目的 采用孟德尔随机化（Mendelian randomization，MR）方法评估肠道菌群与类风湿关节炎（rheumatoid arthritis，RA）之间的因果关系，并预测能够通过调控肠道菌群治疗RA的潜在有效中药。方法 获取RA与肠道菌群全基因组关联研究数据（genome-wide association study，GWAS）。使用R语言进行MR分析，采用逆方差加权法（inverse variance weighted，IVW）探究肠道微生物群与RA之间的潜在因果关联，通过实施敏感性分析来评估分析结果的稳健性和可靠性。对工具变量对应的邻近基因进行基因本体（gene ontology，GO）和京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）富集分析，探索可能涉及RA发病机制的相关通路。通过Coremine数据库、TCMSP数据库预测对“肠-关节”轴存在潜在治疗作用的中药，统计性味归经及有效成分。结果 MR分析发现肠道菌群多尔氏菌属Dorea（OR＝0.852，95% CI：0.744～0.975，P＝0.020）；副血链球菌Streptococcus parasanguinis（OR＝0.918，95% CI：0.847～0.995，P＝0.037）；韦荣球菌属Veillonella_unclassified（OR＝0.926，95% CI：0.869～0.987，P＝0.018）；毛螺菌科（Lachnospiraceae）细菌5_1_63FAA（OR＝1.070，95% CI：1.006～1.138，P＝0.031）与RA患病风险存在显著因果关系。主要通过病毒蛋白与细胞因子受体的相互作用、钙信号通路及自然杀伤细胞介导的细胞毒性通路干预RA。根据临近基因筛选出95味中药，四气主要以寒为主，温、平次之；五味以苦为主，甘、辛次之；归经以肝经为主，肺经、脾经次之；功效以清热药为主，补虚药、活血化瘀药次之。出现频次较高的有效成分为β-谷甾醇（β-sitosterol）、槲皮素（quercetin）、山柰酚（kaempferol）、豆甾醇（stigmasterol）。结论 通过MR分析发现多尔氏菌属、副血链球菌及韦荣球菌属Veillonella_unclassified与RA发病呈负相关，毛螺菌科细菌5_1_63FAA可增加RA发病风险，富集分析得到了肠道菌作用于RA的生物过程及信号通路，升麻、白花蛇舌草、苍耳子、高良姜等中药可以通过改善肠道微生物群治疗RA，其中β-谷甾醇、槲皮素等有效成分具有治疗潜力。这些发现为从“肠-关节”轴视角探索RA的中医药防治提供参考，对RA的达标治疗及药物研发提供新思路。

Objective To evaluate the causal relationship between gut microbiota (GM) and rheumatoid arthritis (RA) using Mendelian randomization (MR), and predict potential effective traditional Chinese medicines (TCMs) that can regulate gut microbiota to treat RA. Methods The genome-wide association study (GWAS) between RA and GM were obtained. MR analysis was conducted using R language, the potential causal relationship between RA and GM was explored using inverse variance weighting (IVW) method. Sensitivity analysis was conducted to evaluate the robustness and reliability of the analysis results. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment were performed on the analysis on adjacent genes corresponding to instrumental variables to explore potential pathways involved in the pathogenesis of RA. Coremine database and TCMSP database were used to predict potential therapeutic effects of TCMs, statistical flavor meridian analysis, and active ingredients on the “gut joint” axis.Results MR analysis found Dorea (OR＝0.852, 95% CI: 0.744 to 0.975, P＝0.020); Streptococcus parasanguinis (OR＝0.918, 95% CI: 0.847 to 0.995, P＝0.037); Veillonella_ unclassified (OR＝0.926, 95% CI: 0.869 to 0.987, P＝0.018); Lachnospiraceae bacterium 5_1_63FAA (OR＝1.070, 95% CI: 1.006 to 1.138, P＝0.031) had a significant causal relationship with the risk of RA disease. RA was mainly intervened through the interaction of viral protein interaction with cytokine receptor, calcium signaling pathway and natural killer cell mediated cytotoxicity. A total of 95 TCMs were screened according to the proximate genes, and the four qi were cold, followed by warmth and flatness; the five flavors were mainly bitter, followed by sweetness and pungency; the attributed meridians were liver meridian, followed by lung meridian and spleen meridian; and the efficacies were mainly heat-removing drugs, followed by deficiency-tonifying drugs and drugs to activate blood circulation and remove blood stasis. The active ingredients with high frequently were β-sitosterol, quercetin, kaempferol, and stigmasterol. Conclusion Through MR analysis, it was found that Dorea, Streptococcus parasanguinis, and Veillonella unclassified were protective factors for the onset of RA, while Lachnospiraceae bacteria 5_1_63FAA can increase the risk of RA. Enrichment analysis revealed the biological processes and signaling pathways of gut bacteria acting on RA. TCMs such as Shengma (Cimicifugae Rhizoma), Baihua Sheshecao (Hedyotis diffusa), Cangerzi (Xanthii Fructus), and Gaoliangjiang (Alpiniae Officinarum Rhizoma) can treat RA by improving the GM, with active ingredients such as β-sitosterol and quercetin having therapeutic potential. These findings provide reference for exploring the TCMs prevention and treatment of RA from the perspective of the “gut joint” axis, and provide new ideas for the standardized treatment and drug development of RA.

Q811.4;R285

中医药传承与创新“百千万”人才工程（岐黄工程）岐黄学者（20210602-1）;国家中医药管理局名老中医传承工作室（975022）;国家自然科学基金青年项目“从肠道微生态失衡探讨寒湿外邪加重类风湿关节炎的病理机制”（81704000）;中国科学技术协会青年人才托举工程（YESS20210352）