Li Zhi-Xuan, Kang Kai-Wen, Zheng Hao, Li Dong-Li, Xu Ju-Cai, Lv Hui-Qing, Wu Ri-Hui, Gan Li-She
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311402, China; School of Pharmacy and Food Engineering, International Healthcare Innovation Institute, Wuyi University, Jiangmen 529020, China.
School of Pharmacy and Food Engineering, International Healthcare Innovation Institute, Wuyi University, Jiangmen 529020, China.
Phytomedicine. 2025 Oct;146:157115. doi: 10.1016/j.phymed.2025.157115. Epub 2025 Aug 12.
Hyperuricemia, a metabolic disorder strongly associated with gout and cardiorenal diseases, has become a global health threat affecting over 15% of the worldwide population. Current pharmacotherapies face limitations due to adverse effects during prolonged use. Natural medicines like Radix Puerariae Lobatae have demonstrated therapeutic potential with superior safety profiles.
This study investigated the anti-hyperuricemic efficacy of compound Puerariae lobatae formulas (PLF1 and PLF2) and their bioactive component puerarin, focusing on their mechanisms for enhancing renal/intestinal uric acid excretion, alleviating pathological damage, and modulating gut microbiota composition.
A hyperuricemic mouse model was established using an adenine/potassium oxonate diet. Mice were treated with PLF1 (250/500 mg/kg), PLF2 (300/600 mg/kg), puerarin (100 mg/kg), or benzbromarone (40 mg/kg, positive control). Plasma and tissue uric acid levels, XOD and ADA activities, and renal/intestinal transporter expression (ABCG2, OAT1) were analyzed. Histopathological examinations were performed using HE staining to assess kidney, liver, and intestinal integrity. Gut microbiota composition was evaluated via PacBio Sequel II 16S rRNA sequencing. Antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) approaches were employed to validate microbiota-dependent effects.
PLF1, PLF2, and puerarin significantly reduced plasma uric acid levels and suppressed XOD/ADA activities. Histopathological analysis demonstrated marked improvements in renal tubular injury, hepatic steatosis, and intestinal structural integrity, including restoration of villus architecture and crypt morphology. The expression of renal ABCG2 and OAT1, as well as intestinal ABCG2, was significantly upregulated, accompanied by enhanced expression of colonic tight junction proteins (ZO-1 and occludin). Antibiotic-induced microbiota depletion abolished the hypouricemic effect of puerarin, while FMT from puerarin-treated donors significantly alleviated hyperuricemia in recipient mice. Gut microbiota analysis revealed that both PLF2 and puerarin selectively enriched the beneficial bacterium Akkermansia muciniphila while simultaneously reducing pathogenic taxa.
This study establishes Puerariae lobatae formulas and puerarin as multi-target therapeutics for hyperuricemia, offering dual advantages over conventional drugs by enhancing renal/intestinal uric acid excretion while also repairing organ damage, and remodeling gut microbiota to enrich probiotics like A. muciniphila. The microbiota-dependent efficacy of puerarin not only underscores its potential as a novel natural therapeutic agent but also provides critical pharmacological evidence for advancing puerarin and Radix Puerariae Lobatae-based formulas in hyperuricemia treatment, bridging traditional herbal medicine with modern microbiota-targeting strategies.
高尿酸血症是一种与痛风和心肾疾病密切相关的代谢紊乱疾病，已成为影响全球超过15%人口的全球性健康威胁。目前的药物治疗由于长期使用时的不良反应而面临局限性。像葛根这样的天然药物已显示出具有卓越安全性的治疗潜力。
本研究调查了复方葛根配方（PLF1和PLF2）及其生物活性成分葛根素的抗高尿酸血症功效，重点关注其增强肾脏/肠道尿酸排泄、减轻病理损伤以及调节肠道微生物群组成的机制。
使用腺嘌呤/氧嗪酸钾饮食建立高尿酸血症小鼠模型。小鼠分别用PLF1（250/500mg/kg）、PLF2（300/600mg/kg）、葛根素（100mg/kg）或苯溴马隆（40mg/kg，阳性对照）进行治疗。分析血浆和组织尿酸水平、黄嘌呤氧化酶（XOD）和腺苷脱氨酶（ADA）活性以及肾脏/肠道转运蛋白表达（ABCG2、OAT1）。使用苏木精-伊红（HE）染色进行组织病理学检查，以评估肾脏、肝脏和肠道的完整性。通过PacBio Sequel II 16S rRNA测序评估肠道微生物群组成。采用抗生素诱导的微生物群耗竭和粪便微生物群移植（FMT）方法来验证微生物群依赖性效应。
PLF1、PLF2和葛根素显著降低血浆尿酸水平并抑制XOD/ADA活性。组织病理学分析表明肾小管损伤、肝脂肪变性和肠道结构完整性有明显改善，包括绒毛结构和隐窝形态的恢复。肾脏ABCG2和OAT1以及肠道ABCG2的表达显著上调，同时结肠紧密连接蛋白（ZO-1和闭合蛋白）的表达增强。抗生素诱导的微生物群耗竭消除了葛根素的降尿酸作用，而来自葛根素治疗供体的FMT显著减轻了受体小鼠的高尿酸血症。肠道微生物群分析显示，PLF2和葛根素均选择性地富集了有益细菌嗜黏蛋白阿克曼氏菌，同时减少了致病菌群。
本研究确立了葛根配方和葛根素作为高尿酸血症的多靶点治疗药物，通过增强肾脏/肠道尿酸排泄、修复器官损伤以及重塑肠道微生物群以富集嗜黏蛋白阿克曼氏菌等益生菌，相对于传统药物具有双重优势。葛根素的微生物群依赖性功效不仅突出了其作为新型天然治疗剂的潜力，还为推进基于葛根素和葛根的配方在高尿酸血症治疗中的应用提供了关键的药理学证据，将传统草药与现代微生物群靶向策略联系起来。
