基于肠-脑轴探讨傅山交通心肾法治疗围绝经期失眠的作用机制研究

Insomnia is an important problem affecting peri-menopausal women. The treatment based on syndrome differentiation is the outstanding advantage of TCM. Clinically, the syndrome of disharmony between heart and kidney is the most common syndrome, but their specific pathogenesis has not yet been fully illuminated .The gut-brain axis is a two-way regulation system between the gastrointestinal tract and the brain. The intestinal microorganisms plays an important role in the sleep-wake cycle by itself or its metabolites through the neuroendocrine pathway. Therefore, this study intends to treat the insomniac women in peri-menopausal period with the syndrome of disharmony between heart and kidney as the research object, and the women of healthy childbearing age as control sample. According to the basic principles of clinical epidemiology, the patients were randomly divided into the experimental group and the control group. The experimental group took Fu Shan ‘S prescription , the control group took Tianwang Buxin Dan, continuous medication for four weeks. To evaluate therapeutic effect of the prescriptions created by Fushan which was used for the insomniac women in peri-menopausal period with the syndrome of disharmony between heart and kidney through the kupperman scoring standard, Pittsburgh sleep scale, TCM syndrome scores, etc. To explore mechanism of the prescriptions created by Fushan by the laboratory indicators of intestinal microbes, sex hormones, central neurotransmitters, and melatonin associated with the intestinal-brain axis, combining with the data of polysomnography. It would clarify the academic theory of "heart and kidney dependence" from the micro level. We also could better inherit and carry forward Mr. Fu Shan's academic thoughts, and expand the clinical application of Mr. Fu Shan's creative prescription.

失眠是影响围绝经期女性的重要问题，中医辨证论治优势突出，尤以心肾不交者最为多见，但具体作用机制尚未完全阐明。肠道菌群通过肠-脑轴的双向调节系统，影响宿主的神经内分泌调节，在睡眠-觉醒周期中扮演着重要的角色。故本研究拟以女性围绝经期心肾不交型失眠患者为研究对象，以育龄期健康女性为对照，按照循证医学的基本原则，将患者随机分为试验组和病例对照组，试验组服用傅山论治“心惊不安，夜卧不睡”原方，病例对照组服用天王补心丹，连续用药四周，通过kupperman评分标准、匹兹堡睡眠量表、中医证候积分等评价傅山所创制的方剂治疗围绝经期心肾不交型失眠症的临床疗效；通过检测与肠-脑轴相关联的肠道菌群及相关激素、神经递质、褪黑素等实验室指标，联合多导睡眠仪相关数据，探讨傅山所创方剂的现代作用机制，以期从微观层面阐明傅山“心肾相依”的学术理论，更好地继承与发扬傅山先生的学术思想，拓展傅山先生创制方剂临床应用。

失眠是困扰围绝经期女性生活质量的重要问题，中医从心肾不交论治临床效果显著，本研究基于傅山“心肾相依”的学术理论，收集2021年4月至2022年6月就诊于山西中医药大学附属医院妇产科门诊的围绝经期心肾不交型失眠症患者78例，随机分为试验组和对照组，每组各39例。试验组服用傅山“心惊不安，夜卧不睡”原方，对照组服用天王补心丹，连续用药4周后，累计脱落病例7例，通过改良kupperman评分、PSQI、中医证候积分及安全性指标评价，结果显示傅山方治疗女性围绝经期心肾不交型失眠症安全可靠，总疗效率为91.43%。为进一步探讨傅山方的作用机制，采用16SrDNA高通量测序技术分析试验组与对照组患者用药治疗前后肠道菌群的特征，结果显示：试验组治疗后Chao1、Observed species、Faith’s_pd等α多样性指数均较治疗前显著上升，且有统计学差异（P<0.05）；在门水平，厚壁菌门治疗后丰度降低，放线菌门、变形菌门、拟杆菌门丰度升高，但差异无统计学意义（P<0.05）；在属水平，布劳特氏菌属丰度降低，志贺氏菌属丰度升高，有统计学意义（P<0.01，P<0.05）；提示傅山方能够有效改善女性围绝经期心肾不交型失眠症患者肠道菌群物种的丰富度和多样性。并另以围绝经期无睡眠障碍的健康女性为对照，将试验组治疗前后及正常组的肠道菌群分析结果与相关激素、神经递质、褪黑素等指标进行相关分析，结果显示试验组治疗前以厚壁菌门为主要标志物种，多与5-HT、NE、MT成负相关，与GnRH、CRH、ACTH、CORT成正相关；治疗后变形菌门成为主要标志物种，多与NE、MT成正相关，与CRH、ACTH、CORT成负相关，促使相关指标较治疗前发生反向调节，多与NE、MT成正相关，与CRH、ACTH、CORT成负相关；这与正常组以拟杆菌门为主要标志物种调控各项指标的变化方向一致，提示傅山方作用的关键可能在于增强肠道菌群中变形菌门的作用，进而通过“脑-肠轴”影响调节女性围绝经期心肾不交型失眠症患者中枢神经递质、激素、褪黑素变化，进而发挥改善睡眠的治疗作用，。本研究对更好地继承与发扬傅山先生的学术思想，拓展傅山先生创制方剂临床应用具有积极的意义。