肠道微生物群与程序性细胞死亡蛋白 1/程序性细胞死亡配体 1 之间的因果关系：一项双向孟德尔随机化研究。
Causal relationships between gut microbiota and programmed cell death protein 1/programmed cell death-ligand 1: A bidirectional Mendelian randomization study.
机构信息
The First Clinical College, Shanxi Medical University, Jinzhong, China.
Department of Oncology, Wuming Hospital of Guangxi Medical University, Nanning, China.
出版信息
Front Immunol. 2023 Mar 9;14:1136169. doi: 10.3389/fimmu.2023.1136169. eCollection 2023.
BACKGROUND
Multiple clinical studies have indicated that the gut microbiota influences the effects of immune checkpoint blockade (ICB) therapy comprising PD-1/PD-L1 inhibitors, but the causal relationship is unclear. Because of numerous confounders, many microbes related to PD-1/PD-L1 have not been identified. This study aimed to determine the causal relationship between the microbiota and PD-1/PD-L1 and identify possible biomarkers for ICB therapy.
METHOD
We used bidirectional two-sample Mendelian randomization with two different thresholds to explore the potential causal relationship between the microbiota and PD-1/PD-L1 and species-level microbiota GWAS to verify the result.
RESULT
In the primary forward analysis, genus_Holdemanella showed a negative correlation with PD-1 [βIVW = -0.25; 95% CI (-0.43 to -0.07); P = 0.028] and genus_Prevotella9 showed a positive correlation with PD-1 [βIVW = 0.2; 95% CI (0.1 to 0.4); P = 0.027]; order_Rhodospirillales [βIVW = 0.2; 95% CI (0.1 to 0.4); P = 0.044], family_Rhodospirillaceae [βIVW = 0.2; 95% CI (0 to 0.4); P = 0.032], genus_Ruminococcaceae_UCG005 [βIVW = 0.29; 95% CI (0.08 to 0.5); P = 0.028], genus_Ruminococcus_gnavus_group [βIVW = 0.22; 95% CI (0.05 to 0.4); P = 0.029], and genus_Coprococcus_2 [βIVW = 0.4; 95% CI (0.1 to 0.6); P = 0.018] were positively correlated with PD-L1; and phylum_Firmicutes [βIVW = -0.3; 95% CI (-0.4 to -0.1); P = 0.031], family_ClostridialesvadinBB60group [βIVW = -0.31; 95% CI (-0.5 to -0.11), P = 0.008], family_Ruminococcaceae [βIVW = -0.33; 95% CI (-0.58 to -0.07); P = 0.049], and genus_Ruminococcaceae_UCG014 [βIVW = -0.35; 95% CI (-0.57 to -0.13); P = 0.006] were negatively correlated with PD-L1. The one significant species in further analysis was species_Parabacteroides_unclassified [βIVW = 0.2; 95% CI (0-0.4); P = 0.029]. Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analyses confirmed the robustness of the MR results.
背景
多项临床研究表明，肠道微生物群影响包括 PD-1/PD-L1 抑制剂在内的免疫检查点阻断（ICB）治疗的效果，但因果关系尚不清楚。由于存在许多混杂因素，许多与 PD-1/PD-L1 相关的微生物尚未被发现。本研究旨在确定微生物群与 PD-1/PD-L1 之间的因果关系，并确定 ICB 治疗的可能生物标志物。
方法
我们使用双向两样本 Mendelian 随机化分析，使用两种不同的阈值来探索微生物群与 PD-1/PD-L1 之间的潜在因果关系，并使用物种水平的微生物组 GWAS 来验证结果。
结果
在主要的正向分析中，属_Holdemanella 与 PD-1 呈负相关[βIVW = -0.25；95%CI（-0.43 至-0.07）；P = 0.028]，属_Prevotella9 与 PD-1 呈正相关[βIVW = 0.2；95%CI（0.1 至 0.4）；P = 0.027]；目_Rhodospirillales[βIVW = 0.2；95%CI（0.1 至 0.4）；P = 0.044]，科_Rhodospirillaceae[βIVW = 0.2；95%CI（0 至 0.4）；P = 0.032]，属_Ruminococcaceae_UCG005[βIVW = 0.29；95%CI（0.08 至 0.5）；P = 0.028]，属_Ruminococcus_gnavus_group[βIVW = 0.22；95%CI（0.05 至 0.4）；P = 0.029]和属_Coprococcus_2[βIVW = 0.4；95%CI（0.1 至 0.6）；P = 0.018]与 PD-L1 呈正相关；而门_Firmicutes[βIVW = -0.3；95%CI（-0.4 至-0.1）；P = 0.031]，科_ClostridialesvadinBB60group[βIVW = -0.31；95%CI（-0.5 至-0.11）；P = 0.008]，科_Ruminococcaceae[βIVW = -0.33；95%CI（-0.58 至-0.07）；P = 0.049]和属_Ruminococcaceae_UCG014[βIVW = -0.35；95%CI（-0.57 至-0.13）；P = 0.006]与 PD-L1 呈负相关。进一步分析中唯一显著的物种是未分类的_Parabacteroides 种[βIVW = 0.2；95%CI（0-0.4）；P = 0.029]。异质性（P > 0.05）和多效性（P > 0.05）分析证实了 MR 结果的稳健性。
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