Research Progress on Vagus Nerve Stimulation for Parkinson’s Disease Based on the Microbiota-Gut-Brain Axis Theory

doi:10.3870/j.issn.1672-0741.25.08.026

Abstract

Abstract: The pathogenesis of Parkinson’s disease is rather complex,and no complete cure is currently available.Recent in-depth studies on the microbiota-gut-brain axis have revealed that bidirectional communication between gut microbiota and the brain is mediated by the vagus nerve.The microbiota-gut-brain axis is closely associated with Parkinson’s disease and represents a promising direction for its diagnosis and treatment.This paper aims to construct a framework centered on“gut microbiota dysbiosis-vagus nerve mediation-α-synuclein-Parkinson’s disease”,organizing intervention strategies targeting the vagus nerve.By analyzing its multiple mechanisms,such as regulating gut microbiota and providing neuroprotection,the study further elucidates its unique advantages in improving both motor and non-motor symptoms of Parkinson’s disease,thereby exploring the potential of vagus nerve stimulation as a treatment for the condition.

Key words: microbiota-gut-brain axis, microbiota, vagus nerve, vagus nerve stimulation, Parkinson’s disease

CLC Number:

R742.5

Wu Xin, Ren Binbin. Research Progress on Vagus Nerve Stimulation for Parkinson’s Disease Based on the Microbiota-Gut-Brain Axis Theory[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(3): 443-449.

References

[1] Armstrong M J,Okun M S.Diagnosis and treatment of Parkinson disease:A review[J].JAMA,2020,323(6):548-560.
[2] Dorsey E R,Sherer T,Okun M S,et al.The emerging evidence of the Parkinson pandemic[J].J Park Dis,2018,8(s1):S3-S8.
[3] 张森,赵晓悦,梁宇,等.帕金森病致病因素及发病机制研究进展[J].药学学报,2020,55(10):2264-2272.
Zhang S,Zhao X Y,Liang Y,et al.Advances in understanding the pathogenic factors and pathogenesis of Parkinson’s disease[J].Acta Pharmaceutica Sinica,2020,55(10):2264-2272.
[4] Braak H,Rüb U,Gai W P,et al.Idiopathic Parkinson’s disease:Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen[J].J Neural Transm,2003,110(5):517-536.
[5] Shannon K M,Keshavarzian A,Dodiya H B,et al.Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s Disease? Evidence from 3 cases[J].Mov Disord,2012,27(6):716-719.
[6] Holmqvist S,Chutna O,Bousset L,et al.Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats[J].Acta Neuropathol,2014,128(6):805-820.
[7] Cryan J F,O’Riordan K J,Cowan C S M,et al.The microbiota-gut-brain axis.[J].Physiol Rev,2019,99(4):1877-2013.
[8] Wahlström 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.
[9] Luxenburger A,Clemmens H,Hastings C,et al.3α,7-dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic acids display neuroprotective properties in common forms of Parkinson’s disease[J].Biomolecules,2022,13(1):76.
[10] Heinken A,Ravcheev D A,Baldini F,et al.Systematic assessment of secondary bile acid metabolism in gut microbes reveals distinct metabolic capabilities in inflammatory bowel disease[J].Microbiome,2019,7(1):75.
[11] Li P,Killinger B A,Ensink E,et al.Gut microbiota dysbiosis is associated with elevated bile acids in Parkinson’s disease[J].Metabolites,2021,11(1):29.
[12] Cuevas E,Burks S,Raymick J,et al.Tauroursodeoxycholic acid(TUDCA)is neuroprotective in a chronic mouse model of Parkinson’s disease[J].Nutr Neurosci,2022,25(7):1374-1391.
[13] Hatano T,Oyama G,Shimo Y,et al.Efficacy and safety of elobixibat in Parkinson’s disease with chronic constipation:CONST-PD study[J].Mov Disord Clin Pract,2024,11(4):352-362.
[14] Magliocca G,Mone P,Di Iorio B R,et al.Short-chain fatty acids in chronic kidney disease:Focus on inflammation and oxidative stress regulation[J].Int J Mol Sci,2022,23(10):5354.
[15] denBesten G,van Eunen K,Groen A K,et al.The role of short-chain fatty acids in the interplay between diet,gut microbiota,and host energy metabolism[J].J Lipid Res,2013,54(9):2325-2340.
[16] Silva Y P,Bernardi A,Frozza R L.The role of short-chain fatty acids from gut microbiota in gut-brain communication[J].Front Endocrinol,2020,11:25.
[17] Erny D,Hrabě de Angelis A L,Jaitin D,et al.Host microbiota constantly control maturation and function of microglia in the CNS[J].Nat Neurosci,2015,18(7):965-977.
[18] Salim S,Ahmad F,Banu A,et al.Gut microbiome and Parkinson’s disease:perspective on pathogenesis and treatment[J].J Adv Res,2023,50:83-105.
[19] Sampson T R,Debelius J W,Thron T,et al.Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease[J].Cell,2016,167(6):1469-1480.e12.
[20] Wu G,Jiang Z,Pu Y,et al.Serum short-chain fatty acids and its correlation with motor and non-motor symptoms in Parkinson’s disease patients[J].BMC Neurol,2022,22(1):13.
[21] Chen S J,Chen C C,Liao H Y,et al.Association of fecal and plasma levels of short-chain fatty acids with gut microbiota and clinical severity in patients with Parkinson disease[J].Neurology,2022,98(8):848-858.
[22] Cai B,Zhong L,Wang Q,et al.Curcumin alleviates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease in mice via modulating gut microbiota and short-chain fatty acids[J].Front Pharmacol,2023,14:1198335.
[23] Roth W,Zadeh K,Vekariya R,et al.Tryptophan metabolism and gut-brain homeostasis[J].Int J Mol Sci,2021,22(6):2973.
[24] Tanaka M,Toldi J,Vécsei L.Exploring the etiological links behind neurodegenerative diseases:inflammatory cytokines and bioactive kynurenines[J].Int J Mol Sci,2020,21(7):2431.
[25] Savitz J.The kynurenine pathway:a finger in every pie[J].Mol Psychiatry,2020,25(1):131-147.
[26] Wilson E,Umans J,Swarovski M,et al.Parkinson’s disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction[J].NPJ Parkinsons Dis,2025,11(1):96.
[27] Ogawa T,Matson W R,Beal M F,et al.Kynurenine pathway abnormalities in Parkinson’s disease[J].Neurology,1992,42(9):1702-1706.
[28] Wang Y,Chen S,Tan J,et al.Tryptophan in the diet ameliorates motor deficits in a rotenone-induced rat Parkinson’s disease model via activating the aromatic hydrocarbon receptor pathway[J].Brain Behav,2021,11(8):e2226.
[29] Wang J Y,Chen J Y,Lian Y Z,et al.Reduced platelet 5-HT content is associated with rest tremor in Parkinson’s disease[J].Parkinsonism Relat Disord,2023,108:105314.
[30] Richard I H,McDermott M P,Kurlan R,et al.A randomized,double-blind,placebo-controlled trial of antidepressants in Parkinson disease[J].Neurology,2012,78(16):1229-1236.
[31] Mertsalmi T H,Pekkonen E,Scheperjans F.Antibiotic exposure and risk of Parkinson’s disease in Finland:a nationwide case-control study[J].Mov Disord,2020,35(3):431-442.
[32] Ternák G,Németh M,Rozanovic M,et al.Antibiotic consumption patterns in European countries are associated with the prevalence of Parkinson’s disease;the possible augmenting role of the narrow-spectrum penicillin[J].Antibiotics,2022,11(9):1145.
[33] Zhou X,Lu J,Wei K,et al.Neuroprotective effect of ceftriaxone on MPTP-induced Parkinson’s disease mouse model by regulating inflammation and intestinal microbiota[J].Oxid Med Cell Longev,2021,2021(1):9424582.
[34] Dominguez-Meijide A,Parrales V,Vasili E,et al.Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo[J].Neurobiol Dis,2021,151:105256.
[35] Sudo N.Microbiome,HPA axis and production of endocrine hormones in the gut[J].Adv Exp Med Biol,2014,817:177-194.
[36] Magistrelli L,Amoruso A,Mogna L,et al.Probiotics may have beneficial effects in Parkinson’s disease:in vitro evidence[J].Front Immunol,2019,10:969.
[37] Tan A H,Lim S Y,Chong K K,et al.Probiotics for constipation in Parkinson disease:A randomized placebo-controlled study[J].Neurology,2021,96(5):772-782.
[38] Chu C,Yu L,Li Y,et al.Meta-analysis of randomized controlled trials of the effects of probiotics in Parkinson’s disease[J].Food Funct,2023,14(8):3406-3422.
[39] Brandt L J,Aroniadis O C.An overview of fecal microbiota transplantation:techniques,indications,and outcomes[J].Gastrointest Endosc,2013,78(2):240-249.
[40] Zhao Z,Ning J,Bao X Q,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[J].Microbiome,2021,9(1):226.
[41] Kuai X Y,Yao X H,Xu L J,et al.Evaluation of fecal microbiota transplantation in Parkinson’s disease patients with constipation[J].Microb Cell Fact,2021,20(1):98.
[42] Cheng Y,Tan G,Zhu Q,et al.Efficacy of fecal microbiota transplantation in patients with Parkinson’s disease:Clinical trial results from a randomized,placebo-controlled design[J].Gut Microbes,2023,15(2):2284247.
[43] Segal A,Zlotnik Y,Moyal-Atias K,et al.Fecal microbiota transplant as a potential treatment for Parkinson’s disease-A case series[J].Clin Neurol Neurosurg,2021,207:106791.
[44] Raybould H E.Gut chemosensing:interactions between gut endocrine cells and visceral afferents[J].Auton Neurosci,2010,153(1/2):41-46.
[45] Chandra R,Hiniker A,Kuo Y M,et al.α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease[J].JCI Insight,2017,2(12):e92295.
[46] Chapelet G,Béguin N,Castellano B,et al.Tau expression and phosphorylation in enteroendocrine cells[J].Front Neurosci,2023,17:1166848.
[47] Johnston G R,Webster N R.Cytokines and the immunomodulatory function of the vagus nerve[J].Br J Anaesth,2009,102(4):453-462.
[48] Ben-Menachem E.Vagus nerve stimulation,side effects,and long-term safety[J].J Clin Neurophysiol,2001,18(5):415-418.
[49] Abbott N J.Inflammatory mediators and modulation of blood-brain barrier permeability[J].Cell Mol Neurobiol,2000,20(2):131-147.
[50] Glass C K,Saijo K,Winner B,et al.Mechanisms underlying inflammation in neurodegeneration[J].Cell,2010,140(6):918-934.
[51] Farrand A Q,Helke K L,Gregory R A,et al.Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson’s disease[J].Brain Stimul,2017,10(6):1045-1054.
[52] Hosomoto K,Sasaki T,Yasuhara T,et al.Continuous vagus nerve stimulation exerts beneficial effects on rats with experimentally induced Parkinson’s disease:Evidence suggesting involvement of a vagal afferent pathway[J].Brain Stimul,2023,16(2):594-603.
[53] Lench D H,Turner T H,McLeod C,et al.Multi-session transcutaneous auricular vagus nerve stimulation for Parkinson’s disease:evaluating feasibility,safety,and preliminary efficacy[J].Front Neurol,2023,14:1210103.
[54] Han W,Tellez L A,Perkins M H,et al.A neural circuit for gut-induced reward[J].Cell,2018,175(3):665-678.e23.
[55] Wang C,Su T,Xiao L,et al.Right vagus nerve stimulation improves motor behavior by exerting neuroprotective effects in Parkinson’s disease rats[J].Ann Transl Med,2022,10(24):1314.
[56] Pifl C,Rajput A,Reither H,et al.Is Parkinson’s disease a vesicular dopamine storage disorder? evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum[J].J Neurosci,2014,34(24):8210-8218.
[57] van Midden V,Simončič U,Pirtošek Z,et al.The effect of taVNS at 25 Hz and 100 Hz on Parkinson’s disease gait-a randomized motion sensor study[J].Mov Disord,2024,39(8):1375-1385.
[58] Kaut O,Janocha L,Weismüller T J,et al.Transcutaneous vagal nerve stimulation improves gastroenteric complaints in Parkinson’s disease patients[J].NeuroRehabilitation,2019,45(4):449-451.
[59] Zhang H,Cao X Y,Wang L N,et al.Transcutaneous auricular vagus nerve stimulation improves gait and cortical activity in Parkinson’s disease:a pilot randomized study[J].CNS Neurosci Ther,2023,29(12):3889-3900.
[60] Menekseoglu A K.Acute effect of transcutaneous auricular vagus nerve stimulation on hand tremor in Parkinson’s disease:a pilot study of case series[J].Sisli Etfal Hastan Tip Bul,2023,57(4):513-519.
[61] Zhang H,Shan A D,Huang Y Y,et al.Transcutaneous auricular vagus nerve stimulation improves cortical functional topological properties and intracortical facilitation in patients with Parkinson’s disease[J].NPJ Parkinsons Dis,2025,11(1):38.
[62] Marano M,Anzini G,Saltarocchi L,et al.Left vagus stimulation modulates contralateral subthalamic β power improving the gait in Parkinson’s disease[J].Mov Disord,2024,39(2):424-428.
[63] Zhang H,Shan A D,Wan C H,et al.Transcutaneous auricular vagus nerve stimulation improves anxiety symptoms and cortical activity during verbal fluency task in Parkinson’s disease with anxiety[J].J Affect Disord,2024,361:556-563.