Yu Xinghao, Chen Yiyin, Lei Lei, Li Pengfei, Lin Dandan, Shen Ying, Hou Chang, Chen Jia, Fan Yi, Jin Yi, Lu Huimin, Wu Depei, Xu Yang
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
BMC Med. 2025 Apr 7;23(1):201. doi: 10.1186/s12916-025-04026-w.
Graft-versus-host disease (GVHD) and relapse are major complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Metabolites play crucial roles in immune regulation, but their causal relationships with GVHD and relapse remain unclear.
We utilized genetic variants from genome-wide association studies (GWAS) of 309 known metabolites as instrumental variables to evaluate their causal effects on acute GVHD (aGVHD), gut GVHD, chronic GVHD (cGVHD), and relapse in different populations. Multiple causal inference methods, heterogeneity assessments, and pleiotropy tests were conducted to ensure result robustness. Multivariable MR analysis was performed to adjust for potential confounders, and validation MR analysis further confirmed key findings. Mediation MR analysis was employed to explore indirect causal pathways.
After correction for multiple testing, we identified elevated pyridoxate and proline levels as protective factors against grade 3-4 aGVHD (aGVHD) and relapse, respectively. Conversely, glycochenodeoxycholate increased the risk of aGVHD, whereas 1-stearoylglycerophosphoethanolamine had a protective effect. The robustness and stability of these findings were confirmed by multiple causal inference approaches, heterogeneity, and horizontal pleiotropy analyses. Multivariable MR analysis further excluded potential confounding pleiotropic effects. Validation MR analyses supported the causal roles of pyridoxate and 1-stearoylglycerophosphoethanolamine, while mediation MR revealed that pyridoxate influences GVHD directly and indirectly via CD39 Tregs. Pathway analyses highlighted critical biochemical alterations, including disruptions in bile acid metabolism and the regulatory roles of vitamin B6 derivatives. Finally, clinical metabolic analyses, including direct fecal metabolite measurements, confirmed the protective role of pyridoxate against aGVHD.
Our findings provide novel insights into the metabolic mechanisms underlying GVHD and relapse after allo-HSCT. Identified metabolites, particularly pyridoxate, may serve as potential therapeutic targets for GVHD prevention and management.
移植物抗宿主病（GVHD）和复发是异基因造血干细胞移植（allo-HSCT）后的主要并发症。代谢物在免疫调节中起关键作用，但其与GVHD和复发之间的因果关系仍不清楚。
我们利用来自309种已知代谢物的全基因组关联研究（GWAS）的遗传变异作为工具变量，评估它们对不同人群急性GVHD（aGVHD）、肠道GVHD、慢性GVHD（cGVHD）和复发的因果效应。进行了多种因果推断方法、异质性评估和多效性检验，以确保结果的稳健性。进行多变量孟德尔随机化（MR）分析以调整潜在的混杂因素，验证性MR分析进一步证实了关键发现。采用中介MR分析来探索间接因果途径。
经过多重检验校正后，我们分别确定吡哆酸和脯氨酸水平升高是预防3-4级aGVHD和复发的保护因素。相反，甘氨鹅去氧胆酸增加了aGVHD的风险，而1-硬脂酰甘油磷酸乙醇胺具有保护作用。多种因果推断方法、异质性和水平多效性分析证实了这些发现的稳健性和稳定性。多变量MR分析进一步排除了潜在的混杂多效性效应。验证性MR分析支持了吡哆酸和1-硬脂酰甘油磷酸乙醇胺的因果作用，而中介MR显示吡哆酸通过CD39 +调节性T细胞直接和间接影响GVHD。通路分析突出了关键的生化改变，包括胆汁酸代谢的破坏和维生素B6衍生物的调节作用。最后，临床代谢分析，包括直接粪便代谢物测量，证实了吡哆酸对aGVHD的保护作用。
我们的发现为allo-HSCT后GVHD和复发的代谢机制提供了新的见解。确定的代谢物，特别是吡哆酸，可能作为预防和治疗GVHD的潜在治疗靶点。
Zotero 插件
