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

doi:10.3969/j.issn.1674-8115.2025.12.006

Abstract

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)

CLC Number:

R541

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,(12): 1606-1619.

Figures/Tables 8

TrendMD

References 56

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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