Research progress on the mechanism and potential applications of gut microbiota-derived extracellular vesicles in ischemic stroke_Journal of Biomedical Engineering

Authors：

XIAO Meng ¹ , LI Xinyue ¹ , LI Jinting ¹ , WU Minmin ¹ , ZHU Luwen ^2,3

1. Heilongjiang University of Chinese Medicine, Harbin 150040, P. R. China;
2. Rehabilitation Center, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150001, P. R. China;
3. Heilongjiang Provincial Key Laboratory of Brain Function and Neurorehabilitation, Harbin 150000, P. R. China;

Corresponding?author：

Keywords：

Gut microbiota; Extracellular vesicles; Ischemic stroke; Delivery vehicle; Mechanism of action; Research progress

DOI：

10.7507/1001-5515.202506074

Video：

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Ischemic stroke (IS) is a common cerebrovascular accident that has garnered widespread attention due to its high rates of disability and mortality. Gut microbiota-derived extracellular vesicles (GMEVs), as a novel type of biological nanomaterial, can regulate various physiological processes in host cells by delivering bioactive substances and mediating membrane component-dependent physical interactions, demonstrating significant application value in the field of biomedicine. This review integrates relevant randomized controlled trials and mechanistic studies from both domestic and international research in recent years, firstly summarizing the evidence linking gut microbiota to IS, and then thoroughly exploring the potential mechanisms and engineering strategies of GMEVs in IS treatment. Finally, the article prospects the future directions for GMEVs in the precise intervention of IS. This review aims to provide a new perspective for understanding the role of the gut-brain axis in IS and to lay a theoretical foundation for the development of neuroprotective or reparative strategies based on GMEVs.

Citation： XIAO Meng, LI Xinyue, LI Jinting, WU Minmin, ZHU Luwen. Research progress on the mechanism and potential applications of gut microbiota-derived extracellular vesicles in ischemic stroke. Journal of Biomedical Engineering, 2026, 43(1): 216-220. doi: 10.7507/1001-5515.202506074 Copy

1.	Vaduganathan M, Mensah G A, Turco J V, et al. The global burden of cardiovascular diseases and risk: a compass for future health. J Am Coll Cardiol, 2022, 80(25): 2361-2371.
2.	《中國卒中中心報告2022》編寫組. 《中國卒中中心報告2022》概要. 中國腦血管病雜志, 2024, 21(8): 565-576.
3.	Yates A G, Pink R C, Erdbrügger U, et al. In sickness and in health: the functional role of extracellular vesicles in physiology and pathology in vivo: part II: pathology. J Extracell Vesicles, 2022, 11(1): e12190.
4.	張冬雪, 鄒偉. 外泌體對缺血性卒中的作用機制及研究進展. 中國卒中雜志, 2022, 17(4): 418-425.
5.	謝國民, 呂中月, 趙翠, 等. 干細胞來源的細胞外囊泡治療急性缺血性卒中的研究進展. 心電與循環, 2024, 43(5): 432-436, 453.
6.	楊淵. 神經干細胞外泌體通過miR-125b-2-3p/B2M/TFRC調控鐵死亡影響腦缺血再灌注損傷的機制研究. 昆明: 昆明醫科大學, 2024.
7.	Guggeis M A, Harris D M, Welz L, et al. Microbiota-derived metabolites in inflammatory bowel disease. Semin Immunopathol, 2025, 47(1): 19.
8.	Schaible P, Henschel J, Erny D. How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells. J Neuroinflammation, 2025, 22(1): 60.
9.	Nakhal M M, Yassin L K, Alyaqoubi R, et al. The microbiota-gut-brain axis and neurological disorders: a comprehensive review. Life (Basel), 2024, 14(10): 1234.
10.	Zhu Z, Yang P, Jia Y, et al. Plasma amino acid neurotransmitters and ischemic stroke prognosis: a multicenter prospective study. Am J Clin Nutr, 2023, 118(4): 754-762.
11.	Wang L, Qin N, Shi L, et al. Gut microbiota and tryptophan metabolism in pathogenesis of ischemic stroke: a potential role for food homologous plants. Mol Nutr Food Res, 2024, 68(23): e2400639.
12.	Wei J, Wang G, Lai M, et al. Faecal microbiota transplantation alleviates ferroptosis after ischaemic stroke. Neuroscience, 2024, 541: 91-100.
13.	Zhang Y, Yang H, Hou S, et al. Influence of the brain gut axis on neuroinflammation in cerebral ischemia reperfusion injury (Review). Int J Mol Med, 2024, 53(3): 30.
14.	Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med, 2016, 22(5): 516-523.
15.	Xin H, Zhang X, Li P, et al. Bifidobacterium bifidum supplementation improves ischemic stroke outcomes in elderly patients: a retrospective study. Medicine (Baltimore), 2024, 103(14): e37682.
16.	Zhang W, Dong X Y, Huang R. Gut microbiota in ischemic stroke: role of gut bacteria-derived metabolites. Transl Stroke Res, 2023, 14(6): 811-828.
17.	Zhang F, Deng Y, Wang H, et al. Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO. Brain Behav Immun, 2024, 115: 667-679.
18.	Huang Q, Xia J. Influence of the gut microbiome on inflammatory and immune response after stroke. Neurol Sci, 2021, 42(12): 4937-4951.
19.	DeBoer M D, Filipp S L, Sims M, et al. Risk of ischemic stroke increases over the spectrum of metabolic syndrome severity. Stroke, 2020, 51(8): 2548-2552.
20.	Adnan S, Nelson J W, Ajami N J, et al. Alterations in the gut microbiota can elicit hypertension in rats. Physiol Genomics, 2017, 49(2): 96-104.
21.	Jonsson A L, B?ckhed F. Role of gut microbiota in atherosclerosis. Nat Rev Cardiol, 2017, 14(2): 79-87.
22.	Islam M R, Arthur S, Haynes J, et al. The role of gut microbiota and metabolites in obesity-associated chronic gastrointestinal disorders. Nutrients, 2022, 14(3): 624.
23.	Xing J, Niu T, Yu T, et al. Faecalibacterium prausnitzii-derived outer membrane vesicles reprogram gut microbiota metabolism to alleviate porcine epidemic diarrhea virus infection. Microbiome, 2025, 13(1): 90.
24.	Wang X, Lin S, Wang L, et al. Versatility of bacterial outer membrane vesicles in regulating intestinal homeostasis. Sci Adv, 2023, 9(11): eade5079.
25.	Wu Y, Huang X, Li Q, et al. Reducing severity of inflammatory bowel disease through colonization of Lactiplantibacillus plantarum and its extracellular vesicles release. J Nanobiotechnology, 2025, 23(1): 227.
26.	Pitt N, Morrissette M, Gates M F, et al. Bacterial membrane vesicles restore gut anaerobiosis. NPJ Biofilms Microbiomes, 2025, 11(1): 48.
27.	Yang Y, Li N, Gao Y, et al. The activation impact of Lactobacillus-derived extracellular vesicles on lipopolysaccharide-induced microglial cell. BMC Microbiol, 2024, 24(1): 70.
28.	Tao S, Fan J, Li J, et al. Extracellular vesicles derived from Lactobacillus johnsonii promote gut barrier homeostasis by enhancing M2 macrophage polarization. J Adv Res, 2025, 69: 545-563.
29.	Nie X, Li Q, Ji H, et al. Bifidobacterium longum NSP001-derived extracellular vesicles ameliorate ulcerative colitis by modulating T cell responses in gut microbiota-(in)dependent manners. NPJ Biofilms Microbiomes, 2025, 11(1): 27.
30.	Tang W, Ni Z, Wei Y, et al. Extracellular vesicles of Bacteroides uniformis induce M1 macrophage polarization and aggravate gut inflammation during weaning. Mucosal Immunol, 2024, 17(5): 793-809.
31.	Kim J Y, Kim C W, Oh S Y, et al. Akkermansia muciniphila extracellular vesicles have a protective effect against hypertension. Hypertens Res, 2024, 47(6): 1642-1653.
32.	Ashrafian F, Shahriary A, Behrouzi A, et al. Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice. Front Microbiol, 2019, 10: 2155.
33.	Shi J, Ma D, Gao S, et al. Probiotic Escherichia coli Nissle 1917-derived outer membrane vesicles modulate the intestinal microbiome and host gut-liver metabolome in obese and diabetic mice. Front Microbiol, 2023, 14: 1219763.
34.	Vaezijoze S, Irani S, Siadat S D, et al. Modulation of satiety hormones by Bacteroides thetaiotaomicron, Bacteroides fragilis and their derivatives. AMB Express, 2025, 15(1): 41.
35.	Zakharzhevskaya N B, Vanyushkina A A, Altukhov I A, et al. Outer membrane vesicles secreted by pathogenic and nonpathogenic Bacteroides fragilis represent different metabolic activities. Sci Rep, 2017, 7(1): 5008.
36.	Olivo-Martínez Y, Martínez-Ruiz S, Cordero-Alday C, et al. Modulation of serotonin-related genes by extracellular vesicles of the probiotic Escherichia coli Nissle 1917 in the interleukin-1β-induced inflammation model of intestinal epithelial cells. Int J Mol Sci, 2024, 25(10): 5338.
37.	楊樟. 植物乳桿菌來源的細胞外囊泡通過miR-101a-3p減少缺血性卒中后神經元凋亡的作用及其機制研究. 貴陽: 貴州醫科大學, 2022.
38.	Gilmore W J, Johnston E L, Bitto N J, et al. Bacteroides fragilis outer membrane vesicles preferentially activate innate immune receptors compared to their parent bacteria. Front Immunol, 2022, 13: 970725.
39.	Bittel M, Reichert P, Sarfati I, et al. Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo. J Extracell Vesicles, 2021, 10(12): e12159.
40.	Kim J H, Lee J, Park J, et al. Gram-negative and gram-positive bacterial extracellular vesicles. Semin Cell Dev Biol, 2015, 40: 97-104.
41.	Stentz R, Jones E, Juodeikis R, et al. The proteome of extracellular vesicles produced by the human gut bacteria Bacteroides thetaiotaomicron in vivo is influenced by environmental and host-derived factors. Appl Environ Microbiol, 2022, 88(16): e0053322.
42.	Wang L, Zhang X, Yang Z, et al. Extracellular vesicles: biological mechanisms and emerging therapeutic opportunities in neurodegenerative diseases. Transl Neurodegener, 2024, 13(1): 60.
43.	Kaisanlahti A, Salmi S, Kumpula S, et al. Bacterial extracellular vesicles-brain invaders? a systematic review. Front Mol Neurosci, 2023, 16: 1227655.
44.	Ji N, Wang F, Wang M, et al. Engineered bacterial extracellular vesicles for central nervous system diseases. J Control Release, 2023, 364: 46-60.
45.	Zheng K, Feng Y, Li L, et al. Engineered bacterial outer membrane vesicles: a versatile bacteria-based weapon against gastrointestinal tumors. Theranostics, 2024, 14(2): 761-787.
46.	Guan M, Xie X T, Zhou D, et al. Engineered bacterial outer membrane vesicles hitchhiking on neutrophils for antibody drug delivery to enhance postoperative immune checkpoint therapy. Adv Sci (Weinh), 2025, 12(27): e2505000.

1. Vaduganathan M, Mensah G A, Turco J V, et al. The global burden of cardiovascular diseases and risk: a compass for future health. J Am Coll Cardiol, 2022, 80(25): 2361-2371.
2. 《中國卒中中心報告2022》編寫組. 《中國卒中中心報告2022》概要. 中國腦血管病雜志, 2024, 21(8): 565-576.
3. Yates A G, Pink R C, Erdbrügger U, et al. In sickness and in health: the functional role of extracellular vesicles in physiology and pathology in vivo: part II: pathology. J Extracell Vesicles, 2022, 11(1): e12190.
4. 張冬雪, 鄒偉. 外泌體對缺血性卒中的作用機制及研究進展. 中國卒中雜志, 2022, 17(4): 418-425.
5. 謝國民, 呂中月, 趙翠, 等. 干細胞來源的細胞外囊泡治療急性缺血性卒中的研究進展. 心電與循環, 2024, 43(5): 432-436, 453.
6. 楊淵. 神經干細胞外泌體通過miR-125b-2-3p/B2M/TFRC調控鐵死亡影響腦缺血再灌注損傷的機制研究. 昆明: 昆明醫科大學, 2024.
7. Guggeis M A, Harris D M, Welz L, et al. Microbiota-derived metabolites in inflammatory bowel disease. Semin Immunopathol, 2025, 47(1): 19.
8. Schaible P, Henschel J, Erny D. How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells. J Neuroinflammation, 2025, 22(1): 60.
9. Nakhal M M, Yassin L K, Alyaqoubi R, et al. The microbiota-gut-brain axis and neurological disorders: a comprehensive review. Life (Basel), 2024, 14(10): 1234.
10. Zhu Z, Yang P, Jia Y, et al. Plasma amino acid neurotransmitters and ischemic stroke prognosis: a multicenter prospective study. Am J Clin Nutr, 2023, 118(4): 754-762.
11. Wang L, Qin N, Shi L, et al. Gut microbiota and tryptophan metabolism in pathogenesis of ischemic stroke: a potential role for food homologous plants. Mol Nutr Food Res, 2024, 68(23): e2400639.
12. Wei J, Wang G, Lai M, et al. Faecal microbiota transplantation alleviates ferroptosis after ischaemic stroke. Neuroscience, 2024, 541: 91-100.
13. Zhang Y, Yang H, Hou S, et al. Influence of the brain gut axis on neuroinflammation in cerebral ischemia reperfusion injury (Review). Int J Mol Med, 2024, 53(3): 30.
14. Benakis C, Brea D, Caballero S, et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med, 2016, 22(5): 516-523.
15. Xin H, Zhang X, Li P, et al. Bifidobacterium bifidum supplementation improves ischemic stroke outcomes in elderly patients: a retrospective study. Medicine (Baltimore), 2024, 103(14): e37682.
16. Zhang W, Dong X Y, Huang R. Gut microbiota in ischemic stroke: role of gut bacteria-derived metabolites. Transl Stroke Res, 2023, 14(6): 811-828.
17. Zhang F, Deng Y, Wang H, et al. Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO. Brain Behav Immun, 2024, 115: 667-679.
18. Huang Q, Xia J. Influence of the gut microbiome on inflammatory and immune response after stroke. Neurol Sci, 2021, 42(12): 4937-4951.
19. DeBoer M D, Filipp S L, Sims M, et al. Risk of ischemic stroke increases over the spectrum of metabolic syndrome severity. Stroke, 2020, 51(8): 2548-2552.
20. Adnan S, Nelson J W, Ajami N J, et al. Alterations in the gut microbiota can elicit hypertension in rats. Physiol Genomics, 2017, 49(2): 96-104.
21. Jonsson A L, B?ckhed F. Role of gut microbiota in atherosclerosis. Nat Rev Cardiol, 2017, 14(2): 79-87.
22. Islam M R, Arthur S, Haynes J, et al. The role of gut microbiota and metabolites in obesity-associated chronic gastrointestinal disorders. Nutrients, 2022, 14(3): 624.
23. Xing J, Niu T, Yu T, et al. Faecalibacterium prausnitzii-derived outer membrane vesicles reprogram gut microbiota metabolism to alleviate porcine epidemic diarrhea virus infection. Microbiome, 2025, 13(1): 90.
24. Wang X, Lin S, Wang L, et al. Versatility of bacterial outer membrane vesicles in regulating intestinal homeostasis. Sci Adv, 2023, 9(11): eade5079.
25. Wu Y, Huang X, Li Q, et al. Reducing severity of inflammatory bowel disease through colonization of Lactiplantibacillus plantarum and its extracellular vesicles release. J Nanobiotechnology, 2025, 23(1): 227.
26. Pitt N, Morrissette M, Gates M F, et al. Bacterial membrane vesicles restore gut anaerobiosis. NPJ Biofilms Microbiomes, 2025, 11(1): 48.
27. Yang Y, Li N, Gao Y, et al. The activation impact of Lactobacillus-derived extracellular vesicles on lipopolysaccharide-induced microglial cell. BMC Microbiol, 2024, 24(1): 70.
28. Tao S, Fan J, Li J, et al. Extracellular vesicles derived from Lactobacillus johnsonii promote gut barrier homeostasis by enhancing M2 macrophage polarization. J Adv Res, 2025, 69: 545-563.
29. Nie X, Li Q, Ji H, et al. Bifidobacterium longum NSP001-derived extracellular vesicles ameliorate ulcerative colitis by modulating T cell responses in gut microbiota-(in)dependent manners. NPJ Biofilms Microbiomes, 2025, 11(1): 27.
30. Tang W, Ni Z, Wei Y, et al. Extracellular vesicles of Bacteroides uniformis induce M1 macrophage polarization and aggravate gut inflammation during weaning. Mucosal Immunol, 2024, 17(5): 793-809.
31. Kim J Y, Kim C W, Oh S Y, et al. Akkermansia muciniphila extracellular vesicles have a protective effect against hypertension. Hypertens Res, 2024, 47(6): 1642-1653.
32. Ashrafian F, Shahriary A, Behrouzi A, et al. Akkermansia muciniphila-derived extracellular vesicles as a mucosal delivery vector for amelioration of obesity in mice. Front Microbiol, 2019, 10: 2155.
33. Shi J, Ma D, Gao S, et al. Probiotic Escherichia coli Nissle 1917-derived outer membrane vesicles modulate the intestinal microbiome and host gut-liver metabolome in obese and diabetic mice. Front Microbiol, 2023, 14: 1219763.
34. Vaezijoze S, Irani S, Siadat S D, et al. Modulation of satiety hormones by Bacteroides thetaiotaomicron, Bacteroides fragilis and their derivatives. AMB Express, 2025, 15(1): 41.
35. Zakharzhevskaya N B, Vanyushkina A A, Altukhov I A, et al. Outer membrane vesicles secreted by pathogenic and nonpathogenic Bacteroides fragilis represent different metabolic activities. Sci Rep, 2017, 7(1): 5008.
36. Olivo-Martínez Y, Martínez-Ruiz S, Cordero-Alday C, et al. Modulation of serotonin-related genes by extracellular vesicles of the probiotic Escherichia coli Nissle 1917 in the interleukin-1β-induced inflammation model of intestinal epithelial cells. Int J Mol Sci, 2024, 25(10): 5338.
37. 楊樟. 植物乳桿菌來源的細胞外囊泡通過miR-101a-3p減少缺血性卒中后神經元凋亡的作用及其機制研究. 貴陽: 貴州醫科大學, 2022.
38. Gilmore W J, Johnston E L, Bitto N J, et al. Bacteroides fragilis outer membrane vesicles preferentially activate innate immune receptors compared to their parent bacteria. Front Immunol, 2022, 13: 970725.
39. Bittel M, Reichert P, Sarfati I, et al. Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo. J Extracell Vesicles, 2021, 10(12): e12159.
40. Kim J H, Lee J, Park J, et al. Gram-negative and gram-positive bacterial extracellular vesicles. Semin Cell Dev Biol, 2015, 40: 97-104.
41. Stentz R, Jones E, Juodeikis R, et al. The proteome of extracellular vesicles produced by the human gut bacteria Bacteroides thetaiotaomicron in vivo is influenced by environmental and host-derived factors. Appl Environ Microbiol, 2022, 88(16): e0053322.
42. Wang L, Zhang X, Yang Z, et al. Extracellular vesicles: biological mechanisms and emerging therapeutic opportunities in neurodegenerative diseases. Transl Neurodegener, 2024, 13(1): 60.
43. Kaisanlahti A, Salmi S, Kumpula S, et al. Bacterial extracellular vesicles-brain invaders? a systematic review. Front Mol Neurosci, 2023, 16: 1227655.
44. Ji N, Wang F, Wang M, et al. Engineered bacterial extracellular vesicles for central nervous system diseases. J Control Release, 2023, 364: 46-60.
45. Zheng K, Feng Y, Li L, et al. Engineered bacterial outer membrane vesicles: a versatile bacteria-based weapon against gastrointestinal tumors. Theranostics, 2024, 14(2): 761-787.
46. Guan M, Xie X T, Zhou D, et al. Engineered bacterial outer membrane vesicles hitchhiking on neutrophils for antibody drug delivery to enhance postoperative immune checkpoint therapy. Adv Sci (Weinh), 2025, 12(27): e2505000.

Journal of Biomedical Engineering

Research progress on the mechanism and potential applications of gut microbiota-derived extracellular vesicles in ischemic stroke

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