Role of CD40 on CD14- CD16+ monocyte in mediating the effect of Dialister on Depression

Objective: To explore the cause-and-effect link between gut microbiota and depression, and to determine and measure the function of immune cells as possible intermediaries.Methods：This research involved conducting a dual-sample Mendelian randomization analysis (MR) on genetically forecasted gut microbiota (7,738 individuals) and depression (25,087 individuals and 92,695 controls), utilizing aggregate data from a genome-wide association study (GWAS). The primary MR analysis employed inverse variance-weighted (IVW), along with additional techniques, and we executed heterogeneity and level pleiotropy tests to corroborate the primary MR findings. Furthermore, genetic variations in immune cell signatures were extracted from an extensive, open-label genome-wide social study (GWAS) with 3757 participants, utilizing a two-phase MR analysis to ascertain and measure the impact of CD40 on the CD14-CD16+ monocyte-driven effects of Microbacterium on depression.Results: By MR analysis, five gut bacteria were associated with a reduced risk of depression: Butyrivibrio (OR=0.9922, 95%, CI=0.9864-0.9980, P=0.0084), Sutterellaceae (OR=0.9843, 95%CI=0.9732-0.9956, P=0.0067), Dialister (OR=0.9887, 95%CI=0.9775-1.0000, P=0.0497), Bacteroides (OR=0.9883, 95%CI=0.9768-1.0000, P=0.0476), Butyrivibrio_crossotus (OR=0.9933, 95%CI=0.9879-0.9988, P=0.0166), and there was no strong evidence of a causal relationship between depression and gut bacteria. The im-muno phenotype were identified as significantly associated with depression risk. In addition, we also found that the proportion of CD40 on CD14- CD16+ monocyte-mediated in genetically predicted Dialister on depression was 5.42%.Conclusions: Our study identified five gut microbiota that reduced the risk of depression, and twenty-seven immunophenotypes are significantly associated with depression. Of these, the CD40-mediated microbiota has small effect on CD14-CD16+ monocytes, but these effects are largely unknown and additional potential factors need to be investigated. Clinically, attention should be paid to the effects of the gut microbiome on depression.

研究目的：本研究旨在探讨肠道菌群与抑郁症之间的因果关联，并明确并量化作为潜在中介因子的免疫细胞的功能。
研究方法：本研究利用全基因组关联研究（genome-wide association study, GWAS）的汇总数据，针对遗传预测的肠道菌群（纳入7738名受试者）与抑郁症（纳入25087名病例及92695名对照）开展双样本孟德尔随机化分析（Mendelian randomization analysis, MR）。主MR分析采用逆方差加权法（inverse variance-weighted, IVW）并辅以其他分析方法，同时通过异质性检验与水平多效性检验验证主MR分析结果的可靠性。此外，本研究从一项纳入3757名受试者的大规模开放标签全基因组社会研究（genome-wide social study, GWAS）中提取免疫细胞特征的遗传变异，并采用两阶段MR分析明确并量化CD40对微杆菌属（Microbacterium）经CD14⁻CD16⁺单核细胞介导的抑郁症效应的影响。
研究结果：通过MR分析发现，5种肠道菌群与抑郁症发病风险降低相关：丁酸弧菌属（Butyrivibrio，OR=0.9922，95%置信区间[CI]=0.9864~0.9980，P=0.0084）、萨特氏菌科（Sutterellaceae，OR=0.9843，95%CI=0.9732~0.9956，P=0.0067）、巨单胞菌属（Dialister，OR=0.9887，95%CI=0.9775~1.0000，P=0.0497）、拟杆菌属（Bacteroides，OR=0.9883，95%CI=0.9768~1.0000，P=0.0476）以及交叉丁酸弧菌（Butyrivibrio_crossotus，OR=0.9933，95%CI=0.9879~0.9988，P=0.0166）；未发现抑郁症与肠道菌群之间存在强因果关联的有力证据。免疫表型被证实与抑郁症发病风险显著相关。此外，本研究还发现，在遗传预测的巨单胞菌属（Dialister）对抑郁症的效应中，CD14⁻CD16⁺单核细胞介导的CD40作用占比为5.42%。
研究结论：本研究明确了5种可降低抑郁症发病风险的肠道菌群，以及27种与抑郁症显著相关的免疫表型。其中，CD40介导的菌群对CD14⁻CD16⁺单核细胞的作用较弱，但此类效应的具体机制尚不明确，仍需进一步探索潜在影响因素。临床层面应重视肠道微生物组对抑郁症的调控作用。