DataSheet_2_The causal relationship between gut microbiota and biliary tract cancer: comprehensive bidirectional Mendelian randomization analysis.xlsx

BackgroundGrowing evidence has shown that gut microbiome composition is associated with Biliary tract cancer (BTC), but the causality remains unknown. This study aimed to explore the causal relationship between gut microbiota and BTC, conduct an appraisal of the gut microbiome’s utility in facilitating the early diagnosis of BTC.
MethodsWe acquired the summary data for Genome-wide Association Studies (GWAS) pertaining to BTC (418 cases and 159,201 controls) from the Biobank Japan (BBJ) database. Additionally, the GWAS summary data relevant to gut microbiota (N = 18,340) were sourced from the MiBioGen consortium. The primary methodology employed for the analysis consisted of Inverse Variance Weighting (IVW). Evaluations for sensitivity were carried out through the utilization of multiple statistical techniques, encompassing Cochrane’s Q test, the MR-Egger intercept evaluation, the global test of MR-PRESSO, and a leave-one-out methodological analysis. Ultimately, a reverse Mendelian Randomization analysis was conducted to assess the potential for reciprocal causality.
ResultsThe outcomes derived from IVW substantiated that the presence of Family Streptococcaceae (OR = 0.44, P = 0.034), Family Veillonellaceae (OR = 0.46, P = 0.018), and Genus Dorea (OR = 0.29, P = 0.041) exerted a protective influence against BTC. Conversely, Class Lentisphaeria (OR = 2.21, P = 0.017), Genus Lachnospiraceae FCS020 Group (OR = 2.30, P = 0.013), and Order Victivallales (OR = 2.21, P = 0.017) were associated with an adverse impact. To assess any reverse causal effect, we used BTC as the exposure and the gut microbiota as the outcome, and this analysis revealed associations between BTC and five different types of gut microbiota. The sensitivity analysis disclosed an absence of empirical indicators for either heterogeneity or pleiotropy.
ConclusionThis investigation represents the inaugural identification of indicative data supporting either beneficial or detrimental causal relationships between gut microbiota and the risk of BTC, as determined through the utilization of MR methodologies. These outcomes could hold significance for the formulation of individualized therapeutic strategies aimed at BTC prevention and survival enhancement.

背景：越来越多的研究证据表明，肠道菌群组成与胆道癌（Biliary tract cancer, BTC）存在相关性，但二者的因果关联尚未明确。本研究旨在探讨肠道菌群与胆道癌之间的因果关系，并评估肠道菌群在辅助胆道癌早期诊断中的应用价值。

方法：本研究从日本生物银行（Biobank Japan, BBJ）数据库中获取了胆道癌的全基因组关联研究（Genome-wide Association Studies, GWAS）汇总数据，共纳入418例病例与159201例对照。此外，从MiBioGen联盟获取了与肠道菌群相关的全基因组关联研究汇总数据，样本量N=18340。本研究采用的主要分析方法为逆方差加权法（Inverse Variance Weighting, IVW）。通过多种统计手段开展敏感性评估，涵盖Cochrane Q检验、MR-Egger截距评估、MR-PRESSO全局检验以及留一法分析。最终通过反向孟德尔随机化（Mendelian Randomization, MR）分析，评估双向因果关系的潜在可能。

结果：逆方差加权法的分析结果证实，链球菌科（Family Streptococcaceae）、韦荣球菌科（Family Veillonellaceae）以及多尔菌属（Genus Dorea）对胆道癌具有保护作用（比值比OR=0.44，P=0.034；OR=0.46，P=0.018；OR=0.29，P=0.041）。与之相反，透镜菌纲（Class Lentisphaeria）、毛螺菌科FCS020群（Genus Lachnospiraceae FCS020 Group）以及Victivallales目（Order Victivallales）与胆道癌风险升高显著相关（OR=2.21，P=0.017；OR=2.30，P=0.013；OR=2.21，P=0.017）。为评估反向因果效应，本研究以胆道癌作为暴露因素、肠道菌群作为结局进行分析，结果显示胆道癌与5种肠道菌群存在显著关联。敏感性分析未发现存在异质性或多效性的实证依据。

结论：本研究首次通过孟德尔随机化方法，明确了肠道菌群与胆道癌风险之间存在有益或有害的因果关联相关的指示性数据。上述研究结果可为制定胆道癌预防及改善患者生存的个体化治疗策略提供重要参考。