Table_1_Genetically predicted plasma metabolites mediate the causal relationship between gut microbiota and primary immune thrombocytopenia (ITP).XLSX

BackgroundPrimary immune thrombocytopenia (ITP) is an immune-mediated hematologic disorder characterized by a reduction in platelet count, increasing the risk of bleeding. Recent studies have indicated a close association between alterations in gut microbiota and the development of ITP. However, the mechanisms by which gut microbiota influence the occurrence and progression of ITP through plasma metabolites remain poorly understood. Evidence suggests extensive interactions between gut microbiota and plasma metabolites, implying a potential role for gut microbiota in influencing ITP through alterations in plasma metabolites, which requires further investigation.
MethodsIn this study, summarized GWAS data (including 211 gut microbiota taxa, 1,400 plasma metabolites or ratios, and an ITP patient cohort) were retrieved from the MiBioGen and GWAS Catalog databases. Using a two-sample Mendelian randomization (MR) approach, we screened gut microbiota and plasma metabolites potentially causally related to ITP. We further identified plasma metabolites serving as mediators through which gut microbiota affect ITP and calculated the strength of the mediation effect. To ensure result stability, we primarily used the inverse variance weighted (IVW) method as the main judgment index. We also utilized MR Egger and inverse variance weighted methods to detect heterogeneity in the results, and employed MR-Egger and MR-PRESSO methods to assess the presence of pleiotropy.
ResultsThough two-sample MR analysis, 8 gut microbiota taxa were found to have causal relationships with ITP. After excluding six plasma metabolites with pleiotropy, 39 plasma metabolites were found to be causally related to ITP (P < 0.05). Eleven plasma metabolites were identified as having causal relationships between gut microbiota and plasma metabolites. Finally, using the delta method, it was calculated that Sphingomyelin levels (8.0%, 95%CI: 0.9% to 11.5%, P = 0.047) and Glucose-to-mannose ratio (6.5%, 95%CI: 0.7% to 9.5%, P = 0.039) are intermediates for Intestinimonas influencing ITP, while Bilirubin (Z,Z) to etiocholanolone glucuronide ratio (5.6%, 95%CI: 4.7% to 6.9%, P = 0.043) is an intermediate for Senegalimassilia influencing ITP.
ConclusionGut microbiota can influence the development of ITP through changes in plasma metabolites. Sphingomyelin levels, Glucose-to-mannose ratio, and Bilirubin (Z,Z) to etiocholanolone glucuronide ratio are newly discovered intermediates through which gut microbiota influence ITP, providing potential indicators and targets for clinical diagnosis and treatment. This study highlights the intricate relationship between gut microbiota and plasma metabolites in the context of ITP, suggesting new avenues for clinical diagnosis and treatment.

背景：原发性免疫性血小板减少症（Primary immune thrombocytopenia, ITP）是一种免疫介导的血液系统疾病，以血小板计数减少为主要特征，会增加出血风险。近期研究表明，肠道菌群失调与ITP的发生发展密切相关。然而，肠道菌群通过血浆代谢物影响ITP发生与进展的具体机制仍未完全阐明。已有证据显示肠道菌群与血浆代谢物之间存在广泛的相互作用，提示肠道菌群可能通过调控血浆代谢物水平参与ITP的发病过程，这一假说仍有待进一步研究验证。
方法：本研究从MiBioGen和全基因组关联研究目录（GWAS Catalog）数据库中获取了汇总的全基因组关联研究（Genome-Wide Association Study, GWAS）数据，涵盖211个肠道菌群分类群、1400个血浆代谢物或其比值，以及一个ITP患者队列。本研究采用双样本孟德尔随机化（two-sample Mendelian randomization, MR）方法，筛选出与ITP存在潜在因果关联的肠道菌群与血浆代谢物；进一步鉴定出介导肠道菌群对ITP产生影响的血浆代谢物，并计算中介效应强度。为确保研究结果的稳定性，本研究主要以逆方差加权（inverse variance weighted, IVW）法作为核心判断指标；同时采用MR Egger与逆方差加权法检测研究结果的异质性，并通过MR-Egger和MR-PRESSO方法评估多效性的存在。
结果：通过双样本孟德尔随机化分析，本研究共筛选出8个与ITP存在因果关联的肠道菌群分类群。在排除6个存在多效性的血浆代谢物后，共鉴定出39个与ITP存在因果关联的血浆代谢物（P < 0.05）。另有11个血浆代谢物被证实可介导肠道菌群与ITP之间的关联。最终通过delta法计算发现，神经鞘磷脂（Sphingomyelin）水平（8.0%，95%CI：0.9%~11.5%，P=0.047）以及葡萄糖与甘露糖比值（Glucose-to-mannose ratio）（6.5%，95%CI：0.7%~9.5%，P=0.039）是Intestinimonas菌属影响ITP发病的中介因子；而(Z,Z)-胆红素与粪胆烷醇酮葡萄糖醛酸苷比值（Bilirubin (Z,Z) to etiocholanolone glucuronide ratio）（5.6%，95%CI：4.7%~6.9%，P=0.043）是Senegalimassilia菌属影响ITP发病的中介因子。
结论：肠道菌群可通过改变血浆代谢物水平影响ITP的发生发展。神经鞘磷脂（Sphingomyelin）水平、葡萄糖与甘露糖比值（Glucose-to-mannose ratio）以及(Z,Z)-胆红素与粪胆烷醇酮葡萄糖醛酸苷比值（Bilirubin (Z,Z) to etiocholanolone glucuronide ratio）是新发现的肠道菌群影响ITP的中介因子，可为临床诊疗提供潜在的生物标志物与治疗靶点。本研究阐明了ITP背景下肠道菌群与血浆代谢物之间的复杂关联，为临床诊疗提供了新的思路与方向。