Chen Guanglei, Jin Yaxian, Chu Cancan, Zheng Yuhao, Chen Yunzhi, Zhu Xing
Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China.
The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China.
Front Microbiol. 2024 Aug 19;15:1414977. doi: 10.3389/fmicb.2024.1414977. eCollection 2024.
Observational studies have suggested an association between gut microbiota and Alzheimer's disease (AD); however, the causal relationship remains unclear, and the role of blood metabolites in this association remains elusive.
To elucidate the causal relationship between gut microbiota and AD and to investigate whether blood metabolites serve as potential mediators.
Univariable Mendelian randomization (UVMR) analysis was employed to assess the causal relationship between gut microbiota and AD, while multivariable MR (MVMR) was utilized to mitigate confounding factors. Subsequently, a two-step mediation MR approach was employed to explore the role of blood metabolites as potential mediators. We primarily utilized the inverse variance-weighted method to evaluate the causal relationship between exposure and outcome, and sensitivity analyses including Contamination mixture, Maximum-likelihood, Debiased inverse-variance weighted, MR-Egger, Bayesian Weighted Mendelian randomization, and MR pleiotropy residual sum and outlier were conducted to address pleiotropy.
After adjustment for reverse causality and MVMR correction, class Actinobacteria (OR: 1.03, 95% CI: 1.01-1.06, = 0.006), family Lactobacillaceae (OR: 1.03, 95% CI: 1.00-1.05, = 0.017), genus (OR: 1.03, 95% CI: 1.00-1.06, = 0.019), genus (OR: 0.97, 95% CI: 0.94-1.00, = 0.027) and genus (OR: 1.03, 95% CI: 1.01-1.05, = 0.009) exhibited causal effects on AD. Moreover, 1-ribosyl-imidazoleacetate levels (-6.62%), Metabolonic lactone sulfate levels (2.90%), and Nonadecanoate (19:0) levels (-12.17%) mediated the total genetic predictive effects of class Actinobacteria on AD risk. Similarly, 2-stearoyl-GPE (18:0) levels (-9.87%), Octadecanedioylcarnitine (C18-DC) levels (4.44%), 1-(1-enyl-stearoyl)-2-oleoyl-GPE (p-18:0/18:1) levels (38.66%), and X-23639 levels (13.28%) respectively mediated the total genetic predictive effects of family Lactobacillaceae on AD risk. Furthermore, Hexadecanedioate (C16-DC) levels (5.45%) mediated the total genetic predictive effects of genus on AD risk; Indole-3-carboxylate levels (13.91%), X-13431 levels (7.08%), Alpha-ketoglutarate to succinate ratio (-13.91%), 3-phosphoglycerate to glycerate ratio (15.27%), and Succinate to proline ratio (-14.64%) respectively mediated the total genetic predictive effects of genus on AD risk.
Our mediation MR analysis provides genetic evidence suggesting the potential mediating role of blood metabolites in the causal relationship between gut microbiota and AD. Further large-scale randomized controlled trials are warranted to validate the role of blood metabolites in the specific mechanisms by which gut microbiota influence AD.
观察性研究表明肠道微生物群与阿尔茨海默病（AD）之间存在关联；然而，因果关系仍不明确，血液代谢物在这种关联中的作用也仍不清楚。
阐明肠道微生物群与AD之间的因果关系，并研究血液代谢物是否作为潜在的介导因素。
采用单变量孟德尔随机化（UVMR）分析评估肠道微生物群与AD之间的因果关系，同时利用多变量孟德尔随机化（MVMR）来减轻混杂因素。随后，采用两步中介孟德尔随机化方法探讨血液代谢物作为潜在介导因素的作用。我们主要利用逆方差加权法评估暴露与结局之间的因果关系，并进行了敏感性分析，包括污染混合、最大似然、去偏逆方差加权、孟德尔随机化Egger回归、贝叶斯加权孟德尔随机化以及孟德尔多效性残差总和与离群值分析，以解决多效性问题。
在调整反向因果关系和MVMR校正后，放线菌纲（OR：1.03，95%CI：1.01 - 1.06，P = 0.006）、乳杆菌科（OR：1.03，95%CI：1.00 - 1.05，P = 0.017）、[具体属1]属（OR：1.03，95%CI：1.00 - 1.06，P = 0.019）、[具体属2]属（OR：0.97，95%CI：0.94 - 1.00，P = 0.027）和[具体属3]属（OR：1.03，95%CI：1.01 - 1.05，P = 0.009）对AD表现出因果效应。此外，1 - 核糖基 - 咪唑乙酸水平（-6.62%）、代谢内酯硫酸盐水平（2.90%）和十九烷酸（19:0）水平（-12.17%）介导了放线菌纲对AD风险的总遗传预测效应。同样，2 - 硬脂酰 - GPE（18:0）水平（-9.87%）、十八烷二酰肉碱（C18 - DC）水平（4.44%）、1 - （1 - 烯基 - 硬脂酰） - 2 - 油酰 - GPE（p - 18:0/18:1）水平（38.66%）和X - 23639水平（13.28%）分别介导了乳杆菌科对AD风险的总遗传预测效应。此外，十六烷二酸（C16 - DC）水平（5.45%）介导了[具体属1]属对AD风险的总遗传预测效应；吲哚 - 3 - 羧酸盐水平（13.91%）、X - 13431水平（7.08%）、α - 酮戊二酸与琥珀酸比值（-13.91%）、3 - 磷酸甘油酸与甘油酸比值（15.27%）以及琥珀酸与脯氨酸比值（-14.64%）分别介导了[具体属2]属对AD风险的总遗传预测效应。
我们的中介孟德尔随机化分析提供了遗传证据，表明血液代谢物在肠道微生物群与AD之间的因果关系中具有潜在的介导作用。需要进一步开展大规模随机对照试验，以验证血液代谢物在肠道微生物群影响AD的具体机制中的作用。
