Table_2_The association between gut microbiome and PCOS: evidence from meta-analysis and two-sample mendelian randomization.XLSX

BackgroundIncreasing evidence from observational studies and clinical experimentation has indicated a link between the gut microbiotas (GMs) and polycystic ovary syndrome (PCOS), however, the causality and direction of causality between gut microbiome and PCOS remains to be established.
MethodsWe conducted a comprehensive search of four databases–PubMed, Cochrane Library, Web of Science, and Embase up until June 1, 2023, and subjected the results to a meta-analysis. In this study, a bidirectional two-sample Mendelian randomization (MR) analysis was employed to investigate the impact of gut microbiota on polycystic ovary syndrome (PCOS). The genome-wide association study (GWAS) data for PCOS comprised 113,238 samples, while the GWAS data for gut microbiota were derived from the MiBioGen consortium, encompassing a total sample size of 18,340 individuals. As the largest dataset of its kind, this study represents the most comprehensive genome-wide meta-analysis concerning gut microbiota composition to date. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables at various taxonomic levels, including Phylum, Class, Order, Family, and Genus. The causal associations between exposures and outcomes were assessed using four established MR methods. To correct for multiple testing, the false discovery rate (FDR) method was applied. The reliability and potential biases of the results were evaluated through sensitivity analysis and F-statistics.
ResultsThe meta-analysis incorporated a total of 20 studies that met the criteria, revealing a close association between PCOS and specific gut microbiota species. As per the results from our MR analysis, we identified six causal associations between the gut microbiome and polycystic ovary syndrome (PCOS). At the genus level, Actinomyces (ORIVW = 1.369, FDR = 0.040), Streptococcus (ORIVW = 1.548, FDR = 0.027), and Ruminococcaceae UCG-005 (ORIVW = 1.488, FDR = 0.028) were identified as risk factors for PCOS. Conversely, Candidatus Soleaferrea (ORIVW = 0.723, FDR = 0.040), Dorea (ORIVW = 0.580, FDR = 0.032), and Ruminococcaceae UCG-011 (ORIVW = 0.732, FDR = 0.030) were found to be protective factors against PCOS. Furthermore, the MR-PRESSO global test and MR-Egger regression indicated that our study results were not affected by horizontal pleiotropy (p > 0.05). Finally, the leave-one-out analysis corroborated the robustness of the MR findings.
ConclusionBoth our meta-analysis and MR study indicates that there is a causal relationship between the gut microbiome and PCOS, which may contribute to providing novel insights for the development of new preventive and therapeutic strategies for PCOS.

背景 越来越多的观察性研究与临床实验证据表明，肠道菌群（gut microbiota, GMs）与多囊卵巢综合征（polycystic ovary syndrome, PCOS）存在关联，但二者之间的因果关系及因果方向仍有待阐明。
方法 本研究全面检索了截至2023年6月1日的PubMed、Cochrane Library、Web of Science及Embase四大数据库，并对检索结果进行了荟萃分析（meta-analysis）。此外，本研究采用双向两样本孟德尔随机化（Mendelian randomization, MR）分析，以探究肠道菌群对多囊卵巢综合征的影响。多囊卵巢综合征的全基因组关联研究（genome-wide association study, GWAS）数据包含113238例样本，而肠道菌群的全基因组关联研究数据则来自MiBioGen联盟，总样本量达18340例。作为同类研究中规模最大的数据集，本研究是迄今为止针对肠道菌群组成的最全面的全基因组荟萃分析。研究选取不同分类学水平（包括门、纲、目、科及属）的单核苷酸多态性（single nucleotide polymorphisms, SNPs）作为工具变量，采用四种已验证的MR方法评估暴露因素与结局之间的因果关联。为校正多重检验，本研究应用了错误发现率（false discovery rate, FDR）方法。通过敏感性分析及F统计量评估研究结果的可靠性与潜在偏倚。
结果 本次荟萃分析共纳入符合标准的20项研究，结果显示多囊卵巢综合征与特定肠道菌群物种存在密切关联。基于MR分析结果，本研究共鉴定出6组肠道菌群与多囊卵巢综合征之间的因果关联。在属水平上，放线菌属（Actinomyces，ORIVW=1.369, FDR=0.040）、链球菌属（Streptococcus，ORIVW=1.548, FDR=0.027）及瘤胃球菌科UCG-005（Ruminococcaceae UCG-005，ORIVW=1.488, FDR=0.028）被鉴定为多囊卵巢综合征的危险因素；反之，Candidatus Soleaferrea（ORIVW=0.723, FDR=0.040）、多尔菌属（Dorea，ORIVW=0.580, FDR=0.032）及瘤胃球菌科UCG-011（Ruminococcaceae UCG-011，ORIVW=0.732, FDR=0.030）则被发现为多囊卵巢综合征的保护因素。此外，MR-PRESSO全局检验及MR-Egger回归分析显示，本研究结果未受到水平多效性的影响（p>0.05）。最后，留一法分析证实了MR研究结果的稳健性。
结论 本研究的荟萃分析及MR研究均表明，肠道菌群与多囊卵巢综合征之间存在因果关系，该发现可为多囊卵巢综合征新型预防与治疗策略的开发提供全新的研究视角。