拟杆菌-乙酸-GPR43/HDAC轴在痛风发生发展中的作用及祛浊通痹方对其干预机制研究

Gout in China will be second only to diabetes. It can seriously affect the living quality and health of the patients. Numerous studies have shown that gut microbiota play a crucial role in urate excretion through intestine and dysfunction of gut flora is one of the important causes of hyperuricemia and gout. Metabolites, such as short chain fatty acids (mainly include acetic acid, propionic acid and butyric acid), are the main intermedia and gut microbiota usually influence their host through those metabolites. Our previous results showed that the abundance of acetogenic Bacteroidaceae increased significantly in patients with gout and so did the concentration of fecal acetate .On the other hand, it was proved that Quzhuotongbi decoction could regulate the structure of gut flora. Based on those results, we speculate that the increase of acetic acid caused by dysbiosis plays an important role in the development of gout while Quzhuotongbi decoction may exert its effect by restoring the balance of intestinal flora and regulating the concentration of acetic acid. We intend to focus on chronic elevated acetic acid that caused by intestinal flora disturbance and study the role of Bacteroidaceae-acetic acid-GPR43/HDAC axis in the development of gout by cell, animal and clinical experiments. We are going to explore the intervention mechanism of Quzhuotongbi decoction as well. Our study facilitates the study of pathogenesis mechanism and personalized treatment of gout. Our study also enriches the efficacy mechanism of traditional Chinese medicine.

痛风是我国仅次于糖尿病的第二大代谢性疾病，严重影响患者的生活质量和生命健康。研究表明肠道微生物是尿酸肠道排泄的主要承担者，肠道菌群结构和功能紊乱是引起高尿酸及痛风的重要原因之一。肠道菌群主要通过包括短链脂肪酸(主要为乙酸、丙酸和丁酸)在内的各种代谢物对宿主进行调控。申请人前期研究发现痛风患者体内产乙酸拟杆菌丰度显著增加，粪上清乙酸含量亦明显升高，而祛浊通痹方具有调节菌群结构的功能。因此，我们推测痛风患者菌群失调引起的乙酸含量升高在痛风发生发展中具有十分重要的作用，祛浊通痹方可能通过恢复肠道菌群平衡、调控乙酸浓度而发挥疗效。我们拟以菌群紊乱导致乙酸慢性升高为着眼点，从细胞、动物模型、临床三个层面深入研究拟杆菌-乙酸-GPR43/HDAC轴在痛风发生发展中的作用，揭示祛浊通痹方的疗效机制，为痛风的病理机制研究及以肠道菌群为靶点的个性化治疗提供新思路和新依据。

痛风是我国仅次于糖尿病的第二大代谢性疾病，严重影响患者的生活质量和生命健康。通过本课题的研究，课题组评估了不同痛风动物模型的有效性，构建了更能反映痛风临床表征的Uox-KO小鼠，探索了不同种类、浓度的短链脂肪酸通过不同作用机制发挥不同生物学功能的科学机制，并将研究内容外延至包括氨基酸在内的菌群代谢小分子，引入了痛风发病的新兴研究热点CD4+ T细胞，为痛风的病理机制研究提供新视角。课题组推动肠道菌群与痛风的研究由相关性研究转化为因果性研究，明确了肠道菌群在痛风发生发展中的作用，为以肠道菌群为靶点的痛风个性化治疗提供理论依据及实验数据支持。揭示了临床疗效确切的祛浊通痹方通过调控菌群-代谢小分子-宿主免疫细胞发挥疗效的作用机制。1) 不同浓度的乙酸在生理或病理状态下可发挥不同的生物学作用，HDAC2是乙酸发挥作用的重要分子；2) 外源和内源性乙酸均能有效改善痛风表征，促使巨噬细胞向M2抑炎型巨噬细胞极化，从而缓解局部及全身炎症；3) 痛风小鼠菌群结构紊乱，乙酸、丁酸等短链脂肪酸含量降低，肠黏膜屏障受损，HDAC2表达升高，GPR43受体活化及黏膜氨基酸运输受到抑制，宿主氨基酸等小分子代谢障碍，进一步引起巨噬细胞极化和CD4+ T细胞增殖分化失调，从而引起尿酸升高及痛风关节炎的发生；4）CD4+ T细胞亚群失衡及相应细胞因子分泌异常在痛风发生中发挥了重要作用，靶向促炎T细胞亚群或相关细胞因子可作为痛风潜在的治疗策略；5）祛浊通痹方可有效恢复肠道菌群结构和功能紊乱，修复受损的肠黏膜屏障功能，提高短链脂肪酸含量，改善宿主氨基酸代谢，调控体内巨噬细胞极化和CD4+ T细胞亚群分化，降低局部及全身炎症水平，减少痛风的发作。