肝郁脾虚型溃疡性结肠炎大鼠肝脏SCD1与结肠5-HT的交互对话及痛泻要方干预机制

Ulcerative colitis, as one of modern refractory diseases by the World Health Organization, is a chronic unspecified inflammatory bowel disease with unknown causes. 5-HT signal system abnormalities can lead to gastrointestinal motility, secretion dysfunction, and is positively correlated with severity of illness, histological damage. SCD1 down-regulation could exacerbate the development of UC, due to a dynamic balance in SCD1 regulating saturated fatty acids and unsaturated fatty acids.It is presumed be associated with 5-HT and SCD1 expression in ulcerative colitis based on literature and experimental study of early speculation.It is possible that 5-HT regulat expression of SCD1 by 5-HT2 receptors in the liver which are important targets for UC treatment and prevention.Thus, it is hypothesized by our research group that Tongxieyaofang regulated UC patients with syndrome of liver qi stagnation and spleen deficiency via balancing liver SD1 and intestinal 5-HT. Therefore, with liver and colon as center, we are to apply disease syndrome integrated animal model to explore relation between 5-HT and SCD1 in UC patients with syndrome of liver qi stagnation and spleen deficiency and Tongxieyaofang’s molecular mechanism from both animal and cellular levels, which is hope for providing a new target point for the treatment of liver qi stagnation and spleen deficiency type UC.

溃疡性结肠炎（UC）是一种原因不明的慢性非特异性炎症性肠道疾病，被世界卫生组织列为当代难治性疾病之一。5-HT信号系统异常可导致胃肠动力、分泌功能紊乱，与UC病情严重程度、组织损伤呈正相关。肝脏SCD1表达下调会加剧UC的发展与SCD1调节饱和脂肪酸与不饱和脂肪酸的动态平衡密切相关。基于文献及前期实验研究推测5-HT与肝脏SCD1表达在UC发病中具有相互的关联性，是UC治疗及预防的重要靶点。5-HT可能作用于肝脏5-HT2受体，调节SCD1的表达。由此提出：痛泻要方治疗肝郁脾虚型UC是通过调节肝脏SCD1与肠道5-HT平衡实现的科学假说。拟围绕肝脏和结肠为中心，运用病证结合模型，结合现代细胞生物学、分子生物学等手段，从动物、细胞水平，探讨肝郁脾虚型溃疡性结肠炎结肠5-HT与SCD1的相互关系及痛泻要方作用的分子机理，为肝郁脾虚型UC的治疗提供一个新的靶点。

溃疡性结肠炎（UC）是一种原因不明的慢性非特异性炎症性肠道疾病，被世界卫生组织列为当代难治性疾病之一。传统研究表明，在UC中5-HT信号系统异常可导致胃肠动力、分泌功能紊乱，肝脏SCD1表达下调会加剧UC的发展，与UC病情严重程度、组织损伤呈正相关；同时，5-HT还可以通过与大脑、外周神经、肝脏等不同组织器官间的各型5-HT受体结合发挥多种生理调控作用。基于中医学肝脏与肠腑的整体观和对中医肝郁脾虚证证候实质的困惑，课题组推测5-HT与肝脏SCD1表达在UC发病中具有相互的关联性，痛泻要方治疗肝郁脾虚型UC可能是通过调节肝脏SCD1与肠道5-HT平衡实现的。本研究以肝郁脾虚证证候实质及痛泻要方干预机制作为研究方向，运用病证结合大鼠模型和细胞模型为研究手段，从中医整体观出发，结合肝脏和肠腑从行为学改变、组织病理学改变、5-HT信号系统、炎症机制、肝脏脂质代谢、氧化应激与自噬调控以及线粒体损伤保护等多个方面开展了相关研究。研究结果表明痛泻要方可改善肝郁脾虚型UC大鼠结肠、肝脏病理学改变，其机制主要有以下几个方面：一是通过降低TNF-α、IL-6、IL-9等炎症因子水平，升高IL-4、IL-10等抗炎因子水平平衡炎症反应；二是通过降低5-HT含量，上调结肠SERT以及肝脏SCD1蛋白表达水平，下调肝脏5-HT2R、SREBP-1蛋白表达水平调控脂质代谢；三是通过降低MDA含量及LC3Ⅱ、Beclin1蛋白表达水平，升高SOD含量调控氧化应激与自噬水平。基于此，课题组认为肝郁脾虚型UC证候的实质可能为局部的炎症因子失调及5-HT信号系统异常，同时伴有轻度的行为异常和肝脏脂质代谢失调。痛泻要方可以通过5-HT信号系统和SCD1作用于肠腑及肝脏，调节免疫炎症，改善脂质代谢，调控氧化应激、自噬水平等发挥治疗作用。