Gut microbiota-host interaction axis and ischemic stroke risk: genetic evidence from a two-sample Mendelian randomization study_West China Medical Journal

Authors：

XU Haicheng ¹ , TAO Yichi ² , ZHANG Bingtao ¹ , TANG Qikai ¹ , ZHANG Zhaoxiang ³ , CHENG Hao ¹ , CHEN Shujuan ¹ , ZHOU Xiaoming ¹ , WU Qi ¹ ,  HUANG Xin ⁴ ,  ZHANG Xin ¹

1. Department of Neurosurgery, Jinling Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu 210093, P. R. China;
2. Department of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai 200540, P. R. China;
3. Jinling Clinical Medical College Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210093, P. R. China;
4. Department of Neurosurgery, Jiangyin People’s Hospital Affiliated to Nantong University, Jiangyin, Jiangsu 214432, P. R. China;

Corresponding?author：

HUANG Xin, Email: drhuangxin123@163.com; ZHANG Xin, Email: xuhaicheng25@163.com

Keywords：

Gut microbiota; ischemic stroke; Mendelian randomization; causal relationship; genome-wide association study

DOI：

10.7507/1002-0179.202601091

Video：

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Objective To evaluate potential causal associations between genus-level gut microbiota and ischemic stroke (IS) risk using two-sample Mendelian randomization (MR). Methods Public genome-wide association study summary statistics for gut microbiota and IS were used. Single nucleotide polymorphisms associated with genus-level taxa (P<1×10^?5) were selected as instrumental variables and processed by linkage disequilibrium clumping, allele harmonization and F-statistic assessment. The inverse-variance weighted (IVW) method was the primary analysis, supplemented by MR-Egger, weighted median, simple mode, weighted mode and sensitivity analyses. Results IVW analysis showed an inverse association between Clostridium innocuum group and IS risk [odds ratio (OR)=0.925, 95% confidence interval (CI) (0.869, 0.985), P=0.015], and Methanobrevibacter [OR=1.069, 95%CI (1.009, 1.132), P=0.023], Senegalimassilia [OR=1.127, 95%CI (1.016, 1.250), P=0.023], Alloprevotella [OR=1.059, 95%CI (1.005, 1.116), P=0.032], Lachnospira [OR=1.181, 95%CI (1.018, 1.371), P=0.029], and Blautia [OR=1.141, 95%CI (1.032, 1.261), P=0.010] were positively associated with IS risk. Sensitivity analyses did not indicate obvious heterogeneity or horizontal pleiotropy. Conclusions Several genus-level gut microbial taxa may be suggestively associated with IS risk. Further validation in independent populations and mechanistic studies are needed.

Citation： XU Haicheng, TAO Yichi, ZHANG Bingtao, TANG Qikai, ZHANG Zhaoxiang, CHENG Hao, CHEN Shujuan, ZHOU Xiaoming, WU Qi, HUANG Xin, ZHANG Xin. Gut microbiota-host interaction axis and ischemic stroke risk: genetic evidence from a two-sample Mendelian randomization study. West China Medical Journal, 2026, 41(7): 1135-1138. doi: 10.7507/1002-0179.202601091 Copy

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25.	Vacca M, Celano G, Calabrese FM, et al. The controversial role of human gut Lachnospiraceae[J]. Microorganisms, 2020, 8(4): 573.
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27.	Han KI, Kim JS, Lee KC, et al. Senegalimassilia faecalis sp. nov., an anaerobic actinobacterium isolated from human faeces, and emended description of the genus Senegalimassilia[J]. Int J Syst Evol Microbiol, 2020, 70(3): 1684-1690.

1. Ho JP, Powers WJ. Contemporary management of acute ischemic stroke[J]. Annu Rev Med, 2025, 76(1): 417-429.
2. Saini V, Guada L, Yavagal DR. Global epidemiology of stroke and access to acute ischemic stroke interventions[J]. Neurology, 2021, 97(20 Suppl 2): S6-S16.
3. 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[J]. Nat Genet, 2018, 50(4): 524-537.
4. Mishra A, Malik R, Hachiya T, et al. Stroke genetics informs drug discovery and risk prediction across ancestries[J]. Nature, 2022, 611(7934): 115-123.
5. Sanz Y, Cryan JF, Deschasaux-Tanguy M, et al. The gut microbiome connects nutrition and human health[J]. Nat Rev Gastroenterol Hepatol, 2025, 22(8): 534-555.
6. Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells[J]. Nat Med, 2016, 22(5): 516-523.
7. Hu W, Kong X, Wang H, et al. Ischemic stroke and intestinal flora: an insight into brain-gut axis[J]. Eur J Med Res, 2022, 27(1): 73.
8. Zhao L, Xiao J, Li S, et al. The interaction between intestinal microenvironment and stroke[J]. CNS Neurosci Ther, 2023, 29(Suppl 1): 185-199.
9. Pluta R, Januszewski S, Czuczwar SJ. The role of gut microbiota in an ischemic stroke[J]. Int J Mol Sci, 2021, 22(2): 915.
10. Birney E. Mendelian randomization[J]. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
11. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization[J]. JAMA, 2017, 318(19): 1925-1926.
12. Qin H, Yang F, Hao P, et al. Gut microbiota and cerebrovascular diseases: a Mendelian randomization study[J]. Front Microbiol, 2023, 14: 1228815.
13. 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.
14. Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization[J]. Stat Methods Med Res, 2017, 26(5): 2333-2355.
15. Sekula P, Del Greco MF, 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.
16. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method[J]. Eur J Epidemiol, 2017, 32(5): 377-389.
17. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator[J]. Genet Epidemiol, 2016, 40(4): 304-314.
18. Burgess S, Zuber V, Gkatzionis A, et al. Modal-based estimation via heterogeneity-penalized weighting: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid[J]. Int J Epidemiol, 2018, 47(4): 1242-1254.
19. Ong JS, MacGregor S. Implementing MR-PRESSO and GCTA-GSMR for pleiotropy assessment in Mendelian randomization studies from a practitioner’s perspective[J]. Genet Epidemiol, 2019, 43(6): 609-616.
20. Stanley D, Mason LJ, Mackin KE, et al. Translocation and dissemination of commensal bacteria in post-stroke infection[J]. Nat Med, 2016, 22(11): 1277-1284.
21. Akhtar M, Chen Y, Ma Z, et al. Gut microbiota-derived short chain fatty acids are potential mediators in gut inflammation[J]. Anim Nutr, 2022, 8(1): 350-360.
22. Bhattacharjee D, Flores C, Woelfel C, et al. Diversity and prevalence of Clostridium innocuum in the human gut microbiota[J]. mSphere, 2022, 8(1): e0056922.
23. Samuel BS, Hansen EE, Manchester JK, et al. Genomic and metabolic adaptations of Methanobrevibacter smithii to the human gut[J]. Proc Natl Acad Sci U S A, 2007, 104(25): 10643-10648.
24. Downes J, Dewhirst FE, Tanner ACR, et al. Description of Alloprevotella rava gen. nov., sp. nov., isolated from the human oral cavity, and reclassification of Prevotella tannerae Moore et al. 1994 as Alloprevotella tannerae gen. nov., comb. nov.[J]. Int J Syst Evol Microbiol, 2013, 63(Pt 4): 1214-1218.
25. Vacca M, Celano G, Calabrese FM, et al. The controversial role of human gut Lachnospiraceae[J]. Microorganisms, 2020, 8(4): 573.
26. Liu X, Mao B, Gu J, et al. Blautia—a new functional genus with potential probiotic properties?[J]. Gut Microbes, 2021, 13(1): e1875796.
27. Han KI, Kim JS, Lee KC, et al. Senegalimassilia faecalis sp. nov., an anaerobic actinobacterium isolated from human faeces, and emended description of the genus Senegalimassilia[J]. Int J Syst Evol Microbiol, 2020, 70(3): 1684-1690.

West China Medical Journal

Gut microbiota-host interaction axis and ischemic stroke risk: genetic evidence from a two-sample Mendelian randomization study

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