Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Immunol. 2024 Jan 12;14:1282072. doi: 10.3389/fimmu.2023.1282072. eCollection 2023.
According to some recent observational studies, the gut microbiota influences atherosclerosis via the gut microbiota-artery axis. However, the causal role of the gut microbiota in atherosclerosis remains unclear. Therefore, we used a Mendelian randomization (MR) strategy to try to dissect this causative link.
The biggest known genome-wide association study (GWAS) (n = 13,266) from the MiBioGen collaboration was used to provide summary data on the gut microbiota for a two-sample MR research. Data on atherosclerosis were obtained from publicly available GWAS data from the FinnGen consortium, including cerebral atherosclerosis (104 cases and 218,688 controls), coronary atherosclerosis (23,363 cases and 187,840 controls), and peripheral atherosclerosis (6631 cases and 162,201 controls). The causal link between gut microbiota and atherosclerosis was investigated using inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode approaches, among which inverse variance weighting was the main research method. Cochran's Q statistic was used to quantify the heterogeneity of instrumental variables (IVs), and the MR Egger intercept test was used to assess the pleiotropy of IVs.
Inverse-variance-weighted (IVW) estimation showed that had a protective influence on cerebral atherosclerosis (OR = 0.10, 95% CI: 0.01-0.67, = 0.018), while (OR = 5.39, 95% CI: 1.50-19.37, = 0.010), (OR = 6.87, 95% CI: 1.60-29.49, = 0.010), (OR = 2.88, 95% CI: 1.18-7.05, = 0.021), and (OR = 5.26, 95% CI: 1.28-21.61, = 0.021) had pathogenic effects on cerebral atherosclerosis. For (OR = 0.87, 95% CI: 0.76-0.99, = 0.039), the (OR = 0.89, 95% CI: 0.80-1.00, = 0.048), the (OR = 0.80, 95% CI: 0.69-0.94, = 0.006), and the (OR = 0.87, 95% CI: 0.77-0.98, = 0.023) were protective against coronary atherosclerosis. However, the (OR = 1.12, 95% CI: 1.00-1.24, = 0.049) had a pathogenic effect on coronary atherosclerosis. Finally, (OR = 0.83, 95% CI: 0.69-0.99, = 0.036), (OR = 0.76, 95% CI: 0.61-0.94, = 0.013), (OR = 0.76, 95% CI: 0.60-0.96, = 0.022), and (OR = 0.65, 95% CI: 0.46-0.92, = 0.013), these four microbiota have a protective effect on peripheral atherosclerosis. However, for the (OR = 1.25, 95% CI: 1.01-1.56, = 0.040) and the (OR = 1.22, 95% CI: 1.04-1.42, = 0.016), there is a pathogenic role for peripheral atherosclerosis. No heterogeneity was found for instrumental variables, and no considerable horizontal pleiotropy was observed.
We discovered that the presence of probiotics and pathogens in the host is causally associated with atherosclerosis, and atherosclerosis at different sites is causally linked to specific gut microbiota. The specific gut microbiota associated with atherosclerosis identified by Mendelian randomization studies provides precise clinical targets for the treatment of atherosclerosis. In the future, we can further examine the gut microbiota's therapeutic potential for atherosclerosis if we have a better grasp of the causal relationship between it and atherosclerosis.
根据一些最近的观察性研究，肠道微生物群通过肠道微生物群-动脉轴影响动脉粥样硬化。然而，肠道微生物群在动脉粥样硬化中的因果作用仍不清楚。因此，我们使用孟德尔随机化（MR）策略试图剖析这种因果关系。
利用 MiBioGen 合作的最大已知全基因组关联研究（GWAS）（n=13266），为双样本 MR 研究提供了肠道微生物群的汇总数据。动脉粥样硬化的数据来自芬兰人基因（FinnGen）联盟公开的可用 GWAS 数据，包括脑动脉粥样硬化（104 例和 218688 例对照）、冠状动脉粥样硬化（23363 例和 187840 例对照）和外周动脉粥样硬化（6631 例和 162201 例对照）。使用逆方差加权、MR-Egger、加权中位数、加权模式和简单模式方法研究了肠道微生物群与动脉粥样硬化之间的因果关系，其中逆方差加权是主要的研究方法。Cochran's Q 统计量用于量化工具变量（IVs）的异质性，MR Egger 截距检验用于评估 IVs 的多效性。
逆方差加权（IVW）估计表明，对脑动脉粥样硬化有保护作用（OR=0.10，95%CI：0.01-0.67，=0.018），而（OR=5.39，95%CI：1.50-19.37，=0.010）、（OR=6.87，95%CI：1.60-29.49，=0.010）、（OR=2.88，95%CI：1.18-7.05，=0.021）和（OR=5.26，95%CI：1.28-21.61，=0.021）对脑动脉粥样硬化有致病性作用。对于（OR=0.87，95%CI：0.76-0.99，=0.039）、（OR=0.89，95%CI：0.80-1.00，=0.048）、（OR=0.80，95%CI：0.69-0.94，=0.006）和（OR=0.87，95%CI：0.77-0.98，=0.023），对冠状动脉粥样硬化有保护作用。然而，（OR=1.12，95%CI：1.00-1.24，=0.049）对冠状动脉粥样硬化有致病性作用。最后，（OR=0.83，95%CI：0.69-0.99，=0.036）、（OR=0.76，95%CI：0.61-0.94，=0.013）、（OR=0.76，95%CI：0.60-0.96，=0.022）和（OR=0.65，95%CI：0.46-0.92，=0.013），这四种肠道微生物群对周围动脉粥样硬化有保护作用。然而，对于（OR=1.25，95%CI：1.01-1.56，=0.040）和（OR=1.22，95%CI：1.04-1.42，=0.016），它们对周围动脉粥样硬化有致病性作用。工具变量无异质性，无明显水平多效性。
我们发现宿主中益生菌和病原体的存在与动脉粥样硬化有因果关系，不同部位的动脉粥样硬化与特定的肠道微生物群有因果关系。孟德尔随机化研究确定的与动脉粥样硬化相关的特定肠道微生物群为动脉粥样硬化的治疗提供了精确的临床靶点。如果我们能更好地把握肠道微生物群与动脉粥样硬化之间的因果关系，未来我们可以进一步研究肠道微生物群治疗动脉粥样硬化的潜在可能性。
