肠道菌群与早晚期梅毒存在因果关系：基于孟德尔随机化方法

The causal association between intestinal flora and early and late syphilis was analyzed based

摘要:

目的 基于孟德尔随机化（MR）研究探讨肠道菌群与梅毒（早期和晚期）之间的因果关系。方法 通过 双向双样本MR分析，利用211个肠道菌群的全基因组关联研究汇总数据，评估肠道菌群与梅毒感染之间的关联。 采用逆方差加权法作为主要分析手段，使用Cochran's Q检验进行异质性分析，使用MR Egger回归检测并调整水平 多效性；通过MR-PRESSO（MR pleiotropy residual sum and outlier）识别并剔除多效性异常值后重新计算因果效应； 使用留一法逐一排除工具变量，评估单核苷酸多态性对因果效应的影响。同时，应用反向MR分析梅毒对肠道菌群 的潜在反向因果影响。结果 早期梅毒患者中，短棒状拟杆菌属（OR = 1.82，95%CI：1.05 ~ 3.13，P =0.032）、解黄酮 菌属（OR = 3.28，95%CI：1.18 ~ 9.14，P =0.023）和毛螺菌科 UCG001 属（OR = 2.47，95%CI：1.36 ~ 4.48，P =0.003）等 与梅毒感染的发生风险呈正相关，而梭状芽孢杆菌目 vadinBB60科（OR = 0.54，95%CI：0.30 ~ 0.95，P =0.033）、毛螺 菌科 NC2004 属（OR = 0.50，95%CI：0.28 ~ 0.92，P = 0.024）和毛螺菌科 UCG008 属（OR = 0.55，95%CI：0.31 ~ 0.97，P = 0.040）与早期梅毒呈负相关。晚期梅毒患者中，柯林斯菌属（OR = 2.63，95%CI：1.05 ~ 6.59，P =0.039）和洪 加泰氏菌属（OR = 2.85，95%CI：1.52 ~ 5.32，P =0.001）与晚期梅毒感染呈正相关，而肽球菌科（OR = 0.45，95%CI： 0.23 ~ 0.88，P =0.020）和袋熊克氏菌属（OR = 0.46，95%CI：0.22 ~ 0.98，P =0.044）与晚期梅毒感染呈负相关。反向 MR 分析未发现梅毒与肠道菌群具有反向因果关联（P > 0.05）。结论 短棒状拟杆菌属、解黄酮菌属和毛螺菌科 UCG001等菌群可能是梅毒感染的危险因素，而梭状芽孢杆菌目 vadinBB60科、肽球菌科、袋熊克氏菌属等可能是 梅毒感染的保护因素。

Abstract:

Objective This study aims to investigate the causal relationship between gut microbiota and syphilis (both early and late stages) using Mendelian randomization (MR) methodology. Methods A bidirectional two-sample MR analysis was conducted using genome-wide association studies (GWAS) summary data from 211 gut microbiota taxa to assess the association between gut microbiota and syphilis infection. The inverse variance weighted method was used as the primary analysis. Cochran’s Q test was employed for heterogeneity analysis, and MR Egger regression was used to detect and adjust for horizontal pleiotropy. MR-PRESSO (MR pleiotropy residual sum and outlier) was applied to identify and exclude pleiotropic outliers, followed by the recalculation of causal effects. A leave-one-out analysis was performed to systematically remove individual instrumental variables and assess their impact on causal effect estimates, ensuring the robustness and reliability of the results. Additionally, reverse MR analysis was used to evaluate the potential reverse causality of syphilis on gut microbiota. Results For early syphilis, results showed that Eubacterium brachy group (OR = 1.82, 95%CI: 1.05-3.13, P =0.032), Flavonifractor (OR = 3.28, 95% CI: 1.18-9.14, P =0.023), and Lachnospiraceae UCG001 (OR = 2.47, 95% CI: 1.36-4.48, P =0.003) were positively associated with the risk of syphilis infection, while Clostridiales vadinBB60 group (OR = 0.54, 95% CI: 0.30-0.95, P =0.033), Trichospirillaceae NC2004 (OR = 0.50, 95% CI: 0.28-0.92, P = 0.024), and Trichospirillaceae UCG008 (OR = 0.55, 95% CI: 0.31-0.97, P = 0.040) were negatively associated with early syphilis. For late syphilis, Collinsella (OR = 2.63, 95% CI: 1.05-6.59, P = 0.039) and Hungatella (OR = 2.85, 95% CI: 1.52-5.32, P =0.001) were associated with disease progression, while Peptococcaceae (OR = 0.45, 95%CI: 0.23-0.88, P =0.020) and Crosteria wombat(OR = 0.46, 95%CI: 0.22-0.98, P = 0.044) were found to have a protective effect. Reverse MR analysis did not identify any significant reverse causal relationship between syphilis and gut microbiota (P> 0.05). Conclusion Eubacterium brachy group, Flavonifractor and Lachnospiraceae UCG001 may be the risk factors for syphilis infection, while Clostridiales vadinBB60 group, Peptococcaceae, and Crosteria wombat may be the protective factors for syphilis infection.