Yang Yihan, Rao Ting, Wei Sheng, Cheng Jing, Zhan Ying, Lin Teng, Chen Jincheng, Zhong Xiaoling, Jiang Yijing, Yang Shanli
The Institution of Rehabilitation Industry, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
Fujian Rehabilitation Hospital, Fujian University of Traditional Chinese Medicine Subsidiary Rehabilitation Hospital, Fuzhou, China.
Front Microbiol. 2024 Aug 23;15:1398618. doi: 10.3389/fmicb.2024.1398618. eCollection 2024.
Both inflammatory cytokines and the gut microbiome are susceptibility factors for vascular dementia (VaD). The trends in the overall changes in the dynamics of inflammatory cytokines and in the composition of the gut microbiome are influenced by a variety of factors, making it difficult to fully explain the different effects of both on the different subtypes of VaD. Therefore, this Mendelian randomization (MR) study identified the inflammatory cytokines and gut microbiome members that influence the risk of developing VaD and their causal effects, and investigated whether inflammatory cytokines are gut microbiome mediators affecting VaD.
We obtained pooled genome-wide association study (GWAS) data for 196 gut microbiota and 41 inflammatory cytokines and used GWAS data for six VaD subtypes, namely, VaD (mixed), VaD (multiple infarctions), VaD (other), VaD (subcortical), VaD (sudden onset), and VaD (undefined). We used the inverse-variance weighted (IVW) method as the primary MR analysis method. We conducted sensitivity analyses and reverse MR analyses to examine reverse causal associations, enhancing the reliability and stability of the conclusions. Finally, we used multivariable MR (MVMR) analysis to assess the direct causal effects of inflammatory cytokines and the gut microbiome on the risk of VaD, and performed mediation MR analysis to explore whether inflammatory factors were potential mediators.
Our two-sample MR study revealed relationships between the risk of six VaD subtypes and inflammatory cytokines and the gut microbiota: 7 inflammatory cytokines and 14 gut microbiota constituents were positively correlated with increased VaD subtype risk, while 2 inflammatory cytokines and 11 gut microbiota constituents were negatively correlated with decreased VaD subtype risk. After Bonferroni correction, interleukin-18 was correlated with an increased risk of VaD (multiple infarctions); macrophage migration inhibitory factor was correlated with an increased risk of VaD (sudden onset); interleukin-4 was correlated with a decreased risk of VaD (other); and were positively and negatively correlated with the risk of VaD (undefined), respectively; and were correlated with a decreased risk of VaD (mixed); and was correlated with an increased risk of VaD (multiple infarctions). Sensitivity analyses revealed no multilevel effects or heterogeneity and no inverse causality between VaD and inflammatory cytokines or the gut microbiota. The MVMR results further confirmed that the causal effects of , , and on VaD remain significant. Mediation MR analysis showed that inflammatory cytokines were not potential mediators.
This study helps us to better understand the pathological mechanisms of VaD and suggests the potential value of targeting increases or decreases in inflammatory cytokines and gut microbiome members for VaD prevention and intervention.
炎性细胞因子和肠道微生物群均为血管性痴呆（VaD）的易感因素。炎性细胞因子动态变化和肠道微生物群组成的总体变化趋势受多种因素影响，难以充分解释二者对不同亚型VaD的不同作用。因此，本孟德尔随机化（MR）研究确定了影响VaD发生风险的炎性细胞因子和肠道微生物群成员及其因果效应，并探讨炎性细胞因子是否为影响VaD的肠道微生物群介质。
我们获取了196种肠道微生物群和41种炎性细胞因子的汇总全基因组关联研究（GWAS）数据，并使用了六种VaD亚型的GWAS数据，即VaD（混合型）、VaD（多发性梗死型）、VaD（其他型）、VaD（皮质下型）、VaD（突发型）和VaD（未定型）。我们采用逆方差加权（IVW）方法作为主要的MR分析方法。我们进行了敏感性分析和反向MR分析以检验反向因果关联，增强结论的可靠性和稳定性。最后，我们使用多变量MR（MVMR）分析来评估炎性细胞因子和肠道微生物群对VaD风险的直接因果效应，并进行中介MR分析以探索炎性因子是否为潜在介质。
我们的两样本MR研究揭示了六种VaD亚型风险与炎性细胞因子和肠道微生物群之间的关系：7种炎性细胞因子和14种肠道微生物群成分与VaD亚型风险增加呈正相关，而2种炎性细胞因子和11种肠道微生物群成分与VaD亚型风险降低呈负相关。经Bonferroni校正后，白细胞介素-18与VaD（多发性梗死型）风险增加相关；巨噬细胞迁移抑制因子与VaD（突发型）风险增加相关；白细胞介素-4与VaD（其他型）风险降低相关；[此处原文缺失部分内容]分别与VaD（未定型）风险呈正相关和负相关；[此处原文缺失部分内容]与VaD（混合型）风险降低相关；[此处原文缺失部分内容]与VaD（多发性梗死型）风险增加相关。敏感性分析显示VaD与炎性细胞因子或肠道微生物群之间无多层次效应或异质性，也无反向因果关系。MVMR结果进一步证实[此处原文缺失部分内容]对VaD的因果效应仍然显著。中介MR分析表明炎性细胞因子不是潜在介质。
本研究有助于我们更好地理解VaD的病理机制，并提示针对炎性细胞因子和肠道微生物群成员的增加或减少进行VaD预防和干预的潜在价值。
