组织病理形态变化；以抗生素干预肠道菌群稳态，用16SrRNA测序技术研究肠道菌群变化；以抑制剂分别阻断TRP-KYN通路神经保护/毒性代谢途径，研究该通路变化对神经可塑性的影响，宏微观结合综合分析了加味温胆汤的抗抑郁调节胃肠动力的作用机制。研究显示：加味温胆汤能够有效改善抑郁模型大鼠的抑郁状态，增强其胃肠动力，具有整体调节肠道菌群构成，增加有益菌Firmicutes和Bacilli的丰度，减少有害菌Bacteroidetes和Bacteroidia的丰度，调节抑郁模型大鼠TRP--KYN通路关键因子的含量变化，调控通路神经保护/毒性代谢产物的比例，调节海马星形胶质细胞及胃肠神经胶质细胞特异性标志物GFAP和S100β的mRNA/蛋白的表达，有效减轻抑郁模型大鼠皮质、海马和下丘脑神经元超微结构的损伤程度，改善胃肠组织超微形态结构，改善神经可塑性发挥抗抑郁、调节胃肠动力的作用。该结果提示：加味温胆汤抗抑郁调节胃肠动力的作用机制可能与其能够调节肠道菌群影响TRP-KYN通路代谢，发挥多效神经保护作用，进而增强神经可塑性有关。本课题为抑郁症发病机制研究开辟了新途径，为加味温胆汤论治抑郁症的有效临床实践提供了新的科学依据。本项目完成了全部技术资料的整理及数据统计总结，在国家及国家级核心期刊发表本项目相关学术论文8篇，1篇已被SCI收录，另有2篇已录用待刊发，参加学术交流会议8次，应邀做大会论文汇报3次；共培养了2名博士研究生与1名硕士研究生。