Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut-Kidney Axis Dysfunction.
Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut-Kidney Axis Dysfunction.
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DOI：
10.1021/acs.jafc.2c06297
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发表时间：
2022-12
影响因子：
6.1
通讯作者：
Peng Wang;Xiaoqi Zhang;Xian Zheng;Jingru Gao;M. Shang;Jinghan Xu;Huichang Liang
中科院分区：
文献类型：
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作者：
Peng Wang;Xiaoqi Zhang;Xian Zheng;Jingru Gao;M. Shang;Jinghan Xu;Huichang Liang
一系列新的研究证据表明，肠肾轴在高尿酸血症(HUA)的发展中起着至关重要的作用，由于高尿酸血症的高患病率，高尿酸血症已被认为是世界范围内日益严重的负担。相关的串扰连接代谢和免疫相关途径，主要负责维持尿酸(UA)代谢的轴向动态平衡。目前，降尿酸类药物仅用于治疗急性痛风性关节炎，因为它们在华中的临床应用存在争议。本研究通过建立C57BL/6J小鼠HUA模型，评价叶酸对尿酸代谢的影响，并进一步探讨其作用机制。叶酸可减轻HUA小鼠肾组织损伤和排泄功能障碍，减轻典型的肝纤维化。分子对接结果也揭示了叶酸代谢单位与尿酸转运蛋白GLUT9和URAT1的构效关系，暗示了潜在的相互作用。叶酸还可减轻HUA诱导的Th1 7/Treg失衡和肠道组织损伤，抑制TLR4/NF-κB信号通路的激活状态，这与肠道通透性受损引起的循环内毒素水平密切相关。此外，叶酸还能恢复华华所致的肠道微生态变化，包括肠道微生物群落结构和物种组成的改变，以及代谢物短链脂肪酸的改变。综上所述，本研究揭示了叶酸干预通过改善肠-肾轴功能障碍对HUA起到改善作用。
Emerging lines of research evidence point to a vital role of gut-kidney axis in the development of hyperuricemia (HUA), which has been identified as an increasing burden worldwide due to the high prevalence. The involved crosstalk which links the metabolic and immune-related pathways is mainly responsible for maintaining the axial homeostasis of uric acid (UA) metabolism. Nowadays, the urate-lowering drugs only aim to treat acute gouty arthritis as a result of their controversial clinical application in HUA. In this study, we established the HUA model of C57BL/6J mice to evaluate the effectiveness of folic acid on UA metabolism and further explored the underlying mechanisms. Folic acid attenuated the kidney tissue injury and excretion dysfunction, as well as the typical fibrosis in HUA mice. Molecular docking results also revealed the structure-activity relationship of the folic acid metabolic unit and the UA transporters GLUT9 and URAT1, implying the potential interaction. Also, folic acid alleviated HUA-induced Th17/Treg imbalance and intestinal tissue damage and inhibited the active state of the TLR4/NF-κB signaling pathway, which is closely associated with the circulating LPS level caused by the impaired intestinal permeability. Furthermore, the changes of intestinal microecology induced by HUA were restored by folic acid, including the alteration in the structure and species composition of the gut microbiome community, and metabolite short-chain fatty acids. Collectively, this study revealed that folic acid intervention exerted improving effects on HUA by ameliorating gut-kidney axis dysfunction.