Deciphering the causal link between gut microbiota and membranous nephropathy: insights into potential inflammatory mechanisms

Membranous nephropathy (MN), a leading cause of adult nephrotic syndrome and renal failure, has been linked to gut microbiota (GM) and their metabolites. However, direct causal relationships and therapeutic implications remain unclear.
We utilized a comprehensive GWAS dataset that encompasses GM, metabolites, and MN through two-sample Mendelian randomization (MR) analyses, bidirectional MR evaluations, and detailed sensitivity tests.
We identified strong causal associations between nine specific types of GM, including class Clostridia (OR = 1.816, 95%CI: 1.021–3.236, p = .042), class Melainabacteria (OR = 0.661, 95%CI: 0.439–0.996, p = .048), order Gastranaerophilales (OR = 0.689, 95%CI: 0.480–0.996, p = .044), genus Alistipes (OR = 0.480, 95%CI: 0.223–0.998, p = .049), genus Butyricicoccus (OR = 0.464, 95%CI: 0.216–0.995, p = .048), genus Butyrivibrio (OR = 0.799, 95%CI: 0.639–0.998, p = .048), genus Ruminococcaceae UCG003 (OR = 0.563, 95%CI: 0.362–0.877, p = .011), genus Streptococcus (OR = 0.619, 95%CI: 0.393–0.973, p = .038), and genus Oscillibacter (OR = 1.90, 95%CI: 1.06–3.40, p = .031). Additionally, the metabolite tryptophan also exhibited a significant causal influence on MN (OR = 0.852, 95%CI: 0.754–0.963, p = .010). Sensitivity and reverse MR analyses confirmed the robustness of these findings. Further exploration using gutMGene database suggests that GM may influence MN by affecting the release of inflammatory factors and modulating inflammatory pathways.
This study offers a comprehensive understanding of the causal links between GM, their metabolites, and MN, which highlight potential pathways for developing new preventive and therapeutic strategies for this condition.

膜性肾病（Membranous Nephropathy, MN）是成人肾病综合征与肾衰竭的主要致病病因，其发病与肠道菌群（Gut Microbiota, GM）及其代谢产物密切相关，但二者间的直接因果关系及潜在治疗意义仍未明确。本研究采用涵盖肠道菌群、代谢产物与膜性肾病的综合全基因组关联研究（Genome-Wide Association Study, GWAS）数据集，通过双样本孟德尔随机化（Mendelian Randomization, MR）分析、双向MR评估以及细致的敏感性检验开展研究。本研究明确了9种特定肠道菌群类群与膜性肾病间的强因果关联，具体包括：梭菌纲（Clostridia）（比值比（Odds Ratio, OR）=1.816，95%置信区间（95% Confidence Interval, 95%CI）：1.021~3.236，P=0.042）、梅兰氏细菌纲（Melainabacteria）（OR=0.661，95%CI：0.439~0.996，P=0.048）、胃厌氧螺菌目（Gastranaerophilales）（OR=0.689，95%CI：0.480~0.996，P=0.044）、阿里茨菌属（Alistipes）（OR=0.480，95%CI：0.223~0.998，P=0.049）、丁酸球菌属（Butyricicoccus）（OR=0.464，95%CI：0.216~0.995，P=0.048）、丁酸弧菌属（Butyrivibrio）（OR=0.799，95%CI：0.639~0.998，P=0.048）、瘤胃球菌科UCG003属（Ruminococcaceae UCG003）（OR=0.563，95%CI：0.362~0.877，P=0.011）、链球菌属（Streptococcus）（OR=0.619，95%CI：0.393~0.973，P=0.038）以及摆动杆菌属（Oscillibacter）（OR=1.90，95%CI：1.06~3.40，P=0.031）。此外，代谢产物色氨酸（tryptophan）对膜性肾病也表现出显著的因果影响（OR=0.852，95%CI：0.754~0.963，P=0.010）。敏感性分析与反向MR分析证实了上述研究结果的稳健性。通过gutMGene数据库开展的进一步探索显示，肠道菌群或通过影响炎症因子释放、调控炎症通路来参与膜性肾病的发生发展。本研究全面阐明了肠道菌群、其代谢产物与膜性肾病之间的因果关联，为开发该疾病新型预防与治疗策略指明了潜在方向。