肠-脑轴功能稳态失衡介导慢性内脏痛中枢敏化的机制研究

The maintenance of the Brain-Gut Axis (BGA) homeostasis is the basis of the normal physiological function of the body. The dysfunction or imbalance of the axis will lead to malfunction or diseases of multiple organs and/or multi-systems. However, researches on the Gut-Brain Axis (GBA) are relatively few. A growing body of research evidence shows that the severe external environmental stressors will seriously affect bidirectional regulations of the brain-gut axis homeostasis, which not only causes serious brain diseases, but also leads to gastrointestinal dysfunction. Therefore, to investigate the molecular mechanisms underlying the GBA homeostasis and its imbalance has great strategic significance. We have previously demonstrated that stress or colorectal inflammatory stimulation during neonatal period of life led to peripheral nerve sensitization, chronic visceral pain and alteration in gut microbiota distribution. Based on our preliminary work, the present project aims to study the effect of intestinal flora disorder on the gut-brain axis function and to verify roles of central nervous system - anterior cingulate cortex (ACC) and the basal lateral amygdala (BLA) neural circuitry in the development and maintenance of chronic visceral pain induced by neonatal chronic stress or colonic inflammation. This project will also investigate the roles of DNA methylation and demethylation homeostasis, which is induced by the environment-gene interactions, in controlling the structure and function of neural circuitry of the central nervous system. Through the implementation of this project, we will try to define the bidirectional regulation of the GBA and BGA homeostasis between functional gastrointestinal diseases and central nerve sensitization. In particular, we will try to unveil the mechanisms by which gut microbiota affects the gut-brain axis in modulation of chronic visceral hypersensitivity induced by neonatal adverse environmental stimulation. The long-term goal is to develop novel drugs to relieve chronic pain by targeting the intestinal flora and related brain areas, which might lay the foundation for further research of translational medicine.

脑-肠轴功能稳态的维持是机体发挥正常生理功能的基础，该轴功能紊乱或失衡将导致多器官和多系统功能障碍，然而有关肠-脑轴的研究报道较少。研究表明不良环境因素刺激将影响脑-肠轴双向调节功能稳态，不但诱发重大脑部疾病，还导致胃肠功能紊乱，为此，明确肠-脑轴稳态维持机制并探讨其失衡分子机制具有重大战略意义。前期我们发现新生期不良刺激导致外周神经敏化、慢性内脏痛和肠道菌群紊乱。本项目拟在此基础上研究肠道菌群紊乱所致肠-脑轴稳态失衡在慢性痛中枢敏化中的作用，验证前扣带皮层-杏仁核神经环路功能增强是慢性痛中枢敏化的重要机制，深入研究DNA甲基化稳态失衡是环境-基因相互作用导致肠-脑轴稳态失衡和慢性痛的表观调控机制。本课题的顺利实施有助于阐明肠-脑轴双向调控稳态与功能性胃肠疾病和中枢敏化之间的关系，明确肠道菌群和相关脑区作为功能性胃肠疾病早期诊断标志物或药物靶标的潜在应用价值，为后续转化医学研究奠定基础。

脑-肠轴功能稳态的维持是机体发挥正常生理功能的基础，该轴功能紊乱或失衡将导致多器官和多系统功能障碍，然而有关肠-脑轴的研究报道相对较少。我们的长期研究目标是明确肠-脑轴稳态维持机制并探讨其失衡分子和神经环路机制。本项目的具体研究目标包括：研究肠道菌群紊乱所致肠-脑轴稳态失衡在慢性痛中枢敏化中的作用，验证前扣带皮层-杏仁核神经环路功能增强是慢性痛中枢敏化的重要机制，深入研究DNA甲基化稳态失衡是环境-基因相互作用导致肠-脑轴稳态失衡和慢性痛的表观调控机制。目前取得的主要研究成果包括：(1) 研究了CL-ACC谷氨酸能神经环路以及PVH-LSV谷氨酸能神经环路在慢性内脏痛中发挥重要的调控作用，而很有可能不参与体表疼痛的调控；(2) 阐明IBS患者和NCI慢性内脏痛大鼠肠道菌群分布特征、建立了大鼠粪菌移植技术（FMT）、检测了粪便中短链脂肪酸浓度改变；(3)重点研究了GRK6降低导致ACC神经元膜P2Y6的积聚，从而导致PMS大鼠内脏超敏反应；同时发现Asic1基因启动子中CpG岛的显著去甲基化；从而初步阐述了慢性内脏痛的分子和表观调控机制；（4）初步阐明了应激激素及其相关受体在HPA轴功能稳态失衡中的作用及其与慢性痛的关系。这些结果明确了肠道菌群和相关脑区作为功能性胃肠疾病早期诊断或药物靶标的潜在应用价值，为后续转化医学研究奠定基础。以上研究结果已发表SCI论文25篇，其中一区、二区14篇；在该项目资助下，培养博士研究生8名，硕士研究生12名，博士后3名，授权发明专利2项，并获得2022年获华夏医学科技奖二等奖1项。项目负责人多次主办国内外高水平学术会议，除担任中国神经科学学会副理事长外，还在多个学术团体担任主任委员、副主任委员、常务委员或理事，以及多本杂志的副主编或编委等职。资助经费已按规定使用。