肠道微生物群与心血管疾病的因果关系评价：双向孟德尔随机化分析

doi:10.3969/j.issn.1674-8115.2025.12.006

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (12): 1606-1619.doi: 10.3969/j.issn.1674-8115.2025.12.006

• 论著 · 循证医学 • 上一篇

肠道微生物群与心血管疾病的因果关系评价：双向孟德尔随机化分析

马会华¹^,², 闫奎坡¹(), 刘刚¹, 徐亚洲¹, 张磊¹, 孙彦琴¹

^1.河南中医药大学第一附属医院，心脏中心/国家区域（中医）心血管诊疗中心，郑州 450000
^2.河南中医药大学第一临床医学院，郑州 450000

收稿日期:2025-04-17 接受日期:2025-06-17 出版日期:2025-12-28 发布日期:2025-12-28
通讯作者: 闫奎坡，主任医师，博士；电子信箱：ykp19821122@163.com。
基金资助:
河南省中医药科学研究专项课题(2016ZY3003,2021JDZX038,2017ZY2017)

Causal relationship between gut microbiota and cardiovascular diseases: a bidirectional Mendelian randomization analysis

MA Huihua¹^,², YAN Kuipo¹(), LIU Gang¹, XU Yazhou¹, ZHANG Lei¹, SUN Yanqin¹

^1.Heart Center National Regional (Traditional Chinese Medicine) Cardiovascular Diagnosis and Treatment Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
^2.The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450000, China

Received:2025-04-17 Accepted:2025-06-17 Online:2025-12-28 Published:2025-12-28
Contact: YAN Kuipo, E-mail: ykp19821122@163.com.
Supported by:
Henan Province Specialized Research Fund for Traditional Chinese Medicine Science(2016ZY3003,2021JDZX038,2017ZY2017)

摘要/Abstract

摘要：

目的·通过孟德尔随机化（Mendelian randomization，MR）方法探讨肠道微生物群与心血管疾病（cardiovascular disease，CVD）之间的因果关系。方法·使用MiBioGen联盟提供的肠道微生物群数据（n=18 340）和IEU Open GWAS数据库提供的4种CVD（心房颤动1 030 836例、冠状动脉疾病547 261例、高血压20 526例、心力衰竭977 323例）相关的遗传位点作为工具变量。研究采用逆方差加权法（inverse variance weighted，IVW）作为主要研究方法。同时，使用Cochran's Q检验评估遗传工具变量的异质性，MR-Egger截距检验评估水平多效性，留一法评估作为工具变量的单核苷酸多态性（single-nucleotide polymorphism，SNP）对暴露和结局因果关系影响的敏感性。采用MR Steiger检验验证肠道微生物群与CVD之间的因果方向。结果·IVW法的研究结果表明：Victivallales（OR=0.939）、霍氏菌属（OR=0.939）、厌氧链球菌属（OR=0.922）、双歧杆菌科（OR=0.916）、黏胶球形菌纲（OR=0.936）、臭气杆菌属（OR=0.909）、Intestinibacter（OR=0.933）、黏胶球形菌门（OR=0.926）和双歧杆菌目（OR=0.916）对心房颤动表现为保护因素，而链状杆菌属（OR=1.057）、毛螺菌科UCG008（OR=1.051）、链球菌属（OR=1.089）和Victivallis（OR=1.038）则为危险因素；乳杆菌目（OR=0.919）和副拟杆菌属（OR=0.866）是冠状动脉疾病的保护因素，而韦荣球菌科（OR=1.065）、Lachnoclostridium（OR=1.093）、毛螺菌科（OR=1.094）、草酸杆菌属（OR=1.062）、臭气杆菌属（OR=1.160）是危险因素；Mollicutes RF9（OR=0.851），红椿菌纲（OR=0.803）、目（OR=0.803）、科（OR=0.803），以及Intestinibacter（OR=0.819）是高血压的保护因素，而Christensenellaceae R7 group（OR=1.218）、脱硫弧菌属（OR=1.167）和消化球菌科（OR=1.230）是危险因素；芽孢杆菌目（OR=0.955）和厌氧链球菌属（OR=0.899）是心力衰竭的保护因素，而瘤胃球菌UCG009（OR=1.107）、Eubacterium oxidoreducens group（OR=1.117）、月形单胞菌目（OR=1.106）、阴性杆菌目（OR=1.107）、Eubacterium eligens group（OR=1.139）和解黄酮菌属（OR=1.144）是危险因素。Cochran's Q检验显示，与CVD存在因果关系的肠道微生物群的SNP之间不存在异质性（均P>0.05）；基因多效性检验未发现多效性（均P>0.05）；留一法敏感性分析证实研究结果的稳健性。MR Steiger方向性检验结果支持肠道微生物群作为暴露、CVD作为结局的因果方向。结论·部分肠道微生物群对CVD存在显著的因果效应；改变其丰度可能影响CVD风险，这为基于微生物群的干预策略提供了潜在靶点。

关键词: 肠道微生物群, 心血管疾病, 孟德尔随机化, 全基因组关联分析, 单核苷酸多态性

Abstract:

Objective ·To investigate the causal relationship between gut microbiota and cardiovascular diseases (CVDs) using Mendelian randomization (MR). Methods ·Instrumental variables included genetic loci from gut microbiota data provided by the MiBioGen consortium (n=18 340) and CVD data from the IEU Open GWAS database, covering four CVD types: atrial fibrillation (n=1 030 836), coronary artery disease (n=547 261), hypertension (n=20 526), and heart failure (n=977 323). The inverse variance weighted (IVW) method was employed as the primary analytical approach. Additionally, Cochran's Q test was used to assess heterogeneity of genetic instruments, the MR-Egger intercept test to evaluate horizontal pleiotropy, and leave-one-out analysis to examine the sensitivity of single-nucleotide polymorphisms (SNPs) on the exposure-outcome causal relationship. The MR Steiger test was applied to validate the causal direction between gut microbiota and CVDs. Results ·The IVW analysis indicated that Victivallales (OR=0.939), Howardella (OR=0.939), Anaerostipes (OR=0.922), Bifidobacteriaceae (OR=0.916), Lentisphaeria (OR=0.936), Odoribacter (OR=0.909), Intestinibacter (OR=0.933), Lentisphaerae (OR=0.926), and Bifidobacteriales (OR=0.916) were protective factors against atrial fibrillation, while Catenibacterium (OR=1.057), Lachnospiraceae UCG008 (OR=1.051), Streptococcus (OR=1.089), and Victivallis (OR=1.038) were risk factors. For coronary artery disease, Lactobacillales (OR=0.919) and Parabacteroides (OR=0.866) were protective factors, while Veillonellaceae (OR=1.065), Lachnoclostridium (OR=1.093), Lachnospiraceae (OR=1.094), Oxalobacter (OR=1.062), and Odoribacter (OR=1.160) were risk factors. For hypertension, Mollicutes RF9 (OR=0.851), Coriobacteriia (OR=0.803), Coriobacteriales (OR=0.803), Coriobacteriaceae (OR=0.803), and Intestinibacter (OR=0.819) were protective factors, while Christensenellaceae R7 group (OR=1.218), Desulfovibrio (OR=1.167) ,and Peptococcaceae (OR=1.230) were risk factors. For heart failure, Bacillales (OR=0.955) and Anaerostipes (OR=0.899) were protective factors, while Ruminococcus UCG009 (OR=1.107), Eubacterium oxidoreducens group (OR=1.117), Selenomonadales (OR=1.106), Negativicutes (OR=1.107), Eubacterium eligens group (OR=1.139), and Flavonifractor (OR=1.144) were risk factors. Cochran's Q test showed no heterogeneity among SNPs of gut microbiota causally associated with CVDs (all P>0.05). The pleiotropy test found no evidence of horizontal pleiotropy (all P>0.05). Leave-one-out sensitivity analysis confirmed the robustness of the results. The MR Steiger directionality test supported the causal direction from gut microbiota (exposure) to CVDs (outcome). Conclusion ·Some gut microbiota have significant causal effects on CVDs; altering their abundance may influence CVD risk, providing potential targets for microbiota-based intervention strategies.

Key words: gut microbiota, cardiovascular disease, Mendelian randomization, genome-wide association study (GWAS), single-nucleotide polymorphism (SNP)

中图分类号:

R541

马会华, 闫奎坡, 刘刚, 徐亚洲, 张磊, 孙彦琴. 肠道微生物群与心血管疾病的因果关系评价：双向孟德尔随机化分析[J]. 上海交通大学学报（医学版）, 2025, 45(12): 1606-1619.

MA Huihua, YAN Kuipo, LIU Gang, XU Yazhou, ZHANG Lei, SUN Yanqin. Causal relationship between gut microbiota and cardiovascular diseases: a bidirectional Mendelian randomization analysis[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(12): 1606-1619.

图/表 8

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GWAS data ID	Disease	Sample size/n	Case/n	Control/n	Population
ebi-a-GCST006414	AF	1 030 836	60 620	970 216	European
ebi-a-GCST005195	CAD	547 261	122 733	424 528	European
ebi-a-GCST008036	Hypertension	20 526	11 863	8 663	European
ebi-a-GCST009541	HF	977 323	47 309	930 014	European

GWAS data ID	Disease	Sample size/n	Case/n	Control/n	Population
ebi-a-GCST006414	AF	1 030 836	60 620	970 216	European
ebi-a-GCST005195	CAD	547 261	122 733	424 528	European
ebi-a-GCST008036	Hypertension	20 526	11 863	8 663	European
ebi-a-GCST009541	HF	977 323	47 309	930 014	European

Outcome	Exposure	MR method	SNP/n	β	se	OR (95%CI)	P value	Correct causal direction	P value (Steiger test)
AF
	Catenibacterium	IVW	5	0.05	0.025	1.057 (1.005‒1.112)	0.030	True	4.85×10^-6
	Victivallales	IVW	8	-0.06	0.023	0.939 (0.896‒0.984)	0.008	True	1.52×10^-6
	Howardella	IVW	10	-0.06	0.019	0.939 (0.904‒0.977)	0.001	True	3.04×10^-5
	Lachnospiraceae UCG008	IVW	11	0.04	0.025	1.051 (1.001‒1.104)	0.047	True	2.52×10^-7
	Anaerostipes	IVW	13	-0.08	0.037	0.922 (0.857‒0.993)	0.030	True	5.20×10^-6
	Bifidobacteriaceae	IVW	11	-0.08	0.034	0.916 (0.855‒0.980)	0.011	True	1.42×10^-5
	Lentisphaeria	IVW	8	-0.06	0.024	0.936 (0.887‒0.983)	0.003	True	3.96×10^-6
	Streptococcus	IVW	15	0.08	0.039	1.089 (1.008‒1.177)	0.029	True	9.37×10^-6
	Victivallis	IVW	10	0.03	0.018	1.038 (1.001‒1.077)	0.043	True	4.62×10^-6
	Odoribacter	IVW	7	-0.09	0.046	0.909 (0.831‒0.996)	0.040	True	1.81×10^-5
	Intestinibacter	IVW	15	-0.06	0.031	0.933 (0.877‒0.993)	0.028	True	2.28×10^-6
	Lentisphaerae	IVW	9	-0.07	0.022	0.926 (0.886‒0.968)	<0.001	True	5.06×10^-6
	Bifidobacteriales	IVW	11	-0.08	0.034	0.916 (0.855‒0.980)	0.011	True	1.35×10^-5
CAD
	Lactobacillales	IVW	15	-0.08	0.032	0.919 (0.862‒0.980)	0.010	True	9.28×10^-7
	Veillonellaceae	IVW	19	0.06	0.026	1.065 (1.011‒1.122)	0.018	True	1.21×10^-5
	Parabacteroides	IVW	6	-0.14	0.050	0.866 (0.784‒0.956)	0.004	True	6.31×10^-5
	Lachnospiraceae	IVW	17	0.09	0.038	1.094 (1.012‒1.183)	0.023	True	7.23×10^-6
	Lachnoclostridium	IVW	13	0.08	0.039	1.093 (1.011‒1.181)	0.025	True	9.14×10^-5
	Oxalobacter	IVW	11	0.05	0.020	1.062 (1.019‒1.106)	0.004	True	6.05×10^-6
	Odoribacter	IVW	7	0.14	0.047	1.160 (1.056‒1.275)	0.001	True	6.42×10^-7
Hypertension
	Mollicutes RF9	IVW	13	-0.16	0.068	0.851 (0.743‒0.974)	0.019	True	7.23×10^-5
	Peptococcaceae	IVW	9	0.20	0.086	1.230 (1.038‒1.458)	0.016	True	2.07×10^-5
	Christensenellaceae R7 group	IVW	10	0.19	0.100	1.218 (1.001‒1.483)	0.049	True	9.97×10^-5
	Coriobacteriales	IVW	14	-0.21	0.085	0.803 (0.679‒0.950)	0.010	True	0.001
	Coriobacteriia	IVW	14	-0.21	0.085	0.803 (0.679‒0.950)	0.010	True	0.002
	Desulfovibrio	IVW	10	0.15	0.062	1.167 (1.033‒1.318)	0.012	True	0.007
	Coriobacteriaceae	IVW	14	-0.21	0.085	0.803 (0.679‒0.950)	0.010	true	0.007
	Intestinibacter	IVW	15	-0.19	0.083	0.819 (0.696‒0.965)	0.010	True	0.015
HF
	Ruminococcaceae UCG009	IVW	12	0.06	0.030	1.107 (1.009‒1.137)	0.022	True	6.12×10^-6
	Eubacterium oxidoreducens group	IVW	4	0.11	0.043	1.117 (1.026‒1.215)	0.010	True	3.26×10^-5
	Bacillales	IVW	9	-0.04	0.022	0.955 (0.913‒0.998)	0.010	True	5.84×10^-6
	Selenomonadales	IVW	12	0.10	0.044	1.106 (1.013‒1.208)	0.023	True	1.53×10^-5
	Anaerostipes	IVW	13	-0.10	0.043	0.899 (0.825‒0.974)	0.013	True	3.77×10^-6
	Negativicutes	IVW	12	0.10	0.044	1.107 (1.014‒1.208)	0.023	True	4.48×10^-5
	Eubacterium eligens group	IVW	7	0.13	0.057	1.139 (1.019‒1.274)	0.022	True	6.43×10^-6
	Flavonifractor	IVW	5	0.13	0.053	1.144 (1.031‒1.270)	0.011	True	1.06×10^-5

Outcome	Exposure	MR method	SNP/n	β	se	OR (95%CI)	P value	Correct causal direction	P value (Steiger test)
AF
	Catenibacterium	IVW	5	0.05	0.025	1.057 (1.005‒1.112)	0.030	True	4.85×10^-6
	Victivallales	IVW	8	-0.06	0.023	0.939 (0.896‒0.984)	0.008	True	1.52×10^-6
	Howardella	IVW	10	-0.06	0.019	0.939 (0.904‒0.977)	0.001	True	3.04×10^-5
	Lachnospiraceae UCG008	IVW	11	0.04	0.025	1.051 (1.001‒1.104)	0.047	True	2.52×10^-7
	Anaerostipes	IVW	13	-0.08	0.037	0.922 (0.857‒0.993)	0.030	True	5.20×10^-6
	Bifidobacteriaceae	IVW	11	-0.08	0.034	0.916 (0.855‒0.980)	0.011	True	1.42×10^-5
	Lentisphaeria	IVW	8	-0.06	0.024	0.936 (0.887‒0.983)	0.003	True	3.96×10^-6
	Streptococcus	IVW	15	0.08	0.039	1.089 (1.008‒1.177)	0.029	True	9.37×10^-6
	Victivallis	IVW	10	0.03	0.018	1.038 (1.001‒1.077)	0.043	True	4.62×10^-6
	Odoribacter	IVW	7	-0.09	0.046	0.909 (0.831‒0.996)	0.040	True	1.81×10^-5
	Intestinibacter	IVW	15	-0.06	0.031	0.933 (0.877‒0.993)	0.028	True	2.28×10^-6
	Lentisphaerae	IVW	9	-0.07	0.022	0.926 (0.886‒0.968)	<0.001	True	5.06×10^-6
	Bifidobacteriales	IVW	11	-0.08	0.034	0.916 (0.855‒0.980)	0.011	True	1.35×10^-5
CAD
	Lactobacillales	IVW	15	-0.08	0.032	0.919 (0.862‒0.980)	0.010	True	9.28×10^-7
	Veillonellaceae	IVW	19	0.06	0.026	1.065 (1.011‒1.122)	0.018	True	1.21×10^-5
	Parabacteroides	IVW	6	-0.14	0.050	0.866 (0.784‒0.956)	0.004	True	6.31×10^-5
	Lachnospiraceae	IVW	17	0.09	0.038	1.094 (1.012‒1.183)	0.023	True	7.23×10^-6
	Lachnoclostridium	IVW	13	0.08	0.039	1.093 (1.011‒1.181)	0.025	True	9.14×10^-5
	Oxalobacter	IVW	11	0.05	0.020	1.062 (1.019‒1.106)	0.004	True	6.05×10^-6
	Odoribacter	IVW	7	0.14	0.047	1.160 (1.056‒1.275)	0.001	True	6.42×10^-7
Hypertension
	Mollicutes RF9	IVW	13	-0.16	0.068	0.851 (0.743‒0.974)	0.019	True	7.23×10^-5
	Peptococcaceae	IVW	9	0.20	0.086	1.230 (1.038‒1.458)	0.016	True	2.07×10^-5
	Christensenellaceae R7 group	IVW	10	0.19	0.100	1.218 (1.001‒1.483)	0.049	True	9.97×10^-5
	Coriobacteriales	IVW	14	-0.21	0.085	0.803 (0.679‒0.950)	0.010	True	0.001
	Coriobacteriia	IVW	14	-0.21	0.085	0.803 (0.679‒0.950)	0.010	True	0.002
	Desulfovibrio	IVW	10	0.15	0.062	1.167 (1.033‒1.318)	0.012	True	0.007
	Coriobacteriaceae	IVW	14	-0.21	0.085	0.803 (0.679‒0.950)	0.010	true	0.007
	Intestinibacter	IVW	15	-0.19	0.083	0.819 (0.696‒0.965)	0.010	True	0.015
HF
	Ruminococcaceae UCG009	IVW	12	0.06	0.030	1.107 (1.009‒1.137)	0.022	True	6.12×10^-6
	Eubacterium oxidoreducens group	IVW	4	0.11	0.043	1.117 (1.026‒1.215)	0.010	True	3.26×10^-5
	Bacillales	IVW	9	-0.04	0.022	0.955 (0.913‒0.998)	0.010	True	5.84×10^-6
	Selenomonadales	IVW	12	0.10	0.044	1.106 (1.013‒1.208)	0.023	True	1.53×10^-5
	Anaerostipes	IVW	13	-0.10	0.043	0.899 (0.825‒0.974)	0.013	True	3.77×10^-6
	Negativicutes	IVW	12	0.10	0.044	1.107 (1.014‒1.208)	0.023	True	4.48×10^-5
	Eubacterium eligens group	IVW	7	0.13	0.057	1.139 (1.019‒1.274)	0.022	True	6.43×10^-6
	Flavonifractor	IVW	5	0.13	0.053	1.144 (1.031‒1.270)	0.011	True	1.06×10^-5

Outcome	Exposure	Cochran's Q				MR-Egger intercept
		MR-Egger		IVW		Intercept	P value
		Q value	P value	Q value	P value	Intercept	P value
AF
	Catenibacterium	0.370	0.946	0.488	0.974	0.010	0.753
	Victivallales	3.948	0.683	4.155	0.761	0.005	0.665
	Howardella	7.364	0.497	7.622	0.572	-0.006	0.624
	Lachnospiraceae UCG008	8.051	0.528	8.162	0.612	0.004	0.747
	Anaerostipes	12.334	0.339	12.561	0.402	-0.003	0.661
	Bifidobacteriaceae	8.821	0.453	9.111	0.521	0.004	0.603
	Lentisphaeria	3.948	0.683	4.155	0.761	0.005	0.665
	Streptococcus	20.126	0.092	20.223	0.123	0.002	0.807
	Victivallis	7.007	0.535	8.153	0.518	0.019	0.315
	Odoribacter	3.621	0.605	4.634	0.591	0.010	0.360
	Intestinibacter	14.962	0.309	17.041	0.253	0.010	0.203
	Lentisphaerae	7.455	0.383	7.841	0.449	0.007	0.566
	Bifidobacteriales	8.821	0.454	9.111	0.521	0.004	0.603
CAD
	Lactobacillales	13.551	0.406	14.344	0.424	-0.005	0.398
	Veillonellaceae	14.934	0.528	1.741	0.495	0.005	0.241
	Parabacteroides	4.608	0.329	4.742	0.448	0.005	0.750
	Lachnospiraceae	21.818	0.112	24.485	0.079	-0.008	0.195
	Lachnoclostridium	5.378	0.911	6.793	0.870	0.011	0.259
	Oxalobacter	3.473	0.942	3.692	0.960	-0.006	0.650
	Odoribacter	4.080	0.537	5.288	0.507	0.012	0.321
Hypertension
	Mollicutes RF9	3.784	0.975	0.711	0.877	<0.001	0.957
	Peptococcaceae	5.131	0.643	0.331	0.178	0.055	0.358
	Christensenellaceae R7 group	6.448	0.597	7.960	0.538	0.008	0.575
	Coriobacteriales	8.827	0.717	9.577	0.728	0.012	0.575
	Coriobacteriia	8.827	0.717	9.577	0.728	0.013	0.145
	Desulfovibrio	3.323	0.912	7.960	0.538	0.222	0.253
	Coriobacteriaceae	8.827	0.717	9.577	0.728	-0.020	0.403
	Intestinibacter	19.114	0.119	21.572	0.087	-0.020	0.403
HF
	Ruminococcaceae UCG009	8.939	0.537	10.956	0.446	0.017	0.185
	Eubacterium oxidoreducens group	2.451	0.293	2.483	0.478	-0.002	0.887
	Bacillales	2.705	0.910	2.870	0.942	0.006	0.697
	Selenomonadales	4.459	0.924	5.180	0.922	-0.007	0.415
	Anaerostipes	9.973	0.532	10.057	0.610	-0.002	0.777
	Negativicutes	4.459	0.924	5.180	0.922	-0.007	0.415
	Eubacterium eligens group	1.547	0.907	6.428	0.376	-0.038	0.078
	Flavonifractor	2.919	0.404	2.919	0.404	0.002	0.903

肠道微生物群与心血管疾病的因果关系评价：双向孟德尔随机化分析

Causal relationship between gut microbiota and cardiovascular diseases: a bidirectional Mendelian randomization analysis

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