叶酸通过改善肠肾轴功能障碍预防 C57BL/6J 小鼠的高尿酸血症,Journal of Agricultural and Food Chemistry

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叶酸通过改善肠肾轴功能障碍预防 C57BL/6J 小鼠的高尿酸血症
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2022-12-06 , DOI: 10.1021/acs.jafc.2c06297
Peng Wang ₁ , Xiaoqi Zhang ₁ , Xian Zheng ₁ , Jingru Gao ₁ , Mengfei Shang ₁ , Jinghan Xu ₁ , Hui Liang ₁

Affiliation

新出现的研究证据表明，肠肾轴在高尿酸血症 (HUA) 的发展中起着至关重要的作用，由于高尿酸血症的患病率高，已被确定为全世界日益增加的负担。连接代谢和免疫相关通路的相关串扰主要负责维持尿酸 (UA) 代谢的轴向稳态。由于降尿酸药物在HUA中的临床应用存在争议，目前降尿酸药物仅针对急性痛风性关节炎。在本研究中，我们建立了 C57BL/6J 小鼠的 HUA 模型，以评估叶酸对 UA 代谢的有效性，并进一步探索其潜在机制。叶酸减轻了 HUA 小鼠的肾组织损伤和排泄功能障碍，以及典型的纤维化。分子对接结果还揭示了叶酸代谢单元与 UA 转运蛋白 GLUT9 和 URAT1 的构效关系，暗示潜在的相互作用。此外，叶酸减轻了 HUA 诱导的 Th17/Treg 失衡和肠组织损伤，抑制了 TLR4/NF-κB 信号通路的活性状态，这与肠道通透性受损引起的循环 LPS 水平密切相关。此外，叶酸可恢复 HUA 引起的肠道微生态变化，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。总的来说，这项研究表明叶酸干预通过改善肠肾轴功能障碍对 HUA 产生改善作用。

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Folic Acid Protects against Hyperuricemia in C57BL/6J Mice via Ameliorating Gut–Kidney Axis Dysfunction

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.

更新日期：2022-12-06

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