基于肠道菌群结构与功能代谢调控探索六味醒神颗粒改善MHE认知功能障碍的机制研究

Minimal hepatic encephalopathy (MHE) is mainly clinical manifestation as cognitive dysfunction. It has high morbidity in hepatocirrhosis, limited treatment,and easily palindromia,while pathogenesis is inadequately understood.The lastest progress prompts that intestinal flora can adjust cognitive function and immune response.Our research group has found 27 specific metabolites in serum are involved in the pathogenesis of MHE, LiuWeiXinShen granules can increase cognitive ability of MHE patients. Therefore, our research group proposes a mechanism hypothesis,that a variation of intestinal flora, serum specific metabolites and inflammatory factor are involved in the pathogenesis of MHE together, LiuWeiXinShen granules can improve the cognitive ability of MHE patients by affecting the the structure and function metabolism of intestinal flora. For this purpose, Our reseach group plan to using 16S RNA amplification and sequencing technology,metabonomics detection technique and ELISA technology , combined with multivariate statistical analysis method,to ensure MHE structure and function of intestinal flora metabolism variation and its metabolites and serum specific expression of inflammatory factors and pathogenic characteristics of relationship may exist, ensure LiuWeiXinShen granules through the mechanism to regulate the intestinal flora as the core to correct MHE cognitive dysfunction. In order to provide new ideas for further understanding the pathogenesis of this disease,and also broaden the vision of MHE treatment by traditional Chinese medicine.

轻微型肝性脑病（MHE）以认知功能障碍为主要表现，在肝硬化中发病率高，治疗手段局限，易复发，其发病机制有待阐明。已证实多种炎性因子参与其中，最新进展提示肠道菌群可调节认知功能与免疫应答。前期课题组发现血清中27个特异性代谢物参与MHE发病，中药六味醒神颗粒可提高MHE患者认知能力。因此，课题组提出肠道菌群变异、血清特异性代谢物及炎性因子交互协同参与MHE发病，六味醒神颗粒可通过影响以肠道菌群结构与功能代谢为核心的相关途径以改善MHE认知功能障碍的假说。为此，课题组采用16s RNA扩增与测序技术、代谢组学检测技术及ELISA技术，结合多元统计分析手段，确定MHE肠道菌群结构及功能代谢变异及其与血清特异性代谢物和炎性因子表达可能存在的致病关联性，明确六味醒神颗粒通过以调控肠道菌群为核心纠正MHE认知功能障碍的疗效机制。旨在为深入认识该病发病机制提供新的思路；亦为MHE中医药治疗拓宽视野。

轻微型肝性脑病（MHE）以认知功能障碍为主要表现，在肝硬化中发病率高，治疗手段局限，易复发，其发病机制有待阐明。已证实多种炎性因子参与其中，最新进展提示肠道菌群调节可认知功能与免疫应答，肠道菌群可直接影响血脑屏障、髓鞘、神经形成及小胶质细胞成熟等基础性神经发育进程，调控多种神经生理活动；亦可通过血脑屏障调节外周与脑的肽信号交流，参与脑对肠道菌群信号响应。研究中通过收集健康人群及MHE患者，六味醒神颗粒干预处理，采用16sRNA扩增与测序技术及代谢组学检测方法，研究MHE发病进程中肠道菌群种属和功能代谢变异及其与血清特异性代谢物、炎性因子表达的交互/协同致病，探索六味醒神颗粒改善MHE认知功能障碍以彰显疗效的菌群种属及代谢路谱。研究中发现MHE患者肠道菌群多样性降低，厚壁菌门细菌比例显著减少，变形菌门细菌比例显著增加，且在氨基酸相关酶、甲烷代谢、精氨酸和脯氨酸代谢功能上存在显著差异，且MHE患者牛磺胆酸、瓜氨酸、D-苯基乳酸、L -酪氨酸、苯甲酸酯、苯丙氨酸、亚油酸、二十碳二烯酸、a-二甲酸、脱氢表雄酮代谢明显异常；六味醒神颗粒能改善MHE患者（痰浊上蒙证）认知功能障碍，改善NCT及DST评分，降低血清炎症因子LPS、TNF-α及IL-6含量，维持MHE患者肠道微生物的多样性，降低放线菌门和拟杆菌门丰度水平，改善MHE患者酮亮氨酸、L-高丝氨酸及β-胡萝卜素代谢物水平，调控谷胱甘肽代谢、苯丙氨酸代谢、组氨酸代谢及丁酸代谢等代谢途径。.研究结果确定了MHE病情进展中肠道菌群结构及功能代谢变异特点，明确六味醒神颗粒通过调控肠道菌群结构及功能代谢，纠正MHE认知功能障碍的机制及途径，解析了六味醒神颗粒通过调控肠道菌群结构-血清特异性代谢物-炎性因子发挥疗效作用的可能机制途径，也为深入研究MHE肠道菌群紊乱与脑神经功能障碍奠定了基础，亦为六味醒神颗粒深入的研发和临床应用提供了科学支撑。