Table1_Causal effects and metabolites mediators between immune cell and risk of colorectal cancer: a Mendelian randomization study.xlsx

ObjectiveThe involvement of immune cells in colorectal cancer (CRC) and their interplay with metabolic disorders are yet to be fully elucidated. This study examines how peripheral immune cells, inferred genetically, affect CRC and investigates the intermediary roles of metabolites.
MethodsWe employed a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal influence of immune cells on CRC. Additionally, a two-step MR strategy was utilized to pinpoint potential metabolites that mediate this effect. Our analysis incorporated data from genome-wide association studies (GWAS), involving 731 immune cell types, 1,400 metabolites, and CRC outcomes. The primary method of analysis was randomized inverse variance weighting (IVW), supported by MR-Egger, weighted median, simple mode, and weighted mode analyses. Sensitivity checks were conducted using Cochran’s Q test, MR-PRESSO test, MR-Egger regression intercept, and leave-one-out analysis.
ResultsThe study identified 23 immune cell types and 17 metabolites that are causally linked to CRC. Our mediation analysis highlighted that nine metabolites act as intermediaries in the relationship between nine specific immune cells and CRC risk. Notably, The ratios of Adenosine 5’-monophosphate (AMP) to aspartate and Retinol (Vitamin A) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) were found to concurrently mediate the promoting effects of Myeloid DC � and BAFF-R on B cells in colorectal cancer (CRC). Moreover, iminodiacetate (IDA) was found to mediate the protective effect of CD14+ CD16- monocytes on CRC, contributing 11.8% to this mediation. In contrast, IDA was also seen to decrease the protective effect of IgD+ CD38br %B cells on CRC risk, with a mediation effect proportion of -10.4%.
ConclusionThis study delineates a complex network involving immune cells, metabolites, and CRC, suggesting a multifaceted pathophysiological interaction. The identified causal links and mediation pathways underscore potential therapeutic targets, providing a foundation for interventions aimed at modulating immune responses to manage CRC.

研究目的：免疫系统细胞在结直肠癌（colorectal cancer, CRC）中的参与作用及其与代谢紊乱的相互关联，目前尚未得到完全阐明。本研究旨在探究经遗传推断的外周免疫细胞如何影响结直肠癌，并解析代谢物在此过程中的中介角色。
方法：本研究采用双样本双向孟德尔随机化（Mendelian randomization, MR）方法，评估免疫细胞对结直肠癌的因果影响。此外，还运用两步孟德尔随机化策略，以确定介导该效应的潜在代谢物。本研究整合了全基因组关联研究（genome-wide association study, GWAS）的数据，涉及731种免疫细胞类型、1400种代谢物以及结直肠癌结局数据。主要分析方法为随机逆方差加权（randomized inverse variance weighting, IVW），辅以MR-Egger、加权中位数、简单众数与加权众数分析。敏感性检验采用Cochran Q检验、MR-PRESSO检验、MR-Egger回归截距法以及留一法分析。
结果：本研究鉴定出23种免疫细胞类型与17种代谢物，二者均与结直肠癌存在因果关联。中介分析显示，9种代谢物在9种特定免疫细胞与结直肠癌发病风险的关联中发挥中介作用。值得注意的是，5'-腺苷一磷酸（Adenosine 5’-monophosphate, AMP）与天冬氨酸的比值，以及视黄醇（维生素A, Retinol）与亚油酰-花生四烯酰甘油（18:2比20:4）的比值，可同时介导髓样树突状细胞（Myeloid DC）和B细胞活化因子受体（BAFF-R）阳性B细胞对结直肠癌的促癌效应。此外，亚氨基二乙酸（iminodiacetate, IDA）可介导CD14+CD16-单核细胞对结直肠癌的保护作用，中介效应占比为11.8%。与之相反，亚氨基二乙酸同时会削弱IgD+CD38br%B细胞对结直肠癌发病风险的保护作用，中介效应占比为-10.4%。
结论：本研究阐明了一条涉及免疫细胞、代谢物与结直肠癌的复杂调控网络，提示三者之间存在多维度的病理生理相互作用。本研究鉴定出的因果关联与中介通路，为潜在的治疗靶点提供了依据，也为靶向调节免疫应答以管理结直肠癌的干预策略奠定了基础。