目的:观察性研究已经建立了肠道菌群与强直性脊柱炎(AS)风险之间的联系;然而,所观察到的关联是否是因果关系尚不清楚.因此,我们进行了双样本孟德尔随机化(MR)分析,以评估肠道微生物群与AS风险之间的潜在因果关系.
方法:从MiBioGen联盟(n=18,340)和荷兰微生物组项目(n=7738)获得肠道微生物群的仪器变体。FinnGen联盟为AS提供了遗传关联汇总统计数据,包括2860例病例和270,964例对照。我们使用逆方差加权(IVW)方法作为主要分析,辅以加权中位数法,基于最大似然的方法,MR多效性残差和异常值测试,和MR-Egger回归。此外,我们进行了反向MR分析,以评估反向因果关系的可能性.
结果:Bonferroni校正后,类拟杆菌属在统计学上与AS风险显著相关(比值比(OR)1.55,95%置信区间(CI)1.22-1.95,P=2.55×10-4)。还观察到11种细菌性状与AS风险相关的证据(IVWP<0.05)。其中,八种与升高的AS风险相关(OR1.37,95%CI1.07-1.74,P=0.011;OR1.31,95%CI1.03-1.65,P=0.026类;OR1.17,95%CI1.01-1.36,P=0.035单杆菌属1.65;OR1.31,95%CI1.03-1.65,P=0.035。三个性状与AS风险呈负相关(Dialister属的OR0.68,95%CI0.53-0.88,P=0.003;Howardella属的OR0.84,95%CI0.72-0.97,P=0.020;Orosillosspira属的OR0.75,95%CI0.59-0.97,P=0.026)。使用替代MR方法时,观察到一致的关联。在反向MR中,在AS和这些细菌性状之间没有检测到统计学上显著的相关性。
结论:我们的结果揭示了几种肠道细菌性状与AS风险的关联,提示肠道菌群在AS发育中的潜在因果作用。然而,需要更多的研究来阐明这些细菌影响AS风险的机制.关键点•观察性研究中肠道微生物群与AS风险的关联尚不清楚。•该MR分析揭示了12种肠道细菌性状与AS风险的关联。
OBJECTIVE: Observational studies have established a connection between gut microbiota and ankylosing spondylitis (AS) risk; however, whether the observed associations are causal remains unclear. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential causal associations of gut microbiota with AS risk.
METHODS: Instrumental variants of gut microbiota were obtained from the MiBioGen consortium (n = 18,340) and the Dutch Microbiome Project (n = 7738). The FinnGen consortium provided genetic association summary statistics for AS, encompassing 2860 cases and 270,964 controls. We used the inverse-variance weighted (IVW) method as the primary analysis, supplemented with the weighted median method, maximum likelihood-based method, MR pleiotropy residual sum and outlier test, and MR-Egger regression. In addition, we conducted a reverse MR analysis to assess the likelihood of reverse causality.
RESULTS: After the Bonferroni correction, species Bacteroides vulgatus remained statistically significantly associated with AS risk (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.22-1.95, P = 2.55 × 10-4). Suggestive evidence of associations of eleven bacterial traits with AS risk was also observed (P < 0.05 by IVW). Among them, eight were associated with an elevated AS risk (OR 1.37, 95% CI 1.07-1.74, P = 0.011 for phylum Verrucomicrobia; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for class Verrucomicrobiae; OR 1.17, 95% CI 1.01-1.36, P = 0.035 for order Bacillales; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for order Verrucomicrobiales; OR 1.43, 95% CI 1.13-1.82, P = 0.003 for family Alcaligenaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for family Verrucomicrobiaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for genus Akkermansia; OR 1.55, 95% CI 1.19-2.02, P = 0.001 for species Sutterella wadsworthensis). Three traits exhibited a negative association with AS risk (OR 0.68, 95% CI 0.53-0.88, P = 0.003 for genus Dialister; OR 0.84, 95% CI 0.72-0.97, P = 0.020 for genus Howardella; OR 0.75, 95% CI 0.59-0.97, P = 0.026 for genus Oscillospira). Consistent associations were observed when employing alternate MR methods. In the reverse MR, no statistically significant correlations were detected between AS and these bacterial traits.
CONCLUSIONS: Our results revealed the associations of several gut bacterial traits with AS risk, suggesting a potential causal role of gut microbiota in AS development. Nevertheless, additional research is required to clarify the mechanisms by which these bacteria influence AS risk. Key Points • The association of gut microbiota with AS risk in observational studies is unclear. • This MR analysis revealed associations of 12 gut bacterial traits with AS risk.