基于孟德尔随机化探讨肠道菌群与失眠的因果关联研究

doi:10.12114/j.issn.1007-9572.2023.0656

摘要/Abstract

摘要： 背景随着失眠的发病率逐渐升高，其严重影响患者的精神及工作状态。肠道菌群被认为是失眠的一个危险因素，但目前存在相关证据较为缺乏的问题，难以准确认识二者之间的关系。目的使用两样本孟德尔随机化作为研究方法，探索肠道菌群与失眠之间的因果关系。方法使用MiBioGen联盟进行的最大可用全基因组关联研究荟萃分析（n=18 340）中肠道菌群的汇总统计数据，根据预设的阈值提取与196种肠道微生物相对丰度显著相关的单核苷酸多态性（SNPs）作为工具变量（IVs）。失眠的汇总统计数据来自英国生物样本库（UK Biobank）（n=462 341）。采用逆方差加权法（IVW）、MR-Egger回归、加权中位数法（WME）、加权众数法（WM）等检测肠道菌群与失眠之间的因果关系，其中以IVW法为主，根据效应指标优势比（OR）和95%置信区间（CI）评估结果。结合敏感性分析、异质性检验、基因多效性检验和异常值检验（MR-PRESSO）等方法来验证结果的稳定性和可靠性。并对发现与失眠有因果关系的菌群进行反向孟德尔随机化分析。结果 IVW结果显示蔷薇菌属（OR=0.787，95%CI=0.671~0.923，PFDR=0.016）、丹毒杆菌属（OR=0.880，95%CI=0.794~0.976，PFDR=0.077）、副普雷沃菌属（OR=0.891，95%CI=0.801~0.991，PFDR=0.083）、瘤胃球菌属UCG014组（OR=0.818，95%CI=0.697~0.961，PFDR=0.072）、巴斯德菌科（OR=0.897，95%CI=0.814~0.988，PFDR=0.081）、巴斯德菌目（OR=0.897，95%CI=0.814~0.988，PFDR=0.094）和失眠有关，未发现IVs存在基因多效性或显著异质性。根据反向孟德尔随机化分析结果，失眠对肠道菌群无显著的因果影响。结论蔷薇菌属、丹毒杆菌属、副普雷沃菌属、瘤胃球菌属UCG014组、巴斯德菌科、巴斯德菌目6种肠道菌群丰度与失眠的发病风险呈负相关，即丰度降低会增加失眠的发病风险，为失眠的保护因素。

关键词: 肠道菌群, 失眠, 孟德尔随机化, 因果关联

Abstract:

Background

As the prevalence of insomnia is gradually increasing, it is seriously affecting the mental and work status of patients. The gut microbiota is considered to be a risk factor for insomnia, but there is a relative lack of evidence to accurately recognize the relationship between gut microbiota and insomnia.

Objective

Using two-sample Mendelian randomization as a research methodology to explore the causal relationship between gut microbiota and insomnia.

Methods

Single nucleotide polymorphisms (SNPs) significantly associated with the relative abundance of 196 gut microorganisms were extracted as instrumental variables (IVs) according to predefined thresholds using pooled statistics of the gut microbiota from the largest available genome-wide meta-analysis of association studies conducted by the MiBioGen consortium (n=18 340). Pooled statistics for insomnia were obtained from the UK Biobank (n=462 341). Inverse variance weighting (IVW), MR-Egger regression, weighted median (WME), and weighted multinomial (WM) were used to detect the causal relationship between gut microbiota and insomnia, with IVW being the predominant method, and the results were assessed according to the effect indicator dominance ratio (OR) and 95% confidence interval (CI). Sensitivity analysis, heterogeneity test, gene multiplicity test, MR multiplicity residual and outlier test (MR-PRESSO) were combined to verify the stability and reliability of the results. Reverse Mendelian randomization analysis was also performed on the colonies found to be causally associated with insomnia.

Results

IVW results showed that genus_Roseburia (OR=0.787, 95%CI=0.671-0.923, P_FDR=0.016), genus_Erysipelatoclostridium (OR=0.880, 95%CI=0.794-0.976, P_FDR=0.077), genus_Paraprevotella (OR=0.891, 95%CI=0.801-0.991, P_FDR=0.083), genus_Ruminococcaceae UCG014 (OR=0.818, 95%CI=0.697-0.961, P_FDR=0.072), family_Pasteurellaceae (OR=0.897, 95%CI=0.814-0.988, P_FDR=0.081), order_Pasteurellales (OR=0.897, 95%CI=0.814-0.988, P_FDR=0.094) were associated with insomnia, and no genetic pleiotropy or significant heterogeneity of IVs was found. According to the results of reverse MR analysis, insomnia had no significant causal effect on gut microbiota.

Conclusion

The abundance of six species of GM from the genus_Roseburia, genus_Erysipelatoclostridium, genus_Paraprevotella, genus_Ruminococcaceae UCG014 group, family_Pasteurellaceae, and order_Pasteurellales is negatively correlated with the risk of developing insomnia, i.e., decreased abundance increased the risk of developing insomnia and is a protective factor against insomnia.

Key words: Intestinal flora, Insomnia, Mendelian randomization, Causal correlation

中图分类号:

R 741　R 378.2

郭玉梦,崔杨霖,张宪忠. 基于孟德尔随机化探讨肠道菌群与失眠的因果关联研究[J]. 中国全科医学, 2025, 28(08): 954-961. DOI: 10.12114/j.issn.1007-9572.2023.0656.
GUO Yumeng,CUI Yanglin,ZHANG Xianzhong. Based on Mendelian Randomization to Explore the Causal Relationship with Insomnia and Gut Microbiota[J]. Chinese General Practice, 2025, 28(08): 954-961. DOI: 10.12114/j.issn.1007-9572.2023.0656.

图/表 6

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暴露	SNPs（个）	方法	β	OR值	95%CI	P值	P_FDR值
蔷薇菌属	11	IVW	-0.240	0.787	0.671~0.923	0.003	0.016
		MR Egger	-0.551	0.576	0.305~1.089	0.124	0.155
		WME	-0.293	0.746	0.601~0.926	0.008	0.020
		WM	-0.358	0.699	0.526~0.929	0.033	0.056
巴斯德菌科	9	IVW	-0.109	0.897	0.814~0.988	0.027	0.081
		MR Egger	-0.180	0.835	0.648~1.078	0.209	0.209
		WME	-0.137	0.872	0.769~0.989	0.032	0.081
		WM	-0.141	0.869	0.751~1.006	0.096	0.160
丹毒杆菌属	13	IVW	-0.128	0.880	0.794~0.976	0.015	0.077
		MR Egger	-0.407	0.666	0.443~1.002	0.077	0.139
		WME	-0.111	0.895	0.785~1.020	0.095	0.139
		WM	-0.155	0.856	0.717~1.022	0.111	0.139
副普雷沃菌属	12	IVW	-0.116	0.891	0.801~0.991	0.033	0.083
		MR Egger	-0.555	0.574	0.319~1.034	0.094	0.157
		WME	-0.168	0.845	0.729~0.980	0.026	0.083
		WM	-0.168	0.845	0.683~1.046	0.150	0.166
瘤胃球菌属UCG014组	10	IVW	-0.200	0.818	0.697~0.961	0.014	0.072
		MR Egger	-0.045	0.956	0.584~1.565	0.863	0.863
		WME	-0.153	0.859	0.719~1.025	0.091	0.198
		WM	-0.125	0.883	0.730~1.067	0.230	0.287
巴斯德菌目	9	IVW	-0.109	0.897	0.814~0.988	0.027	0.094
		MR Egger	-0.180	0.835	0.648~1.078	0.209	0.209
		WME	-0.137	0.872	0.766~0.992	0.037	0.094
		WM	-0.141	0.869	0.754~1.000	0.087	0.144

暴露	SNPs（个）	方法	β	OR值	95%CI	P值	P_FDR值
蔷薇菌属	11	IVW	-0.240	0.787	0.671~0.923	0.003	0.016
		MR Egger	-0.551	0.576	0.305~1.089	0.124	0.155
		WME	-0.293	0.746	0.601~0.926	0.008	0.020
		WM	-0.358	0.699	0.526~0.929	0.033	0.056
巴斯德菌科	9	IVW	-0.109	0.897	0.814~0.988	0.027	0.081
		MR Egger	-0.180	0.835	0.648~1.078	0.209	0.209
		WME	-0.137	0.872	0.769~0.989	0.032	0.081
		WM	-0.141	0.869	0.751~1.006	0.096	0.160
丹毒杆菌属	13	IVW	-0.128	0.880	0.794~0.976	0.015	0.077
		MR Egger	-0.407	0.666	0.443~1.002	0.077	0.139
		WME	-0.111	0.895	0.785~1.020	0.095	0.139
		WM	-0.155	0.856	0.717~1.022	0.111	0.139
副普雷沃菌属	12	IVW	-0.116	0.891	0.801~0.991	0.033	0.083
		MR Egger	-0.555	0.574	0.319~1.034	0.094	0.157
		WME	-0.168	0.845	0.729~0.980	0.026	0.083
		WM	-0.168	0.845	0.683~1.046	0.150	0.166
瘤胃球菌属UCG014组	10	IVW	-0.200	0.818	0.697~0.961	0.014	0.072
		MR Egger	-0.045	0.956	0.584~1.565	0.863	0.863
		WME	-0.153	0.859	0.719~1.025	0.091	0.198
		WM	-0.125	0.883	0.730~1.067	0.230	0.287
巴斯德菌目	9	IVW	-0.109	0.897	0.814~0.988	0.027	0.094
		MR Egger	-0.180	0.835	0.648~1.078	0.209	0.209
		WME	-0.137	0.872	0.766~0.992	0.037	0.094
		WM	-0.141	0.869	0.754~1.000	0.087	0.144

暴露	异质性检验			基因多效性检验		MR-PRESSO
暴露	方法	Q	P值	Egger-intercept	P值	global.test	P值
蔷薇菌属	IVW	4.259	0.935	0.0226	0.348	5.750	0.918
巴斯德菌科	IVW	7.389	0.495	0.009	0.573	8.600	0.613
丹毒杆菌属	IVW	5.410	0.943	0.024	0.194	6.323	0.947
副普雷沃菌属	IVW	11.292	0.419	0.044	0.168	13.695	0.435
瘤胃球菌属UCG014组	IVW	16.924	0.050	-0.014	0.529	20.021	0.111
巴斯德菌目	IVW	7.389	0.495	0.009	0.573	8.600	0.595

暴露	异质性检验			基因多效性检验		MR-PRESSO
暴露	方法	Q	P值	Egger-intercept	P值	global.test	P值
蔷薇菌属	IVW	4.259	0.935	0.0226	0.348	5.750	0.918
巴斯德菌科	IVW	7.389	0.495	0.009	0.573	8.600	0.613
丹毒杆菌属	IVW	5.410	0.943	0.024	0.194	6.323	0.947
副普雷沃菌属	IVW	11.292	0.419	0.044	0.168	13.695	0.435
瘤胃球菌属UCG014组	IVW	16.924	0.050	-0.014	0.529	20.021	0.111
巴斯德菌目	IVW	7.389	0.495	0.009	0.573	8.600	0.595