Song Siyue, Shi Kaiyue, Fan Moqi, Wen Xianghui, Li Jiatao, Guo Yining, Lou Yu, Chen Fusen, Wang Jialu, Huang Lin, Wen Chengping, Shao Tiejuan
College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China.
J Adv Res. 2025 May 19. doi: 10.1016/j.jare.2025.05.036.
Gut microbiota modulation has recently been identified as a prospective avenue for the exploration of novel therapeutic strategies for the management of gout. Nevertheless, the application of a single specific strain or bacterial metabolite for gout intervention has rarely been explored and the underlying regulatory mechanism remains elusive.
To ascertain the potential role and the molecular mechanism of Clostridium butyricum and butyrate in the management of gouty arthritis.
A Uox-KO mouse model of gouty arthritis was developed and the composition of the gut microbiota was analyzed. C. butyricum and butyrate were supplemented to assess functional recovery and intestinal homeostasis. NanoString analysis identified miRNA variations. GC/MS measured butyric acid levels and qPCR detected the abundance of butyrate-producing enzymes and bacteria. Flow cytometry analyzed macrophage polarization and ELISA measured pro-inflammatory cytokine production. Agomir and antagomir were transfected and dual-luciferase reporter assay was adapted for validation of miRNA target binding. siRNA and rescue experiments were performed to validate the role of SOCS7 in macrophage polarization. In addition, a cohort of patients with gouty arthritis were assembled for the purpose of validating the molecular mechanism.
The results of our study demonstrated that a reduction of butyrate levels, resulting from a deficiency of butyrate-producing bacteria, leads to aberrant miR-146a expression. This, in turn, induces an imbalance in macrophage polarization and the onset of gouty arthritis. The administration of C. butyricum and butyrate demonstrated considerable anti-inflammatory efficacy by restoring intestinal homeostasis, modulating miR-146a expression, and skewing macrophage polarization. The SOCS7/JAK2-STAT3 signaling pathway was identified as a pivotal mediator in the skewing of macrophage polarization induced by miR-146a.
Our findings enrich the understanding of the regulatory mechanisms underlying macrophage polarization in gouty arthritis and highlight the potential applications of probiotics and their metabolites in clinical gout treatment.
肠道微生物群调节最近被确定为探索痛风管理新治疗策略的一个有前景的途径。然而，单一特定菌株或细菌代谢物在痛风干预中的应用很少被探索，其潜在的调节机制仍然不清楚。
确定丁酸梭菌和丁酸盐在痛风性关节炎管理中的潜在作用和分子机制。
建立痛风性关节炎的尿酸氧化酶基因敲除（Uox-KO）小鼠模型，并分析肠道微生物群的组成。补充丁酸梭菌和丁酸盐以评估功能恢复和肠道稳态。纳米串分析确定微小RNA（miRNA）的变化。气相色谱/质谱联用（GC/MS）测量丁酸水平，定量聚合酶链反应（qPCR）检测产丁酸盐酶和细菌的丰度。流式细胞术分析巨噬细胞极化，酶联免疫吸附测定（ELISA）测量促炎细胞因子的产生。转染激动剂miRNA（agomir）和拮抗剂miRNA（antagomir），并采用双荧光素酶报告基因测定法验证miRNA靶标结合。进行小干扰RNA（siRNA）和拯救实验以验证细胞因子信号传导抑制因子7（SOCS7）在巨噬细胞极化中的作用。此外，招募了一组痛风性关节炎患者以验证分子机制。
我们的研究结果表明，由于产丁酸盐细菌缺乏导致丁酸盐水平降低，进而导致miR-146a表达异常。这反过来又会导致巨噬细胞极化失衡和痛风性关节炎的发作。丁酸梭菌和丁酸盐的给药通过恢复肠道稳态、调节miR-146a表达和改变巨噬细胞极化表现出显著的抗炎功效。SOCS7/Janus激酶2-信号转导和转录激活因子3（JAK2-STAT3）信号通路被确定为miR-146a诱导的巨噬细胞极化改变中的关键介质。
我们的研究结果丰富了对痛风性关节炎中巨噬细胞极化潜在调节机制的理解，并突出了益生菌及其代谢物在临床痛风治疗中的潜在应用。
