Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Graduate School, Beijing University of Chinese Medicine, Beijing, China.
Front Cell Infect Microbiol. 2023 May 2;13:1171517. doi: 10.3389/fcimb.2023.1171517. eCollection 2023.
Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN.
Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality.
At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found.
Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".
靶向肠道微生物群（GM）的治疗方法可能有助于预防和治疗 IgA 肾病（IgAN）。同时，相关研究表明 GM 与 IgAN 之间存在相关性，但这些混杂证据不能证明 GM 与 IgAN 之间存在因果关系。
基于 MiBioGen 的 GM 全基因组关联研究（GWAS）数据和 FinnGen 研究的 IgAN GWAS 数据，进行了双向孟德尔随机化（MR）研究，以探讨 GM 与 IgAN 之间的因果关系。我们使用逆方差加权（IVW）法作为主要方法，确定 MR 研究中暴露与结局之间的因果关系。此外，我们还使用了额外的分析（MR-Egger、加权中位数）和敏感性分析（Cochrane's Q 检验、MR-Egger 和 MR-PRESSO）来选择有意义的结果，然后使用贝叶斯模型平均（MR-BMA）来检验 MR 研究的结果。最后，进行了反向 MR 分析以估计反向因果关系的概率。
在全基因组关联水平上，IVW 方法和额外分析的结果表明，属 Enterorhabdus 是 IgAN 的保护因素[OR：0.456，95%CI：0.238-0.875，p=0.023]，而属 butyricicoccus 是 IgAN 的危险因素[OR：3.471，95%CI：1.671-7.209，p=0.0008]。在敏感性分析中，未发现结果存在显著的偏倚或异质性。
本研究揭示了 GM 与 IgAN 之间的因果关系，并扩展了与 IgAN 因果相关的细菌分类群的多样性。这些细菌分类群可能成为新的生物标志物，有助于开发针对 IgAN 的靶向治疗方法，进一步加深我们对“肠-肾轴”的理解。
