Causal relationships between gut microbiota and IgA nephropathy: evidence from Mendelian randomization and microbiome validation.

IF 3 3区医学 Q1 UROLOGY & NEPHROLOGY

Renal Failure Pub Date : 2025-12-01 Epub Date: 2025-06-25 DOI:10.1080/0886022X.2025.2522979

Xin Wang, Jiong Liu, Wuda Huoshen, Jing Liu, Xue Qiao, Hong Zhang, Xu-Jie Zhou

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引用次数: 0

Abstract

Background: 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.

Methods: 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 via PICRUSt2.

Results: Three gut microbiota species were protective against IgAN: s_Alistipes_senegalensis (OR = 0.64, p = .002), s_Ruminococcus_bromii (OR = 0.75, p = .040), and s_Bilophila_unclassified (OR = 0.68, p = .040). Six species were associated with increased IgAN risk, including g_Barnesiella (OR = 1.32, p = .030) and s_Rothia_mucilaginosa (OR = 1.52, p = .040). After multiple-testing correction, significant associations persisted for s_Alistipes_senegalensis (p = .043), s_Bacteroides_clarus (p = .035), and s_Bilophila_unclassified (p = .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.

Conclusions: This study reveals specific gut microbes and metabolic pathways potentially driving IgAN, offering novel biomarkers and therapeutic targets for microbiome-based interventions.

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肠道微生物群与IgA肾病之间的因果关系：来自孟德尔随机化和微生物组验证的证据。

背景：新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中的因果作用尚不清楚。本研究采用双样本孟德尔随机化（MR）方法，用16S rRNA数据集验证，以确定这些因果关系。方法：我们使用遗传仪器对来自全基因组关联研究（GWAS）的412个肠道微生物群分类群进行MR分析，作为暴露和IgAN GWAS数据作为结果。采用反方差加权法作为主要分析方法，辅以MR-Egger回归、加权中位数法和Cochran’s Q检验评估多效性和异质性。通过反向、多变量和中介MR分析验证了显著的发现。结果使用属级16S rRNA数据集进行批量校正（concr）验证，并通过PICRUSt2推断微生物功能。结果：3种肠道菌群对IgAN具有保护作用：s_Alistipes_senegalensis （OR = 0.64, p = 0.002）、s_Ruminococcus_bromii （OR = 0.75, p = 0.040）和s_Bilophila_unclassified （OR = 0.68, p = 0.040）。6个物种与IgAN风险增加相关，包括g_Barnesiella （OR = 1.32, p = 0.030）和s_Rothia_mucilaginosa （OR = 1.52, p = 0.040）。经过多次检验校正，s_Alistipes_senegalensis （p = 0.043）、s_Bacteroides_clarus （p = 0.035）和s_Bilophila_unclassified （p = 0.002）存在显著相关性。敏感性分析证实了无多效性或异质性的可靠结果。属水平的验证证实了一致的微生物转移。功能预测显示碳水化合物/脂肪酸代谢上调和尿素循环下调。结论：这项研究揭示了特定的肠道微生物和代谢途径可能驱动IgAN，为基于微生物组的干预提供了新的生物标志物和治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Renal Failure 医学-泌尿学与肾脏学

CiteScore

3.90

自引率

13.30%

发文量

374

审稿时长

1 months

期刊介绍： Renal Failure primarily concentrates on acute renal injury and its consequence, but also addresses advances in the fields of chronic renal failure, hypertension, and renal transplantation. Bringing together both clinical and experimental aspects of renal failure, this publication presents timely, practical information on pathology and pathophysiology of acute renal failure; nephrotoxicity of drugs and other substances; prevention, treatment, and therapy of renal failure; renal failure in association with transplantation, hypertension, and diabetes mellitus.