Mendelian Randomization Highlights Gut Microbiota of Short-chain Fatty Acids’ Producer as Protective Factor of Cerebrovascular Disease


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Background:Recent research advancements have indicated a potential association between gut microbiota and cerebrovascular diseases, although the precise causative pathways and the directionality of this association remain to be fully elucidated.

Objective:This study utilized a bidirectional two-sample Mendelian Randomization (MR) methodology to explore the causal impact of gut microbiota compositions on the risk of cerebrovascular disease.

Methods:Genome-wide Association Study (GWAS) data pertaining to gut microbiota were obtained from the MiBioGen consortium. For Ischemic Stroke (IS), Transient Ischemic Attack (TIA), Vascular Dementia (VD), and Subarachnoid Hemorrhage (SAH), GWAS summary data were sourced from the FinnGen consortium, the IEU Open GWAS project, and the GWAS catalog, respectively.

Results:Our MR analyses identified that specific bacterial strains, notably those involved in the production of Short-chain Fatty Acids (SCFAs), including Barnesiella, Ruminococcus torques group, and Coprobacter, serve as protective factors against IS, TIA, and SAH. Linkage Disequilibrium Score Regression (LDSC) analysis corroborated a significant genetic correlation between these gut microbiota strains and various forms of cerebrovascular disease. In contrast, reverse MR analysis failed to establish a bidirectional causal relationship between genetically inferred gut microbiota profiles and these cerebrovascular conditions.

Conclusion:This investigation has pinpointed particular strains of gut microbiota that play protective or detrimental roles in cerebrovascular disease pathogenesis. These findings offer valuable insights that could be pivotal for the clinical management, prevention, and treatment of cerebrovascular diseases.

作者简介

Shihang Luo

Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China

Email: info@benthamscience.net

Rui Mao

Department of Dermatology, Xiangya Hospital, Central South University

编辑信件的主要联系方式.
Email: info@benthamscience.net

Yi Li

Department of Radiology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University

编辑信件的主要联系方式.
Email: info@benthamscience.net

参考

  1. Sacco RL, Rundek T. Cerebrovascular disease. Curr Opin Neurol 2012; 25(1): 1-4. doi: 10.1097/WCO.0b013e32834f89b1 PMID: 22222890
  2. Goldstein LB. Introduction for focused updates in cerebrovascular disease. Stroke 2020; 51(3): 708-10. doi: 10.1161/STROKEAHA.119.024159 PMID: 32078448
  3. Pandian JD, Gall SL, Kate MP, et al. Prevention of stroke: A global perspective. Lancet 2018; 392(10154): 1269-78. doi: 10.1016/S0140-6736(18)31269-8 PMID: 30319114
  4. Johnson W, Onuma O, Owolabi M, Sachdev S. Stroke: A global response is needed. Bull World Health Organ 2016; 94(9): 634-634A. doi: 10.2471/BLT.16.181636 PMID: 27708464
  5. González VJC, Hachinski V. Insidious cerebrovascular disease-the uncool iceberg. JAMA Neurol 2020; 77(2): 155-6. doi: 10.1001/jamaneurol.2019.3933 PMID: 31738373
  6. O’Brien JT, Thomas A. Vascular dementia. Lancet 2015; 386(10004): 1698-706. doi: 10.1016/S0140-6736(15)00463-8 PMID: 26595643
  7. The Lancet. Transient ischaemic attack: More than a stroke of bad luck. Lancet 2014; 383(9929): 1610. doi: 10.1016/S0140-6736(14)60772-8
  8. Claassen J, Park S. Spontaneous subarachnoid haemorrhage. Lancet 2022; 400(10355): 846-62. doi: 10.1016/S0140-6736(22)00938-2 PMID: 35985353
  9. Tonomura S, Ihara M, Friedland RP. Microbiota in cerebrovascular disease: A key player and future therapeutic target. J Cereb Blood Flow Metab 2020; 40(7): 1368-80. doi: 10.1177/0271678X20918031 PMID: 32312168
  10. Honarpisheh P, Bryan RM, McCullough LD. Aging microbiota-gut-brain axis in stroke risk and outcome. Circ Res 2022; 130(8): 1112-44. doi: 10.1161/CIRCRESAHA.122.319983 PMID: 35420913
  11. Durgan DJ, Lee J, McCullough LD, Bryan RM Jr. Examining the role of the microbiota-gut-brain axis in stroke. Stroke 2019; 50(8): 2270-7. doi: 10.1161/STROKEAHA.119.025140 PMID: 31272315
  12. Kim ES, Yoon BH, Lee SM, et al. Fecal microbiota transplantation ameliorates atherosclerosis in mice with C1q/TNF-related protein 9 genetic deficiency. Exp Mol Med 2022; 54(2): 103-14. doi: 10.1038/s12276-022-00728-w PMID: 35115674
  13. Luo J, Xu Z, Noordam R, van Heemst D, Gao RL. Depression and inflammatory bowel disease: A bidirectional two-sample mendelian randomization study. J Crohn’s Colitis 2022; 16(4): 633-42.
  14. Dusingize JC, Olsen CM, An J, et al. Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses. Int J Epidemiol 2020; 49(4): 1236-45. doi: 10.1093/ije/dyaa009 PMID: 32068838
  15. Budu-Aggrey A, Brumpton B, Tyrrell J, et al. Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study. PLoS Med 2019; 16(1): e1002739. doi: 10.1371/journal.pmed.1002739 PMID: 30703100
  16. Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet 2021; 53(2): 156-65. doi: 10.1038/s41588-020-00763-1 PMID: 33462485
  17. Kurki MI, Karjalainen J, Palta P. FinnGen: Unique genetic insights from combining isolated population and national health register data. Medrix 2022. doi: 10.1101/2022.03.03.22271360
  18. Sollis E, Mosaku A, Abid A, et al. The NHGRI-EBI GWAS Catalog: Knowledgebase and deposition resource. Nucleic Acids Res 2023; 51(D1): D977-85. doi: 10.1093/nar/gkac1010 PMID: 36350656
  19. Hemani G, Zheng J, Elsworth B, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife 2018; 7: e34408. doi: 10.7554/eLife.34408 PMID: 29846171
  20. MiBioGen consortium Available from: https://mibiogen.gcc.rug.nl/
  21. Sakaue S, Kanai M, Tanigawa Y, et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat Genet 2021; 53(10): 1415-24. doi: 10.1038/s41588-021-00931-x PMID: 34594039
  22. Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet 2018; 50(4): 524-37. doi: 10.1038/s41588-018-0058-3 PMID: 29531354
  23. Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: Comparison of allele score and summarized data methods. Stat Med 2016; 35(11): 1880-906. doi: 10.1002/sim.6835 PMID: 26661904
  24. Zhang Q, Zhou J, Zhang X, Mao R, Zhang C. Mendelian randomization supports causality between gut microbiota and chronic hepatitis B. Front Microbiol 2023; 14: 1243811. doi: 10.3389/fmicb.2023.1243811 PMID: 37655340
  25. Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: Subsample and 2-sample instrumental variable estimators. Am J Epidemiol 2013; 178(7): 1177-84. doi: 10.1093/aje/kwt084 PMID: 23863760
  26. Bowden J, Smith DG, Burgess S. Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression. Int J Epidemiol 2015; 44(2): 512-25. doi: 10.1093/ije/dyv080 PMID: 26050253
  27. Hartwig FP, Smith DG, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol 2017; 46(6): 1985-98. doi: 10.1093/ije/dyx102 PMID: 29040600
  28. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50(5): 693-8. doi: 10.1038/s41588-018-0099-7 PMID: 29686387
  29. Burgess S. Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome. Int J Epidemiol 2014; 43(3): 922-9. doi: 10.1093/ije/dyu005 PMID: 24608958
  30. Strimmer K. fdrtool: A versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics 2008; 24(12): 1461-2. doi: 10.1093/bioinformatics/btn209 PMID: 18441000
  31. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet 2017; 13(11): e1007081. doi: 10.1371/journal.pgen.1007081 PMID: 29149188
  32. Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: A practical tutorial. Evid Based Ment Health 2019; 22(4): 153-60. doi: 10.1136/ebmental-2019-300117 PMID: 31563865
  33. Long Y, Tang L, Zhou Y, Zhao S, Zhu H. Causal relationship between gut microbiota and cancers: A two-sample Mendelian randomisation study. BMC Med 2023; 21(1): 66. doi: 10.1186/s12916-023-02761-6 PMID: 36810112
  34. Li P, Wang H, Guo L, et al. Association between gut microbiota and preeclampsia-eclampsia: A two-sample Mendelian randomization study. BMC Med 2022; 20(1): 443. doi: 10.1186/s12916-022-02657-x PMID: 36380372
  35. Zeng X, Gao X, Peng Y, et al. Higher risk of stroke is correlated with increased opportunistic pathogen load and reduced levels of butyrate-producing bacteria in the gut. Front Cell Infect Microbiol 2019; 9: 4. doi: 10.3389/fcimb.2019.00004 PMID: 30778376
  36. Karlsson FH, Fåk F, Nookaew I, et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun 2012; 3(1): 1245. doi: 10.1038/ncomms2266 PMID: 23212374
  37. Li N, Wang X, Sun C, et al. Change of intestinal microbiota in cerebral ischemic stroke patients. BMC Microbiol 2019; 19(1): 191. doi: 10.1186/s12866-019-1552-1 PMID: 31426765
  38. Rosli D, Shahar S, Manaf ZA, Lau HJ. Randomized controlled trial on the effect of partially hydrolyzed guar gum supplementation on diarrhea frequency and gut microbiome count among pelvic radiation patients. JPEN J Parenter Enteral Nutr 2022; 46(2): 475. doi: 10.1002/jpen.2295 PMID: 34813118
  39. Yin J, Liao SX, He Y, et al. Dysbiosis of gut microbiota with reduced trimethylamine‐n‐oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc 2015; 4(11): e002699. doi: 10.1161/JAHA.115.002699 PMID: 26597155
  40. Tian DY, Fan DS. Risk factors, regional disparity and trends of ischemic stroke etiologic subtypes. Chin Med J 2018; 131(2): 127-9. doi: 10.4103/0366-6999.222332 PMID: 29336358
  41. Fei N, Bernabé BP, Lie L, et al. The human microbiota is associated with cardiometabolic risk across the epidemiologic transition. PLoS One 2019; 14(7): e0215262. doi: 10.1371/journal.pone.0215262 PMID: 31339887
  42. Yue C, Li M, Li J, et al. Medium-, long- and medium-chain-type structured lipids ameliorate high-fat diet-induced atherosclerosis by regulating inflammation, adipogenesis, and gut microbiota in ApoE −/− mice. Food Funct 2020; 11(6): 5142-55. doi: 10.1039/D0FO01006E PMID: 32432606
  43. Song Y, Shen H, Liu T, et al. Effects of three different mannans on obesity and gut microbiota in high-fat diet-fed C57BL/6J mice. Food Funct 2021; 12(10): 4606-20. doi: 10.1039/D0FO03331F PMID: 33908936
  44. Geng S, Yang L, Cheng F, et al. Gut microbiota are associated with psychological stress-induced defections in intestinal and blood–brain barriers. Front Microbiol 2020; 10: 3067. doi: 10.3389/fmicb.2019.03067 PMID: 32010111
  45. Aranaz P, Ramos-Lopez O, Cuevas-Sierra A, Martinez JA, Milagro FI, Boj RJI. A predictive regression model of the obesity-related inflammatory status based on gut microbiota composition. Int J Obes 2021; 45(10): 2261-8. doi: 10.1038/s41366-021-00904-4 PMID: 34267323
  46. Pinart M, Dötsch A, Schlicht K, et al. Gut microbiome composition in obese and non-obese persons: A systematic review and meta-analysis. Nutrients 2021; 14(1): 12. doi: 10.3390/nu14010012 PMID: 35010887
  47. Wang B, Liu J, Lei R, et al. Cold exposure, gut microbiota, and hypertension: A mechanistic study. Sci Total Environ 2022; 833: 155199. doi: 10.1016/j.scitotenv.2022.155199 PMID: 35417730
  48. Maciel SS, Feres M, Gonçalves TED, et al. Does obesity influence the subgingival microbiota composition in periodontal health and disease? J Clin Periodontol 2016; 43(12): 1003-12. doi: 10.1111/jcpe.12634 PMID: 27717180
  49. Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci 2009; 106(10): 3698-703. doi: 10.1073/pnas.0812874106 PMID: 19234110
  50. Pluznick JL, Protzko RJ, Gevorgyan H, et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci 2013; 110(11): 4410-5. doi: 10.1073/pnas.1215927110 PMID: 23401498
  51. Chen L, He FJ, Dong Y, et al. Modest sodium reduction increases circulating short-chain fatty acids in untreated hypertensives. Hypertension 2020; 76(1): 73-9. doi: 10.1161/HYPERTENSIONAHA.120.14800 PMID: 32475312
  52. Lee J, Venna VR, Durgan DJ, et al. Young versus aged microbiota transplants to germ-free mice: Increased short-chain fatty acids and improved cognitive performance. Gut Microbes 2020; 12(1): 1814107. doi: 10.1080/19490976.2020.1814107 PMID: 32897773
  53. Lee J, d’Aigle J, Atadja L, et al. Gut microbiota–derived short-chain fatty acids promote poststroke recovery in aged mice. Circ Res 2020; 127(4): 453-65. doi: 10.1161/CIRCRESAHA.119.316448 PMID: 32354259
  54. Chen R, Xu Y, Wu P, et al. Transplantation of fecal microbiota rich in short chain fatty acids and butyric acid treat cerebral ischemic stroke by regulating gut microbiota. Pharmacol Res 2019; 148: 104403. doi: 10.1016/j.phrs.2019.104403 PMID: 31425750
  55. Xia W, Khan I, Li X, et al. Adaptogenic flower buds exert cancer preventive effects by enhancing the SCFA-producers, strengthening the epithelial tight junction complex and immune responses. Pharmacol Res 2020; 159: 104809. doi: 10.1016/j.phrs.2020.104809 PMID: 32502642
  56. Wardlaw JM, Smith C, Dichgans M. Small vessel disease: Mechanisms and clinical implications. Lancet Neurol 2019; 18(7): 684-96. doi: 10.1016/S1474-4422(19)30079-1 PMID: 31097385
  57. Su C, Wu H, Yang X, Zhao B, Zhao R. The relation between antihypertensive treatment and progression of cerebral small vessel disease. Medicine 2021; 100(30): e26749. doi: 10.1097/MD.0000000000026749 PMID: 34397717
  58. Liao Y, Zeng X, Xie X, et al. Bacterial signatures of cerebral thrombi in large vessel occlusion stroke. MBio 2022; 13(4): e01085-22. doi: 10.1128/mbio.01085-22 PMID: 35726919
  59. Gambardella J, Castellanos V, Santulli G. Standardizing translational microbiome studies and metagenomic analyses. Cardiovasc Res 2021; 117(3): 640-2. doi: 10.1093/cvr/cvaa175 PMID: 32569375
  60. Kumar A, Chidambaram V, Mehta JL. Vegetarianism, microbiota, and cardiovascular health: Looking back, and forward. Eur J Prev Cardiol 2022; 29(14): 1895-910. doi: 10.1093/eurjpc/zwac128 PMID: 35727958

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