Department of Endocrinology, Henan Provincial People's Hospital & People's Hospital of Zhengzhou University & People's Hospital of Henan University, Zhengzhou, Henan, China.
Xinxiang Medical University, Xinxiang, Henan, China.
J Diabetes Res. 2024 Oct 23;2024:4545595. doi: 10.1155/2024/4545595. eCollection 2024.
According to the gut-kidney axis theory, gut microbiota (GM) has bidirectional crosstalk with the development of diabetic kidney disease (DKD). However, empirical results have been inconsistent, and the causal associations remain unclear. This study was aimed at exploring the causal relationship between GM and DKD as well as the glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR). Two-sample Mendelian randomisation (MR) analysis was performed with inverse-variance weighting as the primary method, together with four additional modes (MR-Egger regression, simple mode, weighted mode, and weighted median). We utilised summary-level genome-wide association study statistics from public databases for this MR analysis. Genetic associations with DKD were downloaded from the IEU Open GWAS project or CKDGen consortium, and associations with GM (196 taxa from five levels) were downloaded from the MiBioGen repository. In forward MR analysis, we identified 13 taxa associated with DKD, most of which were duplicated in Type 2 diabetes with renal complications but not in Type 1 diabetes. We observed a causal association between genetic signature contributing to the relative abundance of Erysipelotrichaceae UCG003 and that for both DKD and GFR. Similarly, host genetic signature defining the abundance of Ruminococcaceae UCG014 was found to be simultaneously associated with DKD and UACR. In reverse MR analysis, the abundance of 14 other GM taxa was affected by DKD, including the phylum Proteobacteria, which remained significant after false discovery rate correction. Sensitivity analyses revealed no evidence of outliers, heterogeneity, or horizontal pleiotropy. Our findings provide compelling causal genetic evidence for the bidirectional crosstalk between specific GM taxa and DKD development, contributing valuable insights for a comprehensive understanding of the pathological mechanisms of DKD and highlighting the possibility of prevention and management of DKD by targeting GM.
根据肠-肾轴理论，肠道微生物群（GM）与糖尿病肾病（DKD）的发展存在双向相互作用。然而，经验结果并不一致，因果关系仍不清楚。本研究旨在探讨 GM 与 DKD 以及肾小球滤过率（GFR）和尿白蛋白与肌酐比（UACR）之间的因果关系。采用两样本 Mendelian 随机化（MR）分析，以逆方差加权作为主要方法，同时结合另外四种模式（MR-Egger 回归、简单模式、加权模式和加权中位数）。我们利用公共数据库中的汇总水平全基因组关联研究统计数据进行了这项 MR 分析。从 IEU Open GWAS 项目或 CKDGen 联盟下载与 DKD 相关的遗传关联，从 MiBioGen 存储库下载与 GM（五个水平的 196 个分类群）相关的遗传关联。在正向 MR 分析中，我们鉴定出 13 个与 DKD 相关的分类群，其中大多数在 2 型糖尿病合并肾脏并发症中重复出现，但在 1 型糖尿病中没有。我们观察到，与 Erysipelotrichaceae UCG003 相对丰度相关的遗传特征与 DKD 和 GFR 之间存在因果关系。同样，定义 Ruminococcaceae UCG014 丰度的宿主遗传特征被发现与 DKD 和 UACR 同时相关。在反向 MR 分析中，14 种其他 GM 分类群的丰度受 DKD 影响，包括在经过错误发现率校正后仍具有统计学意义的厚壁菌门。敏感性分析未发现异常值、异质性或水平多效性的证据。我们的研究结果为特定 GM 分类群与 DKD 发展之间的双向相互作用提供了强有力的因果遗传证据，为全面理解 DKD 的病理机制提供了有价值的见解，并强调了通过靶向 GM 预防和管理 DKD 的可能性。
