Current research status on the mechanism of vagus nerve stimulation in the brain-gut axis_Journal of Epilepsy

Authors：

ZENG Long ^1,2,3,4 , LIU Haolin ^1,2,3,4 , XIE Tao ^1,2,3,4 , YUAN Jin'e ^1,2,3,4 ,  XU Yuting ^1,2,3,4

1. Center of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 51000, China;
2. Engineering Research Center for Diagnosis and Treatment of CerebroVascular Diseases, Ministry of Education, Guangzhou 51000, China;
3. Guangdong Provincial Key Laboratory of Brain Function Repair and Regeneration, Guangzhou 51000, China;
4. Guangdong Institute of Neurosurgery, Guangzhou 51000, China;

Corresponding author：

XU Yuting, Email: wjsw-xh@qq.com

Keywords：

Vagus nerve stimulation; Brain-gut axis; Epilepsy; Gut microbiota

DOI：

10.7507/2096-0247.202406012

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Vagus nerve stimulation was first used in the treatment of refractory epilepsy and depression, and its indications have expanded in recent years. The brain-gut axis is a bidirectional communication network pathway connecting the gut to the brain, maintaining homeostatic balance of the gut microbiota and shaping brain function. The vagus nerve plays an important role in brain-gut axis mechanisms in neurological disorders, which may be an important rationale for vagus nerve stimulation in the treatment of related diseases. Recent studies have shown that vagus nerve stimulation modulates the intestinal microenvironment and the intestinal microbiota, but the specific mechanisms of this alteration need further investigation. Fecal transplants or oral probiotics combined with vagus nerve stimulation may become an important therapeutic tool in the future, especially to improve the efficacy of vagus nerve stimulation for epilepsy; the gut microbiota may also be a predictive target for the efficacy of vagus nerve stimulation for epilepsy.

Citation： ZENG Long, LIU Haolin, XIE Tao, YUAN Jin'e, XU Yuting. Current research status on the mechanism of vagus nerve stimulation in the brain-gut axis. Journal of Epilepsy, 2024, 10(5): 411-416. doi: 10.7507/2096-0247.202406012 Copy

1.	Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. Journal of Internal Medicine, 2017, 282(1): 46-63.
2.	Dawson J, Liu CY, Francisco GE, et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet, 2021, 397(10284): 1545-1553.
3.	Austelle CW, O'Leary GH, Thompson S, et al. A comprehensive review of vagus nerve stimulation for depression. Neuromodulation, 2022, 25(3): 309-315.
4.	Kimberley TJ, Pierce D, Prudente CN, et al. Vagus nerve stimulation paired with upper limb rehabilitation after chronic stroke. Stroke, 2018, 49(11): 2789-2792.
5.	Baig SS, Kamarova M , Ali A, et al. Transcutaneous vagus nerve stimulation (tVNS) in stroke: the evidence, challenges and future directions. Auton Neurosci, 2022, 237: 102909.
6.	Redgrave J, Day D, Leung H, et al. Safety and tolerability of transcutaneous vagus nerve stimulation in humans: a systematic review. Brain Stimul, 2018, 11(6): 1225-1238.
7.	Ma J, Qiao P, Li Q, et al. Vagus nerve stimulation as a promising adjunctive treatment for ischemic stroke. Neurochem Int, 2019, 131: 104539.
8.	Bora G, Atkinsonet SN, Pan A, et al. Impact of auricular percutaneous electrical nerve field stimulation on gut microbiome in adolescents with irritable bowel syndrome: a pilot study. J Dig Dis, 2023, 24(5): 348-358.
9.	Assenza G, Campana C, Colicchio G, et al. Transcutaneous and invasive vagal nerve stimulations engage the same neural pathways: in-vivo human evidence. Brain Stimul, 2017, 10(4): 853-854.
10.	Nunes NS, Chandran P, Sundby M, et al. Therapeutic ultrasound attenuates DSS-induced colitis through the cholinergic anti-inflammatory pathway. EBioMedicine, 2019, 45: 495-510.
11.	Gigliotti JC, Huang L, Bajwa A, et al. Ultrasound modulates the splenic neuroimmune axis in attenuating AKI. J Am Soc Nephrol, 2015, 26(10): 2470-81.
12.	Lin WS, Chou CL, Chang MH, et al. Vagus nerve magnetic modulation facilitates dysphagia recovery in patients with stroke involving the brainstem - a proof of concept study. Brain Stimul, 2018, 11(2): 264-270.
13.	Ryvlin P, Rheims S, Hirsch LJ, et al. Neuromodulation in epilepsy: state-of-the-art approved therapies. Lancet Neurol, 2021, 20(12): 1038-1047.
14.	Varesi A, Pierella E, Romeo M, et al. The potential role of gut microbiota in Alzheimer's Disease: from diagnosis to treatment. Nutrients, 2022, 14(3): 11562.
15.	Damiani F, Cornuti S, Tognini P. The gut-brain connection: exploring the influence of the gut microbiota on neuroplasticity and neurodevelopmental disorders. Neuropharmacology, 2023, 231: 109491.
16.	Ding M, Lang Y, Shu H, et al. Microbiota-gut-brain axis and epilepsy: a review on mechanisms and potential therapeutics. Front Immunol, 2021, 12: 742449.
17.	Lum GR, Ha SM, Olson CA, et al. Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice. Cell Rep, 2023, 42(12): 113521.
18.	Qian XH, Chen SY, Tang HD. Multi-strain probiotics ameliorate Alzheimer's-like cognitive impairment and pathological changes through the AKT/GSK-3beta pathway in senescence-accelerated mouse prone 8 mice. Brain Behav Immun, 2024, 119: 14-27.
19.	Zhao Z, Ning J, Bao XQ, et al. Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis. Microbiome, 2021, 9(1): 226.
20.	Nikolova VL, Smith MRB, Hall LJ, et al. Perturbations in gut microbiota composition in psychiatric disorders: a review and Meta-analysis. JAMA Psychiatry, 2021, 78(12): 1343-1354.
21.	Li T, Zheng LN, Han XH. Fenretinide attenuates lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling. Biomed Pharmacother, 2020, 125: 109680.
22.	Simpson CA, Diaz-Arteche C, Eliby D, et al. The gut microbiota in anxiety and depression - a systematic review. Clin Psychol Rev, 2021, 83: 101943.
23.	Messaoudi M, Violle N, Bisson JF, et al. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes, 2011, 2(4): 256-61.
24.	Hoppner R, Gasser L, Mork H, et al. Vagus nerve cross-sectional area decreases in Parkinson's disease. Parkinsonism Relat Disord, 2023, 114: 105769.
25.	Schreiber LS, Wozniak D, Scheller E, et al. Enlarged cross-sectional area of the left vagus nerve in patients with major depressive disorder. Front Psychiatry, 2023, 14: 1237983.
26.	Niu J, Zhang L, Ding Q, et al. Vagus nerve ultrasound in chronic inflammatory demyelinating polyradiculoneuropathy and Charcot-Marie-Tooth Disease Type 1A. J Neuroimaging, 2020, 30(6): 910-916.
27.	Wang S, Ishima T, Zhang J, et al. Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve. J Neuroinflammation, 2020, 17(1): 241.
28.	Zhang J, Ma L, Chang L, et al. A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration. Transl Psychiatry, 2020, 10(1): 186.
29.	Ma L, Zhang J, Fujita Y, et al. Effects of spleen nerve denervation on depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in mice after administration of lipopolysaccharide: A role of brain-spleen axis. J Affect Disord, 2022, 317: 156-165.
30.	Pu Y, Tan Y, Qu Y, et al. A role of the subdiaphragmatic vagus nerve in depression-like phenotypes in mice after fecal microbiota transplantation from Chrna7 knock-out mice with depression-like phenotypes. Brain Behav Immun, 2021, 94: 318-326.
31.	Yang Y, Eguchi A, Wan X, et al. A role of gut-microbiota-brain axis via subdiaphragmatic vagus nerve in depression-like phenotypes in Chrna7 knock-out mice. Prog Neuropsychopharmacol Biol Psychiatry, 2023, 120: 110652.
32.	Wang S, Ishima T, Qu Y, et al. Ingestion of Faecalibaculum rodentium causes depression-like phenotypes in resilient Ephx2 knock-out mice: a role of brain-gut-microbiota axis via the subdiaphragmatic vagus nerve. J Affect Disord, 2021, 292: 565-573.
33.	Chen C, Zhou Y, Wang H, et al. Gut inflammation triggers C/EBPbeta/delta-secretase-dependent gut-to-brain propagation of Abeta and Tau fibrils in Alzheimer's disease. EMBO J, 2021, 40(17): e106320.
34.	Das TK, Blasco-Conesa MP, Korf J, et al. Bacterial amyloid curli associated gut epithelial neuroendocrine activation predominantly observed in Alzheimer's Disease mice with central amyloid-beta pathology. J Alzheimers Dis, 2022, 88(1): 191-205.
35.	Lee CW, Hsu LF, Wu IL, et al. Exposure to polystyrene microplastics impairs hippocampus-dependent learning and memory in mice. J Hazard Mater, 2022, 430: 128431.
36.	Wang X, Eguchi A, Yang Y, et al. Key role of the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve in demyelination of the cuprizone-treated mouse brain. Neurobiol Dis, 2023, 176: 105951.
37.	Bonaz B, Bazin T, Pellissier S. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Front Neurosci, 2018, 12: 49.
38.	Hachem, LD, Wong SM, Ibrahim GM. The vagus afferent network: emerging role in translational connectomics. Neurosurg Focus, 2018, 45(3): E2.
39.	Browning KN, Carson KE. Central neurocircuits regulating food intake in response to gut inputs-preclinical evidence. Nutrients, 2021, 13(3): 365-372.
40.	Clyburn C, Browning KN. Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions. Am J Physiol Gastrointest Liver Physiol, 2021, 320(5): G880-G887.
41.	Ottaviani MM, Macefield VG. Structure and functions of the vagus nerve in mammals. Compr Physiol, 2022, 12(4): 3989-4037.
42.	Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol, 2016, 594(20): 5781-5790.
43.	Bonaz B, Sinniger V, Pellissier S. The vagus nerve in the neuro-immune axis: implications in the pathology of the gastrointestinal tract. Front Immunol, 2017, 8: 1452.
44.	Komegae EN, Farmer DG, Brooks VL, et al. Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway. Brain Behav Immun, 2018, 73: 441-449.
45.	Wu Y, Zhang Y, Xie B, et al. RhANP attenuates endotoxin-derived cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota-brain axis. J Neuroinflammation, 2021, 18(1): 300.
46.	Ni SJ, Yao ZY, Wei X, et al. Vagus nerve stimulated by microbiota-derived hydrogen sulfide mediates the regulation of berberine on microglia in transient middle cerebral artery occlusion rats. Phytother Res, 2022, 36(7): 2964-2981.
47.	Liu Y, Sanderson D, Mian MF, et al. Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response. Neuropharmacology, 2021, 195: 108682.
48.	Wang Y, Tan Q, Pan M, et al. Minimally invasive vagus nerve stimulation modulates mast cell degranulation via the microbiota-gut-brain axis to ameliorate blood-brain barrier and intestinal barrier damage following ischemic stroke. Int Immunopharmacol, 2024, 132: 112030.
49.	Liu J, Dai Q, Qu T, et al. Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome. Neurobiol Dis, 2024, 193: 106440.

1. Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. Journal of Internal Medicine, 2017, 282(1): 46-63.
2. Dawson J, Liu CY, Francisco GE, et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet, 2021, 397(10284): 1545-1553.
3. Austelle CW, O'Leary GH, Thompson S, et al. A comprehensive review of vagus nerve stimulation for depression. Neuromodulation, 2022, 25(3): 309-315.
4. Kimberley TJ, Pierce D, Prudente CN, et al. Vagus nerve stimulation paired with upper limb rehabilitation after chronic stroke. Stroke, 2018, 49(11): 2789-2792.
5. Baig SS, Kamarova M , Ali A, et al. Transcutaneous vagus nerve stimulation (tVNS) in stroke: the evidence, challenges and future directions. Auton Neurosci, 2022, 237: 102909.
6. Redgrave J, Day D, Leung H, et al. Safety and tolerability of transcutaneous vagus nerve stimulation in humans: a systematic review. Brain Stimul, 2018, 11(6): 1225-1238.
7. Ma J, Qiao P, Li Q, et al. Vagus nerve stimulation as a promising adjunctive treatment for ischemic stroke. Neurochem Int, 2019, 131: 104539.
8. Bora G, Atkinsonet SN, Pan A, et al. Impact of auricular percutaneous electrical nerve field stimulation on gut microbiome in adolescents with irritable bowel syndrome: a pilot study. J Dig Dis, 2023, 24(5): 348-358.
9. Assenza G, Campana C, Colicchio G, et al. Transcutaneous and invasive vagal nerve stimulations engage the same neural pathways: in-vivo human evidence. Brain Stimul, 2017, 10(4): 853-854.
10. Nunes NS, Chandran P, Sundby M, et al. Therapeutic ultrasound attenuates DSS-induced colitis through the cholinergic anti-inflammatory pathway. EBioMedicine, 2019, 45: 495-510.
11. Gigliotti JC, Huang L, Bajwa A, et al. Ultrasound modulates the splenic neuroimmune axis in attenuating AKI. J Am Soc Nephrol, 2015, 26(10): 2470-81.
12. Lin WS, Chou CL, Chang MH, et al. Vagus nerve magnetic modulation facilitates dysphagia recovery in patients with stroke involving the brainstem - a proof of concept study. Brain Stimul, 2018, 11(2): 264-270.
13. Ryvlin P, Rheims S, Hirsch LJ, et al. Neuromodulation in epilepsy: state-of-the-art approved therapies. Lancet Neurol, 2021, 20(12): 1038-1047.
14. Varesi A, Pierella E, Romeo M, et al. The potential role of gut microbiota in Alzheimer's Disease: from diagnosis to treatment. Nutrients, 2022, 14(3): 11562.
15. Damiani F, Cornuti S, Tognini P. The gut-brain connection: exploring the influence of the gut microbiota on neuroplasticity and neurodevelopmental disorders. Neuropharmacology, 2023, 231: 109491.
16. Ding M, Lang Y, Shu H, et al. Microbiota-gut-brain axis and epilepsy: a review on mechanisms and potential therapeutics. Front Immunol, 2021, 12: 742449.
17. Lum GR, Ha SM, Olson CA, et al. Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice. Cell Rep, 2023, 42(12): 113521.
18. Qian XH, Chen SY, Tang HD. Multi-strain probiotics ameliorate Alzheimer's-like cognitive impairment and pathological changes through the AKT/GSK-3beta pathway in senescence-accelerated mouse prone 8 mice. Brain Behav Immun, 2024, 119: 14-27.
19. Zhao Z, Ning J, Bao XQ, et al. Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis. Microbiome, 2021, 9(1): 226.
20. Nikolova VL, Smith MRB, Hall LJ, et al. Perturbations in gut microbiota composition in psychiatric disorders: a review and Meta-analysis. JAMA Psychiatry, 2021, 78(12): 1343-1354.
21. Li T, Zheng LN, Han XH. Fenretinide attenuates lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling. Biomed Pharmacother, 2020, 125: 109680.
22. Simpson CA, Diaz-Arteche C, Eliby D, et al. The gut microbiota in anxiety and depression - a systematic review. Clin Psychol Rev, 2021, 83: 101943.
23. Messaoudi M, Violle N, Bisson JF, et al. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes, 2011, 2(4): 256-61.
24. Hoppner R, Gasser L, Mork H, et al. Vagus nerve cross-sectional area decreases in Parkinson's disease. Parkinsonism Relat Disord, 2023, 114: 105769.
25. Schreiber LS, Wozniak D, Scheller E, et al. Enlarged cross-sectional area of the left vagus nerve in patients with major depressive disorder. Front Psychiatry, 2023, 14: 1237983.
26. Niu J, Zhang L, Ding Q, et al. Vagus nerve ultrasound in chronic inflammatory demyelinating polyradiculoneuropathy and Charcot-Marie-Tooth Disease Type 1A. J Neuroimaging, 2020, 30(6): 910-916.
27. Wang S, Ishima T, Zhang J, et al. Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve. J Neuroinflammation, 2020, 17(1): 241.
28. Zhang J, Ma L, Chang L, et al. A key role of the subdiaphragmatic vagus nerve in the depression-like phenotype and abnormal composition of gut microbiota in mice after lipopolysaccharide administration. Transl Psychiatry, 2020, 10(1): 186.
29. Ma L, Zhang J, Fujita Y, et al. Effects of spleen nerve denervation on depression-like phenotype, systemic inflammation, and abnormal composition of gut microbiota in mice after administration of lipopolysaccharide: A role of brain-spleen axis. J Affect Disord, 2022, 317: 156-165.
30. Pu Y, Tan Y, Qu Y, et al. A role of the subdiaphragmatic vagus nerve in depression-like phenotypes in mice after fecal microbiota transplantation from Chrna7 knock-out mice with depression-like phenotypes. Brain Behav Immun, 2021, 94: 318-326.
31. Yang Y, Eguchi A, Wan X, et al. A role of gut-microbiota-brain axis via subdiaphragmatic vagus nerve in depression-like phenotypes in Chrna7 knock-out mice. Prog Neuropsychopharmacol Biol Psychiatry, 2023, 120: 110652.
32. Wang S, Ishima T, Qu Y, et al. Ingestion of Faecalibaculum rodentium causes depression-like phenotypes in resilient Ephx2 knock-out mice: a role of brain-gut-microbiota axis via the subdiaphragmatic vagus nerve. J Affect Disord, 2021, 292: 565-573.
33. Chen C, Zhou Y, Wang H, et al. Gut inflammation triggers C/EBPbeta/delta-secretase-dependent gut-to-brain propagation of Abeta and Tau fibrils in Alzheimer's disease. EMBO J, 2021, 40(17): e106320.
34. Das TK, Blasco-Conesa MP, Korf J, et al. Bacterial amyloid curli associated gut epithelial neuroendocrine activation predominantly observed in Alzheimer's Disease mice with central amyloid-beta pathology. J Alzheimers Dis, 2022, 88(1): 191-205.
35. Lee CW, Hsu LF, Wu IL, et al. Exposure to polystyrene microplastics impairs hippocampus-dependent learning and memory in mice. J Hazard Mater, 2022, 430: 128431.
36. Wang X, Eguchi A, Yang Y, et al. Key role of the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve in demyelination of the cuprizone-treated mouse brain. Neurobiol Dis, 2023, 176: 105951.
37. Bonaz B, Bazin T, Pellissier S. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Front Neurosci, 2018, 12: 49.
38. Hachem, LD, Wong SM, Ibrahim GM. The vagus afferent network: emerging role in translational connectomics. Neurosurg Focus, 2018, 45(3): E2.
39. Browning KN, Carson KE. Central neurocircuits regulating food intake in response to gut inputs-preclinical evidence. Nutrients, 2021, 13(3): 365-372.
40. Clyburn C, Browning KN. Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions. Am J Physiol Gastrointest Liver Physiol, 2021, 320(5): G880-G887.
41. Ottaviani MM, Macefield VG. Structure and functions of the vagus nerve in mammals. Compr Physiol, 2022, 12(4): 3989-4037.
42. Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol, 2016, 594(20): 5781-5790.
43. Bonaz B, Sinniger V, Pellissier S. The vagus nerve in the neuro-immune axis: implications in the pathology of the gastrointestinal tract. Front Immunol, 2017, 8: 1452.
44. Komegae EN, Farmer DG, Brooks VL, et al. Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway. Brain Behav Immun, 2018, 73: 441-449.
45. Wu Y, Zhang Y, Xie B, et al. RhANP attenuates endotoxin-derived cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota-brain axis. J Neuroinflammation, 2021, 18(1): 300.
46. Ni SJ, Yao ZY, Wei X, et al. Vagus nerve stimulated by microbiota-derived hydrogen sulfide mediates the regulation of berberine on microglia in transient middle cerebral artery occlusion rats. Phytother Res, 2022, 36(7): 2964-2981.
47. Liu Y, Sanderson D, Mian MF, et al. Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response. Neuropharmacology, 2021, 195: 108682.
48. Wang Y, Tan Q, Pan M, et al. Minimally invasive vagus nerve stimulation modulates mast cell degranulation via the microbiota-gut-brain axis to ameliorate blood-brain barrier and intestinal barrier damage following ischemic stroke. Int Immunopharmacol, 2024, 132: 112030.
49. Liu J, Dai Q, Qu T, et al. Ameliorating effects of transcutaneous auricular vagus nerve stimulation on a mouse model of constipation-predominant irritable bowel syndrome. Neurobiol Dis, 2024, 193: 106440.

Journal of Epilepsy

Current research status on the mechanism of vagus nerve stimulation in the brain-gut axis

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content