桑白皮stilbenes抑制FKN/CX3CR1通路改善果糖诱导中枢炎症的机制研究

Adverse changes in the structure of gut microbiota cause gut immune system imbalance, which is one major factor for the development of neuroinflammation and cognitive disorders. Stimulated FKN/CX3CR1 axis may be the critical mediating path. It has been reported that stilbenes could inhibit neuroinflammation and improve animal cognitive disorders, however, the underlying molecular mechanisms are still not fully understood. In this project, wild type and CX3CR1-/- mice will be used to investigate the relevance between FKN/CX3CR1 activation with fructose-induced gut microbiota changes, immune system imbalance, neuroinflammation and animal cognitive disorder to illustrate the critical role of FKN/CX3CR1 axis. Furthermore, we explore the beneficial effects of stilbenes from Mori Cortex on these adverse changes induced by fructose in animals to reveal the key targets in the improvement of these compounds on neuroinflammation and cognitive disorder. High CX3CR1-expressed THP-1 macrophage will be used to investigate the inhibitory activities and characteristics of stilbenes on CX3CR1 to reveal their quantitative structure-activity relationship. The above work will provide the scientific basis for the improvement of the cognitive deficits associated with central inflammation by stilbenes from Mori Cortex, and provide new targets for the development of new anti-neuroinflammation drugs.

机体肠道菌群结构改变所致免疫系统失衡是引起中枢炎症和认知行为障碍的重要因素，FKN/CX3CR1通路激活可能起关键作用。Stilbenes可抑制中枢炎症改善动物认知行为，但其作用机制仍需探索。本项目拟在野生和CX3CR1-/-小鼠上研究果糖诱导动物FKN/CX3CR1通路激活与肠道菌群结构改变、免疫系统失衡、中枢炎症和认知行为障碍等关联，阐明FKN/CX3CR1通路的激活在其中的关键作用；进一步研究桑白皮stilbenes对果糖诱导上述效应的逆转作用，揭示其通过抑制该通路改善中枢炎症和认知障碍的作用机制和潜在靶点；并在稳定高表达CX3CR1的THP-1巨噬细胞上进行验证靶点，明确stilbenes抑制CX3CR1作用特点，初步揭示该类化合物抑制CX3CR1构-效关系。上述工作为桑白皮stilbenes治疗与中枢炎症相关的认知行为障碍提供科学依据，并为抑制中枢炎症的新型药物研发提供新的靶标。

系列研究证据显示长期高果糖饮食在增加肥胖症、非酒精性脂肪肝等代谢疾病的风险同时，对中枢神经系统也可能产生有害效应。本项目首先观察到高果糖饮食小鼠中枢海马区神经炎症和神经元丢失，并证实中枢FKN/CX3CR1通路激活导致小胶质细胞聚集并发生炎症反应，姜黄素可以抑制高果糖饮食小鼠中枢FKN/CX3CR1通路活化和小胶质细胞炎症反应，保护海马区新生神经元，提示该通路可能是干预高果糖饮食模型动物中枢神经炎症的潜在靶标。.同时，我们发现高果糖饮食可能通过其引起肠道菌群紊乱，造成肠道菌代谢产物短链脂肪酸 (SCFAs) 减少和氧化应激损伤，抑制结肠NLRP6炎症小体的激活使肠道屏障损伤，进而促使进入血液的内毒素增加，是造成中枢海马区神经炎症的主要因素。补充SCFAs可恢复肠道菌群结构，激活结肠NLRP6炎症小体，改善肠道屏障损伤，降低血液内毒素水平，从而抑制高果糖饮食所引起的海马区神经炎症和减少神经元丢失。此外,抗氧化剂桑皮苷A和白藜芦醇能恢复肠道菌群结构，促进肠道菌群产生短链脂肪酸而激活NLRP6炎症小体，并降低氧化应激改善肠道屏障损伤，从而降低血液内毒素水平，抑制海马区神经炎症。本项目研究揭示了高果糖饮食诱导肠道菌群紊乱和肠道屏障损伤促进海马区神经炎症和神经元丢失的新机制，阐明了NLRP6炎症小体在维持肠道菌群平衡和保护肠道屏障所起的重要作用，以及氧化应激对肠道屏障的损害效应。本文研究也提示通过补充SCFAs、桑皮苷A和白藜芦醇以激活肠道NLRP6炎症小体，或可成为改善高果糖饮食所造成的肠道菌群紊乱、肠道屏障损伤、海马区神经炎症和神经元丢失的重要预防和治疗措施。