南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (11): 2405-2415.doi: 10.12122/j.issn.1673-4254.2025.11.13

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戈登杆菌属丰度降低与肾结石风险增加相关:一项孟德尔随机化分析与动物实验研究

潘兴旭1(), 张秉祺2, 张智华1,3(), 曹秋实1,3()   

  1. 1.湖北中医药大学,基础医学院,湖北 武汉 430065
    2.湖北中医药大学,中医学院,湖北 武汉 430065
    3.湖北时珍实验室,湖北 武汉 430065
  • 收稿日期:2025-06-24 出版日期:2025-11-20 发布日期:2025-11-28
  • 通讯作者: 张智华,曹秋实 E-mail:17860358705@163.com;1868@hbucm.edu.cn;2987@hbucm.edu.cn
  • 作者简介:潘兴旭,在读硕士研究生,E-mail: 17860358705@163.com
  • 基金资助:
    国家自然科学基金青年项目(82305082);湖北省自然科学基金计划项目资助(2023AFB396);湖北省自然科学基金中医药创新发展联合基金(2024AFD265)

Reduced intestinal abundance of Gordonibacter increases risk of kidney stones: a Mendelian randomization study and evidence from rat models

Xingxu PAN1(), Bingqi ZHANG2, Zhihua ZHANG1,3(), Qiushi CAO1,3()   

  1. 1.School of Basic Medical Sciences, Wuhan 430065, China
    2.School of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China, Wuhan 430065, China
    3.Hubei Shizhen Laboratory, Wuhan 430065, China
  • Received:2025-06-24 Online:2025-11-20 Published:2025-11-28
  • Contact: Zhihua ZHANG, Qiushi CAO E-mail:17860358705@163.com;1868@hbucm.edu.cn;2987@hbucm.edu.cn
  • Supported by:
    Natural Science Foundation for the Youth of China(82305082)

摘要:

目的 通过孟德尔随机化和动物实验探讨肠道菌群和肾结石之间的因果关系。 方法 基于MiBioGen联盟肠道菌群全基因组关联(GWAS)数据和IEU Open GWAS数据肾结石数据(ukb-b-8297),分别作为暴露因素和结局变量。主要采用逆方差加权法(IVW)进行分析,并辅以MR-Egger回归法、加权中位数法(WME)、加权模式法(WM)和简单众数法(SM),同时进行异质性、多效性和留一法敏感性分析。动物实验中,将12只雄性SD大鼠随机分为对照组和模型组,6只/组,通过1%乙二醇和2%氯化铵联合建立草酸钙肾结石模型,连续干预28 d后收集尿液、血液及肠道样本。检测肾功能以及肠道屏障相关指标,并结合组织学染色以及免疫组化评估肾脏与结肠的病理学变化。采用16S rRNA测序分析肠道菌群多样性以及丰度差异,并利用Wilcoxon秩和检验及LEfSe分析筛选差异菌属。 结果 MR分析显示,毛螺杆菌科NK4A136 group(Lachnospiraceae NK4A136group,OR=0.9974,95% CI:0.9948~0.9999,P=0.0393)、戈登杆菌属(Gordonibacter,OR=0.9987,95%CI:0.9974~0.9999,P=0.0403)丰度降低与肾结石风险增加相关,未发现异质性和水平多效性(P>0.05),敏感性分析提示结果稳健。动物实验中,模型组大鼠出现明显的肾功能损伤和草酸钙结晶沉积,肠道屏障相关蛋白表达水平下降(P<0.05),16S rRNA测序结果显示,模型组菌群α、β多样性均低于对照组,戈登杆菌丰度降低,LEfSe分析亦将其鉴定为差异菌属,而毛螺杆菌科NK4A136 group在两组间的差异无统计学意义。 结论 MR分析和动物实验均提示戈登杆菌属丰度降低与肾结石风险增加相关;毛螺杆菌科NK4A136 group在MR分析中显示为肾结石发生的保护因素,但在动物实验中差异没有统计学意义,具体的机制仍需进一步验证。

关键词: 肠道菌群, 肾结石, 孟德尔随机化, 毛螺杆菌科NK4A136 group, 戈登杆菌属

Abstract:

Objective To investigate the causal relationship between gut microbiota and kidney stones. Methods Mendelian randomization analysis was conducted based on data from the MiBioGen consortium gut microbiota GWAS (exposure factors) and the IEU Open GWAS kidney stone dataset ukb-b-8297 (outcome variables) using the inverse variance weighted, MR-Egger regression, weighted median, weighted mode, and simple mode methods. Heterogeneity, pleiotropy, and leave-one-out sensitivity analyses were also performed. In the animal experiment, 12 male SD rats were randomized into control group with saline treatment and kidney stone model group treated with 1% ethylene glycol and 2% ammonium chloride for 28 consecutive days. Urine, blood, and intestinal samples of the rats were collected for testing the changes in renal function and intestinal barrier-related indicators, and kidney and colon pathologies were examined with histological staining and immunohistochemistry. The changes in diversity and abundance of gut microbiota were analyzed using 16S rRNA gene sequencing. Results Mendelian randomization analysis showed that decreased abundances of Lachnospiraceae NK4A136 group (OR=0.9974, 95% CI: 0.9948-0.9999, P=0.0393) and Gordonibacter (OR=0.9987, 95% CI: 0.9974-0.9999, P=0.0403) were associated with an increased risk of kidney stones without significant heterogeneity or horizontal pleiotropy, and sensitivity analyses suggested robustness of the results. The rat models of kidney stones exhibited significant renal function impairment and calcium oxalate crystal deposition, accompanied by decreased expressions of intestinal barrier-related proteins with lowered intestinal α- and β-diversity indices. Intestinal Gordonibacter abundance was significantly reduced in the rat models while the Lachnospiraceae NK4A136 group did not differ significantly between the control and model groups. Conclusion Decreased Gordonibacter abundance in gut microbiota is associated with an increased risk of kidney stones. The protective role of the Lachnospiraceae NK4A136 group against kidney stones as suggested by Mendelian randomization analysis fails to be supported by the experimental evidence and awaits further investigation.

Key words: gut microbiota, kidney stones, Mendelian randomization, Lachnospiraceae NK4A136group, Gordonibacter