Wang Qi, Dai Huajie, Hou Tianzhichao, Hou Yanan, Wang Tiange, Lin Hong, Zhao Zhiyun, Li Mian, Zheng Ruizhi, Wang Shuangyuan, Lu Jieli, Xu Yu, Liu Ruixin, Ning Guang, Wang Weiqing, Bi Yufang, Zheng Jie, Xu Min
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Stroke. 2023 Sep;25(3):350-360. doi: 10.5853/jos.2023.00381. Epub 2023 Sep 26.
We investigated the causal relationships between the gut microbiota (GM), stroke, and potential metabolite mediators using Mendelian randomization (MR).
We leveraged the summary statistics of GM (n=18,340 in the MiBioGen consortium), blood metabolites (n=115,078 in the UK Biobank), and stroke (cases n=60,176 and controls n=1,310,725 in the Global Biobank Meta-Analysis Initiative) from the largest genome-wide association studies to date. We performed bidirectional MR analyses to explore the causal relationships between the GM and stroke, and two mediation analyses, two-step MR and multivariable MR, to discover potential mediating metabolites.
Ten taxa were causally associated with stroke, and stroke led to changes in 27 taxa. In the two-step MR, Bifidobacteriales order, Bifidobacteriaceae family, Desulfovibrio genus, apolipoprotein A1 (ApoA1), phospholipids in high-density lipoprotein (HDL_PL), and the ratio of apolipoprotein B to ApoA1 (ApoB/ApoA1) were causally associated with stroke (all P<0.044). The causal associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were validated using the weighted median method in an independent cohort. The three GM taxa were all positively associated with ApoA1 and HDL_PL, whereas Desulfovibrio genus was negatively associated with ApoB/ApoA1 (all P<0.010). Additionally, the causal associations between the three GM taxa and ApoA1 remained significant after correcting for the false discovery rate (all q-values <0.027). Multivariable MR showed that the associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were mediated by ApoA1 and HDL_PL, each accounting for 6.5% (P=0.028) and 4.6% (P=0.033); the association between Desulfovibrio genus and stroke was mediated by ApoA1, HDL_PL, and ApoB/ApoA1, with mediated proportions of 7.6% (P=0.019), 4.2% (P=0.035), and 9.1% (P=0.013), respectively.
The current MR study provides evidence supporting the causal relationships between several specific GM taxa and stroke and potential mediating metabolites.
我们使用孟德尔随机化（MR）研究了肠道微生物群（GM）、中风和潜在代谢物介质之间的因果关系。
我们利用了迄今为止最大规模的全基因组关联研究中GM（MiBioGen联盟中的18340例）、血液代谢物（英国生物银行中的115078例）和中风（全球生物银行荟萃分析倡议中的病例60176例和对照1310725例）的汇总统计数据。我们进行了双向MR分析以探索GM与中风之间的因果关系，并进行了两项中介分析，即两步MR和多变量MR，以发现潜在的中介代谢物。
10个分类群与中风存在因果关联，中风导致27个分类群发生变化。在两步MR中，双歧杆菌目、双歧杆菌科、脱硫弧菌属、载脂蛋白A1（ApoA1）、高密度脂蛋白中的磷脂（HDL_PL）以及载脂蛋白B与ApoA1的比值（ApoB/ApoA1）与中风存在因果关联（所有P<0.044）。使用加权中位数方法在一个独立队列中验证了双歧杆菌目、双歧杆菌科与中风之间的因果关联。这三个GM分类群均与ApoA1和HDL_PL呈正相关，而脱硫弧菌属与ApoB/ApoA1呈负相关（所有P<0.010）。此外，在校正错误发现率后，这三个GM分类群与ApoA1之间的因果关联仍然显著（所有q值<0.027）。多变量MR显示，双歧杆菌目、双歧杆菌科与中风之间的关联由ApoA1和HDL_PL介导，分别占6.5%（P=0.028）和4.6%（P=0.033）；脱硫弧菌属与中风之间的关联由ApoA1、HDL_PL和ApoB/ApoA1介导，介导比例分别为7.6%（P=0.019）、4.2%（P=0.035）和9.1%（P=0.013）。
当前的MR研究提供了证据，支持几种特定的GM分类群与中风以及潜在中介代谢物之间的因果关系。
