Yu Yunfeng, Yang Xinyu, Deng Juan, Yin Yuman, Wu Yongjun, Yu Rong
School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
Int Urol Nephrol. 2025 Apr 21. doi: 10.1007/s11255-025-04519-w.
The effects of gut microbiome and its metabolites on diabetic nephropathy (DN) have been inadequately elucidated. The aim of this study is to assess the causal effect of gut microbiome on DN and the mediated effect of metabolites by a two-step Mendelian randomization (MR).
Datasets of gut microbiome, metabolites, and DN were acquired in genome-wide association studies and screened for single nucleotide polymorphisms according to the underlying assumptions of MR. Subsequently, inverse variance weighted was used as the primary method for MR analysis to assess the causal effect of gut microbiome on DN and the mediated effect of metabolites. Finally, MR-Egger intercept, Cochran's Q test, and leave-one-out sensitivity analysis were used to assess the horizontal pleiotropy, heterogeneity, and robustness of the results, respectively.
The MR analysis demonstrated that Parabacteroides merdae increased the genetic susceptibility to DN by reducing acetylcarnitine (C2) to propionylcarnitine (C3) ratio (mediated proportion 8.95%, mediated effect 0.024) and alpha-ketobutyrate to 3-methyl-2-oxovalerate ratio (mediated proportion 19.90%, mediated effect 0.053). MR Egger showed that these results lack horizontal pleiotropy (p ≥ 0.05). Cochran's Q and sensitivity analysis suggested these results had no heterogeneity (p ≥ 0.05) and were robust.
Our findings revealed the pathway by which Parabacteroides merdae increased the genetic susceptibility to DN by regulating acetylcarnitine (C2) to propionylcarnitine (C3) ratio and alpha-ketobutyrate to 3-methyl-2-oxovalerate ratio. It provides new genetic insights for understanding the pathogenesis of DN and related drug research.
肠道微生物群及其代谢产物对糖尿病肾病（DN）的影响尚未得到充分阐明。本研究旨在通过两步孟德尔随机化（MR）评估肠道微生物群对DN的因果效应以及代谢产物的介导效应。
在全基因组关联研究中获取肠道微生物群、代谢产物和DN的数据集，并根据MR的基本假设筛选单核苷酸多态性。随后，采用逆方差加权法作为MR分析的主要方法，以评估肠道微生物群对DN的因果效应以及代谢产物的介导效应。最后，分别采用MR-Egger截距、 Cochr an's Q检验和留一法敏感性分析来评估结果的水平多效性、异质性和稳健性。
MR分析表明，屎拟杆菌通过降低乙酰肉碱（C2）与丙酰肉碱（C3）的比值（介导比例8.95%，介导效应0.024）以及α-酮丁酸与3-甲基-2-氧代戊酸的比值（介导比例19.90%，介导效应0.053）增加了DN的遗传易感性。MR Egger分析表明这些结果不存在水平多效性（p≥0.05）。 Cochr an's Q检验和敏感性分析表明这些结果无异质性（p≥0.05）且具有稳健性。
我们的研究结果揭示了屎拟杆菌通过调节乙酰肉碱（C2）与丙酰肉碱（C3）的比值以及α-酮丁酸与3-甲基-2-氧代戊酸的比值增加DN遗传易感性的途径。它为理解DN的发病机制和相关药物研究提供了新的遗传学见解。
