Huang Haoxiang, Chen Bohong, Feng Cong, Chen Wei, Wu Dapeng
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
Mamm Genome. 2025 Mar;36(1):306-316. doi: 10.1007/s00335-024-10081-0. Epub 2024 Nov 7.
IgA nephropathy (IgAN) is a chronic glomerular disease characterized by the deposition of IgA antibodies in the kidney's mesangium. Its pathogenesis involves genetic, immune, and environmental factors, particularly within the mucosal immune system and gut microbiota. Immune cells play a central role in mediating these processes, which this study investigates using Mendelian Randomization (MR) to explore causal relationships among gut microbiota, inflammatory markers, blood cells, and immune cells in IgAN pathogenesis. We conducted a two-sample MR analysis using Genome-Wide Association Study (GWAS) summary data to assess the causal effects of gut microbiota, inflammatory markers, and blood cell traits on IgAN. Data sources included the FinnGen dataset for IgAN and relevant GWAS datasets for immune traits, blood cells, and inflammatory markers. Inverse variance weighting (IVW) was the primary MR method, supported by sensitivity analyses. We particularly examined the mediation effect of immune cells on these exposures' influence on IgAN. Significant associations were found between several factors and IgAN. Gut microbiota traits, such as Firmicutes E and Sporomusales, increased IgAN risk, while Citrobacter A and Herbinix reduced it. Inflammatory markers, including Interleukin-10 and Fibroblast Growth Factor 23, promoted IgAN onset. Blood cell traits like red blood cell perturbation response increased risk, while monocyte perturbation response was protective. Immune traits played a key mediating role, with Transitional %B cells reducing IgAN risk and CD28- CD25 + + CD8br %T cells increasing it. This study highlights the pivotal mediating role of immune cells in the interactions between gut microbiota, inflammatory markers, and IgAN risk. These findings identify potential biomarkers and therapeutic targets, providing new insights into the immune mechanisms underlying IgAN and opportunities for intervention.
IgA肾病（IgAN）是一种慢性肾小球疾病，其特征是IgA抗体在肾脏系膜中沉积。其发病机制涉及遗传、免疫和环境因素，特别是在黏膜免疫系统和肠道微生物群中。免疫细胞在介导这些过程中起核心作用，本研究使用孟德尔随机化（MR）来探究肠道微生物群、炎症标志物、血细胞和免疫细胞在IgAN发病机制中的因果关系。我们使用全基因组关联研究（GWAS）汇总数据进行了两样本MR分析，以评估肠道微生物群、炎症标志物和血细胞特征对IgA肾病的因果效应。数据来源包括IgA肾病的芬兰基因组数据集以及免疫特征、血细胞和炎症标志物的相关GWAS数据集。逆方差加权（IVW）是主要的MR方法，并辅以敏感性分析。我们特别研究了免疫细胞对这些暴露因素影响IgA肾病的中介作用。发现几个因素与IgA肾病之间存在显著关联。肠道微生物群特征，如厚壁菌门E和芽孢杆菌目，增加了IgA肾病风险，而柠檬酸杆菌A和赫氏菌属则降低了风险。炎症标志物，包括白细胞介素-10和成纤维细胞生长因子23，促进了IgA肾病的发病。血细胞特征，如红细胞扰动反应增加了风险，而单核细胞扰动反应则具有保护作用。免疫特征起着关键的中介作用，过渡性%B细胞降低了IgA肾病风险，而CD28-CD25++CD8br%T细胞则增加了风险。本研究强调了免疫细胞在肠道微生物群、炎症标志物和IgA肾病风险之间相互作用中的关键中介作用。这些发现确定了潜在的生物标志物和治疗靶点，为IgA肾病潜在的免疫机制提供了新见解和干预机会。
