目的：通过孟德尔随机化（Mendelian randomization，MR）分析探究肠道微生物群、血浆代谢物与重症 肌无力（myasthenia gravis，MG）之间的因果关联，以及可能的中介机制。方法：利用公开可用的全基因组关 联研究（GWAS）汇总数据，包括473种肠道微生物物种（n=5959）、1400 种血浆代谢物（n=8299）及病例（197 例MG患者和354945名对照）。采用双向MR来评估肠道微生物群与MG之间的因果关系，并进行多步骤 MR和中介分析来研究代谢物的中介作用。结果：有23种肠道微生物分类单元与MG存在因果关联（IVW, P＜0.05），并且MG对2种肠道微生物的丰度存在反向因果影响。有9种血浆代谢物与MG存在因果关联 （IVW, P＜0.05），并且MG对这些血浆代谢物没有反向因果影响。CAG-269显著增加了具有保护作用的代 谢产物1-亚油酰基-GPI（18∶2）（OR=1.120, P=0.027）和1-棕榈酰基-GPI（16∶0）（OR=1.141, P=0.017），并降低 了风险代谢产物3-羟基异丁酸（OR=0.902, P=0.045）；江埃拉科属（Jiangellaceae）降低了风险代谢产物苯乙 酰谷氨酰胺（OR=0.701, P=0.042）；CAG-448 降低了风险代谢产物 N-乙酰-2-氨基壬酸（OR=0.910, P= 0.049）。多变量MR表明，CAG-269的保护作用是通过减少3-羟基异丁酸（中介效应14.1%）和增加1-亚油 酰基-GPI（18∶2）（中介效应12.8%）、1-棕榈酰基-GPI（16∶0）（中介效应12.9%）来实现的；而江埃拉科属的风 险作用是通过减少苯乙酰谷氨酰胺（中介效应 14.9%）来实现的；CAG-448 的风险作用是通过减少 N-乙 酰-2-氨基壬酸（中介效应7.4%）来实现的。结论：本研究通过MR提供了遗传证据，表明部分肠道微生物群 和血浆代谢物与MG存在因果关联。

This study aims to use Mendelian randomization (MR) analysis to explore the causal associations between gut microbiota, blood metabolites, and myasthenia gravis (MG), as well as the potential mediating mechanisms. Methods: Publicly available genome-wide association study (GWAS) summary data were utilized, encompassing 473 gut microbial taxa (n=5959), 1400 plasma metabolites, and cases (197 MG patients and 354945 controls). Bidirectional MR was employed to assess causal relationships between gut microbiota and MG, with multistep MR and mediation analyses conducted to investigate the mediating roles of metabolites. Results: A total of 23 gut microbial taxa exhibited causal associations with MG (IVW, P<0.05), while MG demonstrated reverse causal effects on the abundance of two gut microbial species. Nine plasma metabolites showed causal links with MG (IVW, P<0.05), with no reverse causal influence of MG on these metabolites. CAG-269 significantly increased the protective metabolites 1-linoleoyl-GPI (18∶2) (OR=1.120, P= 0.027) and 1-palmitoyl-GPI (16∶0) (OR=1.141, P=0.017), while decreasing the risk metabolite 3-hydroxyisobutyric acid (OR=0.902, P=0.045). The genus Jiangellaceae reduced the risk metabolite phenylacetylglutamine (OR= 0.701, P=0.042), and CAG-448 lowered the risk metabolite N-acetyl-2-aminononanoic acid (OR=0.910, P= 0.049). Multivariable MR analysis revealed that the protective effect of CAG-269 was mediated through reductions in 3-hydroxyisobutyric acid (mediation effect: 14.1% ) and increases in 1-linoleoyl-GPI (18 ∶ 2) (12.8% ) and 1-palmitoyl-GPI (16 ∶ 0) (12.9% ). Conversely, the risk-enhancing effect of Jiangellaceae was mediated by reductions in phenylacetylglutamine (14.9% ), and the risk-enhancing effect of CAG-448 was mediated by reductions in N-acetyl-2-aminononanoic acid (7.4% ). Conclusion: This MR study provides genetic evidence supporting causal associations between select gut microbial taxa, plasma metabolites, and MG.