基于肠道微生物的变化探讨亚健康状态双向转化特点及维康颗粒的调节机制

Suboptimal health status (SHS) has become a serious public health problem. However, both the etiology and mechanisms associated with SHS require further elucidation. Applicant’s previous research indicates that SHS may be regression to health or progression to disease because of its bi–directional and translational nature. SHS can be distinguished from the healthy individual in gut microbial diversity and community pattern. The beneficial bacteria significantly decreased in SHS and the harmful bacteria increased, compared with healthy individuals; while compared with the disease, beneficial bacteria significantly increased in SHS and harmful bacteria decreased. Structural changes of gut microbiota to healthy state induced by treatment of Weikang Granule. Accordingly, it is theorized that the imbalances of gut microbial communities may play an important role in SHS, and the feature of the gut microbiota in SHS may be the biological basis for the bi–directional and translational nature of SHS. Basing on the previous study, in this project, we will adopt the methods of combination of disease and syndrome, and correspondence of syndrome and prescription, and adopt the intervention means of Weikang Granule. First of all, a prospective SHS population cohort was established, and we aim to investigate the change characteristics of gut microbiota in SHS individuals clinically, and in the making animal model of the mouse with SHS. Secondly, we will investigate how the gut microbiota impact the occurrence of SHS, by applying the antibiotic clearance mouse model and the fecal microbiota transplantation. Eventually, conducting bioinformatics method for integrated analysis, we will ascertain how the unbalance of homeostasis in gut microbiota works in the development of SHS, clarify its role in the bi–directional and translational nature of SHS, and confirm the regulation mechanism of gut microbiota in the treatment of SHS by Weikang Granule.

亚健康已成为严重的公共卫生问题，其发生发展机制尚不清楚。申请者前期研究表明亚健康有回归健康又可进展为疾病的双向转化特点；亚健康状态在肠道微生物的群落模式能够跟健康状态显著区分，与健康状态比较，其有益菌群丰度显著下降，有害菌群升高；与疾病比较，其有益菌群丰度显著增多，有害菌群减少；经中药维康颗粒干预后可使其肠道菌群结构向健康恢复。推测肠道微生物的稳态失衡可能在亚健康的发生发展中起重要作用，亚健康的肠道微生物特征可能是其双向转化特点的生物学基础。本项目拟在前期基础上，采用病证结合和方证相应方法，以维康颗粒为干预手段，首先建立前瞻性亚健康人群队列，并采取临床研究结合动物实验，明确亚健康的肠道微生物变化特征；其次利用抗生素清除小鼠模型探讨肠道微生物对亚健康发生的影响；最后用生物信息学整合，明确肠道微生物变化对亚健康发生的影响，阐明其在亚健康双向转化特点中的作用，明确维康颗粒的肠道微生物调节作用。

亚健康已成为严重的公共卫生问题，其发生发展机制尚不清楚。前期研究表明亚健康有回归健康又可进展为疾病的双向转化特点；亚健康状态在肠道微生物的群落模式能够跟健康状态显著区分，与健康状态比较，其有益菌群丰度显著下降，有害菌群升高；与疾病比较，其有益菌群丰度显著增多，有害菌群减少；经中药维康颗粒干预后可使其肠道菌群结构向健康恢复。本项目在前期基础上，采用病证结合和方证相应方法，以维康颗粒为干预手段，首先建立前瞻性人群队列，严格选出亚健康人，并采取临床研究结合动物实验，明确亚健康的肠道微生物变化特征；其次利用抗生素清除小鼠模型探讨肠道微生物对亚健康发生的影响。结果表明：相对于健康状态，亚健康状态的肠道微生物丰度和多样性明显降低，Faecalibacterium菌属、柔嫩梭菌、两形真杆菌、颤螺菌属、Odoribacter属、产甲酸草酸杆菌等有益菌明显降低，而活泼瘤胃球菌、瘤胃球菌属、Ruminococcus torques、Streptococcus luteciae及Acinetobacter菌属等有害菌过度生长，健康状况指数与肠道菌群密切相关。亚健康维康颗粒治疗亚健康状态的临床有效率（P<0.05）和症状积分（P<0.01）明显优于对照组，且增加了有益菌群丰度，降低了有害菌群丰度。将受试者/小鼠菌群移植入抗生素清除小鼠，发现小鼠精神状态较差，力竭游泳时间显著延长，而移植维康颗粒治疗组的小鼠能起到一定的调节作用；肠道微生物的变化特征均显示粪菌移植实验菌属定植成功，且亚健康状态和对应受体小鼠菌群结构类似，而健康对照和对应受体小鼠的菌群结构类似，维康颗粒治疗组和对应受体小鼠菌群结构类似。总之，本项目从肠道微生物角度探索亚健康状态的发生发展，为亚健康状态的诊治提供客观依据，为亚健康状态具有双向转化特点提供生物学证据，为维康颗粒防治亚健康状态的临床应用提供科学依据。