Wang Xin, Liu Jiong, Huoshen Wuda, Liu Jing, Qiao Xue, Zhang Hong, Zhou Xu-Jie
Renal Division, Peking University First Hospital, Beijing, China.
Kidney Genetics Center, Peking University Institute of Nephrology, Beijing, China.
Ren Fail. 2025 Dec;47(1):2522979. doi: 10.1080/0886022X.2025.2522979. Epub 2025 Jun 25.
Emerging evidence links gut microbiota strongly with IgA Nephropathy (IgAN). However, the causal role of specific gut microbiota in IgAN remains unclear. This study used a two-sample Mendelian randomization (MR) approach, validated with 16S rRNA datasets, to identify these causal relationships.
We performed MR analysis using genetic instruments for 412 gut microbiota taxa from genome-wide association studies (GWAS) as exposures and IgAN GWAS data as outcomes. The inverse-variance weighted method was used as the primary analysis, supplemented by MR-Egger regression, weighted median methods, and Cochran's Q test to assess pleiotropy and heterogeneity. Significant findings were validated using reverse, multivariable, and mediation MR analyses. Results were validated using genus-level 16S rRNA datasets with batch correction (ConQuR), and microbial function was inferred PICRUSt2.
Three gut microbiota species were protective against IgAN: (OR = 0.64, = .002), (OR = 0.75, = .040), and (OR = 0.68, = .040). Six species were associated with increased IgAN risk, including (OR = 1.32, = .030) and (OR = 1.52, = .040). After multiple-testing correction, significant associations persisted for ( = .043), ( = .035), and ( = .002). Sensitivity analyses confirmed robust results without pleiotropy or heterogeneity. Genus-level validation confirmed consistent microbial shifts. Functional predictions showed upregulation of carbohydrate/fatty acid metabolism and downregulation of the urea cycle.
This study reveals specific gut microbes and metabolic pathways potentially driving IgAN, offering novel biomarkers and therapeutic targets for microbiome-based interventions.
越来越多的证据表明肠道微生物群与IgA肾病（IgAN）密切相关。然而，特定肠道微生物群在IgAN中的因果作用仍不清楚。本研究采用两样本孟德尔随机化（MR）方法，并结合16S rRNA数据集进行验证，以确定这些因果关系。
我们使用全基因组关联研究（GWAS）中412种肠道微生物分类群的遗传工具作为暴露因素，IgAN的GWAS数据作为结果进行MR分析。采用逆方差加权法作为主要分析方法，并辅以MR-Egger回归、加权中位数法和Cochran's Q检验来评估多效性和异质性。使用反向、多变量和中介MR分析对显著结果进行验证。结果使用经过批次校正（ConQuR）的属水平16S rRNA数据集进行验证，并通过PICRUSt2推断微生物功能。
三种肠道微生物对IgAN具有保护作用：（比值比=0.64，P=0.002），（比值比=0.75，P=0.040），以及（比值比=0.68，P=0.040）。六种微生物与IgAN风险增加相关，包括（比值比=1.32，P=0.030）和（比值比=1.52，P=0.040）。经过多重检验校正后，（P=0.043）、（P=0.035）和（P=0.002）的显著关联仍然存在。敏感性分析证实了结果的稳健性，不存在多效性或异质性。属水平验证证实了一致微生物变化。功能预测显示碳水化合物/脂肪酸代谢上调，尿素循环下调。
本研究揭示了可能驱动IgAN的特定肠道微生物和代谢途径，为基于微生物群的干预提供了新的生物标志物和治疗靶点。
