收稿日期: 2025-04-17
录用日期: 2025-06-17
网络出版日期: 2025-12-28
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
Received date: 2025-04-17
Accepted date: 2025-06-17
Online published: 2025-12-28
Supported by
Henan Province Specialized Research Fund for Traditional Chinese Medicine Science(2016ZY3003,2021JDZX038,2017ZY2017)
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。
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 . DOI: 10.3969/j.issn.1674-8115.2025.12.006
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.
| [1] | LI Y, CAO G Y, JING W Z, et al. Global trends and regional differences in incidence and mortality of cardiovascular disease, 1990?2019: findings from 2019 global burden of disease study[J]. Eur J Prev Cardiol, 2023, 30(3): 276-286. |
| [2] | 刘明波, 何新叶, 杨晓红, 等. 《中国心血管健康与疾病报告2023》要点解读[J]. 临床心血管病杂志, 2024, 40(8): 599-616. |
| LIU M B, HE X Y, YANG X H, et al. Interpretation of Report on Cardiovascular Health and Diseases in China 2023[J]. Journal of Clinical Cardiology, 2024, 40(8): 599-616. | |
| [3] | SHI H Q, TER HORST R, NIELEN S, et al. The gut microbiome as mediator between diet and its impact on immune function[J]. Sci Rep, 2022, 12(1): 5149. |
| [4] | OJO O, FENG Q Q, OJO O O, et al. The role of dietary fibre in modulating gut microbiota dysbiosis in patients with type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials[J]. Nutrients, 2020, 12(11): 3239. |
| [5] | TELLE-HANSEN V H, GAUNDAL L, BASTANI N, et al. Replacing saturated fatty acids with polyunsaturated fatty acids increases the abundance of Lachnospiraceae and is associated with reduced total cholesterol levels: a randomized controlled trial in healthy individuals[J]. Lipids Health Dis, 2022, 21(1): 92. |
| [6] | WANG Z N, KLIPFELL E, BENNETT B J, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease[J]. Nature, 2011, 472(7341): 57-63. |
| [7] | UFNAL M, JAZWIEC R, DADLEZ M, et al. Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin Ⅱ in rats[J]. Can J Cardiol, 2014, 30(12): 1700-1705. |
| [8] | LI D D, LU Y, YUAN S, et al. Gut microbiota-derived metabolite trimethylamine-N-oxide and multiple health outcomes: an umbrella review and updated meta-analysis[J]. Am J Clin Nutr, 2022, 116(1): 230-243. |
| [9] | B?CKHED F, LEY R E, SONNENBURG J L, et al. Host-bacterial mutualism in the human intestine[J]. Science, 2005, 307(5717): 1915-1920. |
| [10] | SAVAGE D C. Associations of indigenous microorganisms with gastrointestinal mucosal epithelia[J]. Am J Clin Nutr, 1970, 23(11): 1495-1501. |
| [11] | MAZMANIAN S K, LIU C H, TZIANABOS A O, et al. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system[J]. Cell, 2005, 122(1): 107-118. |
| [12] | LI M, WANG B H, ZHANG M H, et al. Symbiotic gut microbes modulate human metabolic phenotypes[J]. Proc Natl Acad Sci USA, 2008, 105(6): 2117-2122. |
| [13] | WANG H R, REN S J, LV H L, et al. Gut microbiota from mice with cerebral ischemia-reperfusion injury affects the brain in healthy mice[J]. Aging (Albany NY), 2021, 13(7): 10058-10074. |
| [14] | WAN S Z, NIE Y, ZHANG Y, et al. Gut microbial dysbiosis is associated with profibrotic factors in liver fibrosis mice[J]. Front Cell Infect Microbiol, 2020, 10: 18. |
| [15] | JIE Z Y, XIA H H, ZHONG S L, et al. The gut microbiome in atherosclerotic cardiovascular disease[J]. Nat Commun, 2017, 8(1): 845. |
| [16] | TANG W H W, B?CKHED F, LANDMESSER U, et al. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review[J]. J Am Coll Cardiol, 2019, 73(16): 2089-2105. |
| [17] | WAN Y, WANG F L, YUAN J H, et al. Effects of dietary fat on gut microbiota and faecal metabolites, and their relationship with cardiometabolic risk factors: a 6-month randomised controlled-feeding trial[J]. Gut, 2019, 68(8): 1417-1429. |
| [18] | DELANNOY-BRUNO O, DESAI C, RAMAN A S, et al. Evaluating microbiome-directed fibre snacks in gnotobiotic mice and humans[J]. Nature, 2021, 595(7865): 91-95. |
| [19] | SMITH G D, EBRAHIM S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?[J]. Int J Epidemiol, 2003, 32(1): 1-22. |
| [20] | DAVEY SMITH G, HEMANI G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies[J]. Hum Mol Genet, 2014, 23(R1): R89-R98. |
| [21] | SEKULA P, DEL GRECO M F, PATTARO C, et al. Mendelian randomization as an approach to assess causality using observational data[J]. J Am Soc Nephrol, 2016, 27(11): 3253-3265. |
| [22] | WANG J, KURILSHIKOV A, RADJABZADEH D, et al. Meta-analysis of human genome-microbiome association studies: the MiBioGen consortium initiative[J]. Microbiome, 2018, 6(1): 101. |
| [23] | KURILSHIKOV A, MEDINA-GOMEZ C, BACIGALUPE R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition[J]. Nat Genet, 2021, 53(2): 156-165. |
| [24] | WU F S, HUANG Y, HU J L, et al. Mendelian randomization study of inflammatory bowel disease and bone mineral density[J]. BMC Med, 2020, 18(1): 312. |
| [25] | BURGESS S, BUTTERWORTH A, THOMPSON S G. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013, 37(7): 658-665. |
| [26] | LONG Y W, TANG L H, ZHOU Y Y, et al. Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study[J]. BMC Med, 2023, 21(1): 66. |
| [27] | LAWLOR D A, HARBORD R M, STERNE J A C, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology[J]. Stat Med, 2008, 27(8): 1133-1163. |
| [28] | HEMANI G, TILLING K, DAVEY SMITH G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data[J]. PLoS Genet, 2017, 13(11): e1007081. |
| [29] | TANG W H, WANG Z N, LEVISON B S, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk[J]. N Engl J Med, 2013, 368(17): 1575-1584. |
| [30] | KOH A, DE VADDER F, KOVATCHEVA-DATCHARY P, et al. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites[J]. Cell, 2016, 165(6): 1332-1345. |
| [31] | WAHLSTR?M A, SAYIN S I, MARSCHALL H U, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism[J]. Cell Metab, 2016, 24(1): 41-50. |
| [32] | GUO Y, LUO S Y, YE Y X, et al. Intermittent fasting improves cardiometabolic risk factors and alters gut microbiota in metabolic syndrome patients[J]. J Clin Endocrinol Metab, 2021, 106(1): 64-79. |
| [33] | KOREN O, SPOR A, FELIN J, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis[J]. Proc Natl Acad Sci USA, 2011, 108(Suppl 1): 4592-4598. |
| [34] | HUTCHINSON A N, TING? L N, BRUMMER R J. The potential effects of probiotics and ω-3 fatty acids on chronic low-grade inflammation[J]. Nutrients, 2020, 12(8): 2402. |
| [35] | BRON P A, KLEEREBEZEM M, BRUMMER R J, et al. Can probiotics modulate human disease by impacting intestinal barrier function?[J]. Br J Nutr, 2017, 117(1): 93-107. |
| [36] | RUSCICA M, PAVANELLO C, GANDINI S, et al. Nutraceutical approach for the management of cardiovascular risk—a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study[J]. Nutr J, 2019, 18(1): 13. |
| [37] | LIU J L, AN N, MA C, et al. Correlation analysis of intestinal flora with hypertension[J]. Exp Ther Med, 2018, 16(3): 2325-2330. |
| [38] | MAYERHOFER C C K, KUMMEN M, HOLM K, et al. Low fibre intake is associated with gut microbiota alterations in chronic heart failure[J]. ESC Heart Fail, 2020, 7(2): 456-466. |
| [39] | WANG M, XIONG H, LU L, et al. Serum lipopolysaccharide is associated with the recurrence of atrial fibrillation after radiofrequency ablation by increasing systemic inflammation and atrial fibrosis[J]. Oxid Med Cell Longev, 2022, 2022: 2405972. |
| [40] | KONG B, FU H, XIAO Z, et al. Gut microbiota dysbiosis induced by a high-fat diet increases susceptibility to atrial fibrillation[J]. Can J Cardiol, 2022, 38(12): 1962-1975. |
| [41] | INZAUGARAT M E, JOHNSON C D, HOLTMANN T M, et al. NLR family pyrin domain-containing 3 inflammasome activation in hepatic stellate cells induces liver fibrosis in mice[J]. Hepatology, 2019, 69(2): 845-859. |
| [42] | LIU P N, YU S S, LIU J R, et al. Effects of Lactobacillus on hyperlipidemia in high-fat diet-induced mouse model[J]. Arch Med Sci, 2020, 19(3): 792-799. |
| [43] | CHEN L H, LIU W E, LI Y M, et al. Lactobacillus acidophilus ATCC 4356 attenuates the atherosclerotic progression through modulation of oxidative stress and inflammatory process[J]. Int Immunopharmacol, 2013, 17(1): 108-115. |
| [44] | HUANG Y, WANG J F, QUAN G H, et al. Lactobacillus acidophilus ATCC 4356 prevents atherosclerosis via inhibition of intestinal cholesterol absorption in apolipoprotein E-knockout mice[J]. Appl Environ Microbiol, 2014, 80(24): 7496-7504. |
| [45] | AHN H Y, KIM M, CHAE J S, et al. Supplementation with two probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, reduces fasting triglycerides and enhances apolipoprotein A-V levels in non-diabetic subjects with hypertriglyceridemia[J]. Atherosclerosis, 2015, 241(2): 649-656. |
| [46] | 李亚梦, 崔美泽, 孙婧, 等. 肠道菌群及其代谢产物氧化三甲胺: 冠心病治疗的新靶点[J]. 生物工程学报, 2021, 37(11): 3745-3756. |
| LI Y M, CUI M Z, SUN J, et al. Gut microbiota and its metabolite trimethylamine-N-oxide (TMAO): a novel regulator in coronary artery disease[J]. Chinese Journal of Biotechnology, 2021, 37(11): 3745-3756. | |
| [47] | KATSIMICHAS T, THEOFILIS P, TSIOUFIS K, et al. Gut microbiota and coronary artery disease: current therapeutic perspectives[J]. Metabolites, 2023, 13(2): 256. |
| [48] | WANG Y, XU Y Y, YANG M, et al. Butyrate mitigates TNF-α-induced attachment of monocytes to endothelial cells[J]. J Bioenerg Biomembr, 2020, 52(4): 247-256. |
| [49] | CHEN W J, ZHANG S, WU J F, et al. Butyrate-producing bacteria and the gut-heart axis in atherosclerosis[J]. Clin Chim Acta, 2020, 507: 236-241. |
| [50] | YU Y J, RAKA F, ADELI K. The role of the gut microbiota in lipid and lipoprotein metabolism[J]. J Clin Med, 2019, 8(12): 2227. |
| [51] | TORTELOTE G G. Therapeutic strategies for hypertension: exploring the role of microbiota-derived short-chain fatty acids in kidney physiology and development[J]. Pediatr Nephrol, 2025. |
| [52] | LUO Q, HU Y L, CHEN X, et al. Effects of gut microbiota and metabolites on heart failure and its risk factors: a two-sample Mendelian randomization study[J]. Front Nutr, 2022, 9: 899746. |
| [53] | CHIONCEL O, AMBROSY A P. Trimethylamine N-oxide and risk of heart failure progression: marker or mediator of disease[J]. Eur J Heart Fail, 2019, 21(7): 887-890. |
| [54] | SUN X L, JIAO X F, MA Y R, et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome[J]. Biochem Biophys Res Commun, 2016, 481(1/2): 63-70. |
| [55] | KEITEL V, REINEHR R, GATSIOS P, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells[J]. Hepatology, 2007, 45(3): 695-704. |
| [56] | ROMANO K A, MARTINEZ-DEL CAMPO A, KASAHARA K, et al. Metabolic, epigenetic, and transgenerational effects of gut bacterial choline consumption[J]. Cell Host Microbe, 2017, 22(3): 279-290.e7. |
/
| 〈 |
|
〉 |