Chen Li, Yi Ying, Zhu Yun
The Second People's Hospital of China, Three Gorges University, The Second People's Hospital of Yichang, Yichang 443000, Hubei, China.
The Second People's Hospital of China, Three Gorges University, The Second People's Hospital of Yichang, No. 21 Xiling 1st Road, Xiling District, Yichang 443000, Hubei, China.
Open Med (Wars). 2025 Jul 17;20(1):20251240. doi: 10.1515/med-2025-1240. eCollection 2025.
This study aimed to investigate the potential causal relationship between immune cell and the risk of ulcerative colitis (UC), and to explore whether serum metabolites may mediate this association, thereby suggesting potential biomarkers or therapeutic targets.
We conducted a Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies to evaluate both the direct effects and potential mediating roles of 731 immune cells and 1,400 serum metabolites in relation to UC. Instrumental variables were rigorously selected based on genome-wide significance and linkage disequilibrium thresholds. The primary analytical method was inverse variance weighted, supplemented by MR-Egger regression and weighted median methods to ensure robustness. Cochran's test, MR-Egger intercept, and leave-one-out analysis were employed to evaluate heterogeneity and pleiotropy. Mediation MR analysis was conducted to examine potential metabolite-mediated pathways.
We identified a statistically significant positive causal effect of CD39⁺ CD4⁺ T cell on UC risk (OR = 1.05, 95% CI = 1.03-1.08, = 0.05). Sensitivity analyses confirmed the robustness of this association, and reverse MR analysis indicated no causal effect of UC on CD39⁺ CD4⁺ T cell, suggesting a unidirectional relationship. Mediation analysis further revealed that succinyl carnitine (C4DC) partially mediated the effect of CD39⁺ CD4⁺ T cell on UC, with a mediation proportion of 3.3%.
Our findings suggest that CD39⁺ CD4⁺ T cell may increase the risk of UC, potentially by modulating the levels of succinyl carnitine (C4DC). These results indicate a potential immunometabolic pathway in UC pathogenesis and highlight CD39⁺ CD4⁺ T cell and C4DC as promising targets for further research. However, additional experimental validation is required to confirm these findings and assess their clinical relevance.
本研究旨在探讨免疫细胞与溃疡性结肠炎（UC）风险之间的潜在因果关系，并探究血清代谢物是否可能介导这种关联，从而提示潜在的生物标志物或治疗靶点。
我们使用全基因组关联研究的汇总统计数据进行孟德尔随机化（MR）分析，以评估731种免疫细胞和1400种血清代谢物与UC相关的直接效应和潜在中介作用。基于全基因组显著性和连锁不平衡阈值严格选择工具变量。主要分析方法为逆方差加权，并辅以MR-Egger回归和加权中位数方法以确保稳健性。采用 Cochr an检验、MR-Egger截距和留一法分析来评估异质性和多效性。进行中介MR分析以检验潜在的代谢物介导途径。
我们发现CD39⁺ CD4⁺ T细胞对UC风险具有统计学显著的正向因果效应（OR = 1.05，95% CI = 1.03 - 1.08，P = 0.05）。敏感性分析证实了这种关联的稳健性，反向MR分析表明UC对CD39⁺ CD4⁺ T细胞无因果效应，提示存在单向关系。中介分析进一步显示，琥珀酰肉碱（C4DC）部分介导了CD39⁺ CD4⁺ T细胞对UC的影响，中介比例为3.3%。
我们的研究结果表明，CD39⁺ CD4⁺ T细胞可能通过调节琥珀酰肉碱（C4DC）水平增加UC风险。这些结果表明UC发病机制中存在潜在的免疫代谢途径，并突出了CD39⁺ CD4⁺ T细胞和C4DC作为进一步研究的有前景靶点。然而，需要额外的实验验证来证实这些发现并评估其临床相关性。
