Exploration of Neuroprotective Therapy

Table 1. Summary of studies investigating the oral microbiota in neurological diseases.

Disease	Study/Design	Oral niche and method	Key microbial taxa (↑/↓)	Main findings	Clinical outcomes/readouts	Ref.
AD	Systematic review and meta-analysis	Mixed (saliva, subgingival plaque); 16S or targeted PCR	↑ Porphyromonas gingivalis, Fusobacterium nucleatum, ↓ commensal streptococci	Oral dysbiosis is consistently associated with AD/MCI; it links to systemic inflammation and neuroinflammatory pathways	Worse cognitive performance; higher dementia risk signals	[12]
AD	Mechanism-oriented human/experimental evidence	Saliva/gingival sources; targeted detection of virulence factors	↑ P. gingivalis; gingipains	P. gingivalis and virulence factors promote Aβ accumulation and impaired clearance; amplify neuroinflammation	Association with amyloid burden and AD pathology surrogates	[14]
AD	Clinical association studies	Periodontal status + oral microbiota; 16S	↑ Periodontal pathogens; ↑ inflammatory signatures	Periodontitis/oral dysbiosis associated with ↑ Aβ and tau phosphorylation	Worse cognition; AD-related biomarker shifts	[15]
PD	Case-control/cross-sectional	Saliva; 16S rRNA gene profiling	Shift toward pro-inflammatory genera (e.g., Prevotella, Neisseria in selected cohorts), ↓ beneficial taxa	Distinct oral dysbiosis pattern in PD; correlations with systemic inflammation	Associations with motor symptom severity/progression markers	[24]
PD	Systematic review and meta-analysis	Mixed oral niches; 16S	↓ α-diversity; compositional instability	Lower diversity and specific taxa changes correlate with PD severity	Links to motor decline; candidate oral biomarkers proposed	[25]
Migraine	Case-control	Saliva; 16S	Differential abundance across ~20+ genera; ↑ Veillonella, ↓ beneficial taxa (e.g., Faecalibacterium)	Distinct oral microbial signatures vs. controls; altered α/β diversity	Headache frequency/intensity associations in subgroups	[12, 29, 30]
Migraine	Multimodal biomarker study	Oral sampling + clinical phenotyping	Oral microbial “signatures.”	Oral dysbiosis proposed as an adjunctive biomarker for migraine stratification	Diagnostic/prognostic utility under evaluation	[34]

Return to article view

AD: Alzheimer’s disease; MCI: mild cognitive impairment; PD: Parkinson’s disease; Aβ: amyloid-beta; ↑/↓: microbial abundance increases/decreases.

Declarations

Author contributions

ZL: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. YS: Conceptualization, Writing—original draft. J Liu: Conceptualization, Writing—review & editing. J Li: Validation, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Hernández-Zulueta J, Bolaños-Chang AJ, Santa Cruz-Pavlovich FJ, Valero Rodríguez AD, Lizárraga Madrigal A, Del Rio-Murillo XI, et al. Microbial Dynamics in Ophthalmic Health: Exploring the Interplay between Human Microbiota and Glaucoma Pathogenesis. Medicina (Kaunas). 2024;60:592. [DOI] [PubMed] [PMC]

Adil NA, Omo-Erigbe C, Yadav H, Jain S. The Oral-Gut Microbiome-Brain Axis in Cognition. Microorganisms. 2025;13:814. [DOI] [PubMed] [PMC]

Nishanth K, Tariq E, Nzvere FP, Miqdad M, Cancarevic I. Role of Smoking in the Pathogenesis of Multiple Sclerosis: A Review Article. Cureus. 2020;12:e9564. [DOI] [PubMed] [PMC]

Manske S. Gastrointestinal Health: A Foundation for Whole-body Wellness. Altern Ther Health Med. 2024;30:6–10. [PubMed]

Butler CA, Adams GG, Blum J, Byrne SJ, Carpenter L, Gussy MG, et al. Breastmilk influences development and composition of the oral microbiome. J Oral Microbiol. 2022;14:2096287. [DOI] [PubMed] [PMC]

Agranyoni O, Rowley T, Johnson SB, Volk H, Schleif W, Hernandez RG, et al. Oral microbiome composition is associated with depressive symptoms during pregnancy. Brain Behav Immun Health. 2025;45:100978. [DOI] [PubMed] [PMC]

Superdock DK, Zhang W, Poole AC. Processing and storage methods affect oral and gut microbiome composition. Front Microbiol. 2023;14:1253570. [DOI] [PubMed] [PMC]

Moghadam MT, Mojtahedi A, Bakhshayesh B, Babakhani S, Ajorloo P, Shariati A, et al. The Effect of Bacterial Composition Shifts in the Oral Microbiota on Alzheimer’s Disease. Curr Mol Med. 2024;24:167–81. [DOI] [PubMed]

Montagnani M, Bottalico L, Potenza MA, Charitos IA, Topi S, Colella M, et al. The Crosstalk between Gut Microbiota and Nervous System: A Bidirectional Interaction between Microorganisms and Metabolome. Int J Mol Sci. 2023;24:10322. [DOI] [PubMed] [PMC]

10.

Chen Y, Lu H, Ding Y, Liu S, Ding Y, Lu B, et al. Dietary Protective Potential of Fucoxanthin as an Active Food Component on Neurological Disorders. J Agric Food Chem. 2023;71:3599–619. [DOI] [PubMed]

11.

Wang M, Ma Y, Zeng B, Yang W, Huang C, Tang B. Influence of the Gut Microbiota, Metabolism and Environment on Neuropsychiatric Disorders. Curr Rev Clin Exp Pharmacol. 2025;20:334–48. [DOI] [PubMed]

12.

Martínez-Martínez V, Rodríguez-Lozano FJ, Pecci-Lloret MP, Pérez-Guzmán N. Association Between Oral Dysbiosis and Alzheimer’s Disease: A Systematic Review. J Clin Med. 2025;14:3415. [DOI] [PubMed] [PMC]

13.

Du Y, He C, An Y, Huang Y, Zhang H, Fu W, et al. The Role of Short Chain Fatty Acids in Inflammation and Body Health. Int J Mol Sci. 2024;25:7379. [DOI] [PubMed] [PMC]

14.

Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne). 2020;11:25. [DOI] [PubMed] [PMC]

15.

Caetano-Silva ME, Rund L, Hutchinson NT, Woods JA, Steelman AJ, Johnson RW. Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids. Sci Rep. 2023;13:2819. [DOI] [PubMed] [PMC]

16.

Fock E, Parnova R. Mechanisms of Blood-Brain Barrier Protection by Microbiota-Derived Short-Chain Fatty Acids. Cells. 2023;12:657. [DOI] [PubMed] [PMC]

17.

Prado C, Pacheco R. Targeting short-chain fatty acids receptors signalling for neurological disorders treatment. Explor Neuroprot Ther. 2024;4:100–7. [DOI]

18.

Liu Y, Dai M. Trimethylamine N-Oxide Generated by the Gut Microbiota Is Associated with Vascular Inflammation: New Insights into Atherosclerosis. Mediators Inflamm. 2020;2020:4634172. [DOI] [PubMed] [PMC]

19.

Shanmugham M, Devasia AG, Chin YL, Cheong KH, Ong ES, Bellanger S, et al. Time-dependent specific molecular signatures of inflammation and remodelling are associated with trimethylamine-N-oxide (TMAO)-induced endothelial cell dysfunction. Sci Rep. 2023;13:20303. [DOI] [PubMed] [PMC]

20.

Ge P, Duan H, Tao C, Niu S, Hu Y, Duan R, et al. TMAO Promotes NLRP3 Inflammasome Activation of Microglia Aggravating Neurological Injury in Ischemic Stroke Through FTO/IGF2BP2. J Inflamm Res. 2023;16:3699–714. [DOI] [PubMed] [PMC]

21.

Pritchard AB, Fabian Z, Lawrence CL, Morton G, Crean S, Alder JE. An Investigation into the Effects of Outer Membrane Vesicles and Lipopolysaccharide of Porphyromonas gingivalis on Blood-Brain Barrier Integrity, Permeability, and Disruption of Scaffolding Proteins in a Human in vitro Model. J Alzheimers Dis. 2022;86:343–64. [DOI] [PubMed]

22.

Lei S, Li J, Yu J, Li F, Pan Y, Chen X, et al. Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway. Int J Oral Sci. 2023;15:3. [DOI] [PubMed] [PMC]

23.

Sun J, Feng S, Ding T, Wang T, Du L, Kang W, et al. Fusobacterium nucleatum dysregulates inflammatory cytokines and NLRP3 inflammasomes in oral cells. Oral Dis. 2024;30:4767–81. [DOI] [PubMed]

24.

Feng YK, Wu QL, Peng YW, Liang FY, You HJ, Feng YW, et al. Oral P. gingivalis impairs gut permeability and mediates immune responses associated with neurodegeneration in LRRK2 R1441G mice. J Neuroinflammation. 2020;17:347. [DOI] [PubMed] [PMC]

25.

Choi Y, Han HS, Chong GO, Le TM, Nguyen HDT, Lee OE, et al. Updates on Group B Streptococcus Infection in the Field of Obstetrics and Gynecology. Microorganisms. 2022;10:2398. [DOI] [PubMed] [PMC]

26.

Groeger S, Zhou Y, Ruf S, Meyle J. Pathogenic Mechanisms of Fusobacterium nucleatum on Oral Epithelial Cells. Front Oral Health. 2022;3:831607. [DOI] [PubMed] [PMC]

27.

Chen Y, Huang Z, Tang Z, Huang Y, Huang M, Liu H, et al. More Than Just a Periodontal Pathogen -the Research Progress on Fusobacterium nucleatum. Front Cell Infect Microbiol. 2022;12:815318. [DOI] [PubMed] [PMC]

28.

Versele R, Sevin E, Gosselet F, Fenart L, Candela P. TNF-α and IL-1β Modulate Blood-Brain Barrier Permeability and Decrease Amyloid-β Peptide Efflux in a Human Blood-Brain Barrier Model. Int J Mol Sci. 2022;23:10235. [DOI] [PubMed] [PMC]

29.

Aijaz M, Ahmad M, Ahmad S, Afzal M, Kothiyal P. The gut-brain axis: role of gut microbiota in neurological disease pathogenesis and pharmacotherapeutics. Naunyn Schmiedebergs Arch Pharmacol. 2025;[Epub ahead of print]. [DOI] [PubMed]

30.

Chaple-Gil AM, Santiesteban-Velázquez M, Urbizo Vélez JJ. Association Between Oral Microbiota Dysbiosis and the Risk of Dementia: A Systematic Review. Dent J (Basel). 2025;13:227. [DOI] [PubMed] [PMC]

31.

Zhu H, Huang C, Luo Z, Wu L, Cheng X, Wu H. Porphyromonas gingivalis Induces Disturbance of Kynurenine Metabolism Through the Gut-Brain Axis: Implications for Alzheimer’s Disease. J Dent Res. 2025;104:439–48. [DOI] [PubMed]

32.

Mosaddad SA, Mahootchi P, Safari S, Rahimi H, Aghili SS. Interactions between systemic diseases and oral microbiota shifts in the aging community: A narrative review. J Basic Microbiol. 2023;63:831–54. [DOI] [PubMed]

33.

Deng L, Guan G, Cannon RD, Mei L. Age-related oral microbiota dysbiosis and systemic diseases. Microb Pathog. 2025;205:107717. [DOI] [PubMed]

34.

Martínez M, Postolache TT, García-Bueno B, Leza JC, Figuero E, Lowry CA, et al. The Role of the Oral Microbiota Related to Periodontal Diseases in Anxiety, Mood and Trauma- and Stress-Related Disorders. Front Psychiatry. 2022;12:814177. [DOI] [PubMed] [PMC]

35.

Parra-Torres V, Melgar-Rodríguez S, Muñoz-Manríquez C, Sanhueza B, Cafferata EA, Paula-Lima AC, et al. Periodontal bacteria in the brain-Implication for Alzheimer’s disease: A systematic review. Oral Dis. 2023;29:21–8. [DOI] [PubMed]

36.

Bello-Corral L, Alves-Gomes L, Fernández-Fernández JA, Fernández-García D, Casado-Verdejo I, Sánchez-Valdeón L. Implications of gut and oral microbiota in neuroinflammatory responses in Alzheimer’s disease. Life Sci. 2023;333:122132. [DOI] [PubMed]

37.

Collard A, Mathieu A, Landa P, Pelletier A, Lavigne GJ, Droit A, et al. Supragingival Microbiota Alterations in Individuals With Sleep Bruxism: A Pilot Study. J Oral Rehabil. 2025;52:1319–27. [DOI] [PubMed] [PMC]

38.

Qian J, Lu J, Cheng S, Zou X, Tao Q, Wang M, et al. Periodontitis salivary microbiota exacerbates colitis-induced anxiety-like behavior via gut microbiota. NPJ Biofilms Microbiomes. 2023;9:93. [DOI] [PubMed] [PMC]

39.

Bowland GB, Weyrich LS. The Oral-Microbiome-Brain Axis and Neuropsychiatric Disorders: An Anthropological Perspective. Front Psychiatry. 2022;13:810008. [DOI] [PubMed] [PMC]

40.

Borsom EM, Lee K, Cope EK. Do the Bugs in Your Gut Eat Your Memories? Relationship between Gut Microbiota and Alzheimer’s Disease. Brain Sci. 2020;10:814. [DOI] [PubMed] [PMC]

41.

Yay E, Yilmaz M, Toygar H, Balci N, Alvarez Rivas C, Bolluk Kılıç B, et al. Oral and gut microbial profiling in periodontitis and Parkinson’s disease. J Oral Microbiol. 2024;16:2331264. [DOI] [PubMed] [PMC]

42.

Rajasekaran JJ, Krishnamurthy HK, Bosco J, Jayaraman V, Krishna K, Wang T, et al. Oral Microbiome: A Review of Its Impact on Oral and Systemic Health. Microorganisms. 2024;12:1797. [DOI] [PubMed] [PMC]

43.

Murcia-Flores L, Sánchez-García A, Pecci-Lloret MP, Rodríguez-Lozano FJ. Association between oral dysbiosis and Parkinson’s disease: a systematic review. Front Cell Infect Microbiol. 2025;15:1564362. [DOI] [PubMed] [PMC]

44.

Colombo APV, Lourenço TGB, de Oliveira AM, da Costa ALA. Link Between Oral and Gut Microbiomes: The Oral-Gut Axis. Adv Exp Med Biol. 2025;1472:71–87. [DOI] [PubMed]

45.

Jeon JH, Lourenco JM, Fagan MM, Welch CB, Sneed SE, Dubrof S, et al. Changes in Oral Microbial Diversity in a Piglet Model of Traumatic Brain Injury. Brain Sci. 2022;12:1111. [DOI] [PubMed] [PMC]

46.

Jiang W, Wang T, Liu C, Deng M, Ren X, Wang F, et al. A 16S rRNA gene sequencing based study of oral microbiota in migraine patients in China. Bioengineered. 2021;12:2523–33. [DOI] [PubMed] [PMC]

47.

Gorenshtein A, Shihada K, Leibovitch L, Liba T, Goren A. The association between migraine and gut microbiota: a systematic review. Acta Neurol Belg. 2025;125:977–87. [DOI] [PubMed] [PMC]

48.

Yong D, Lee H, Min H, Kim K, Oh H, Chu MK. Altered gut microbiota in individuals with episodic and chronic migraine. Sci Rep. 2023;13:626. [DOI] [PubMed] [PMC]

49.

Qu K, Li MX, Gan L, Cui ZT, Li JJ, Yang R, et al. To analyze the relationship between gut microbiota, metabolites and migraine: a two-sample Mendelian randomization study. Front Microbiol. 2024;15:1325047. [DOI] [PubMed] [PMC]

50.

Kiecka A, Szczepanik M. Migraine and the microbiota. Can probiotics be beneficial in its prevention? - a narrative review. Pharmacol Rep. 2024;76:251–62. [DOI] [PubMed]

51.

Zhong Y, Kang X, Bai X, Pu B, Smerin D, Zhao L, et al. The Oral-Gut-Brain Axis: The Influence of Microbes as a Link of Periodontitis With Ischemic Stroke. CNS Neurosci Ther. 2024;30:e70152. [DOI] [PubMed] [PMC]

52.

Cho S, Jung Y, Oh HS, Yum J, Song S, Jeong J, et al. Oral and Gut Dysbiosis in Migraine: Oral Microbial Signatures as Biomarkers of Migraine. Neurol Neuroimmunol Neuroinflamm. 2025;12:e200437. [DOI] [PubMed] [PMC]

53.

You M, Chen N, Yang Y, Cheng L, He H, Cai Y, et al. The gut microbiota-brain axis in neurological disorders. MedComm (2020). 2024;5:e656. [DOI] [PubMed] [PMC]

54.

Parra I, Martínez I, Vásquez-Celaya L, Gongora-Alfaro JL, Tizabi Y, Mendieta L. Neuroprotective and Immunomodulatory Effects of Probiotics in a Rat Model of Parkinson’s Disease. Neurotox Res. 2023;41:187–200. [DOI] [PubMed]

55.

Daniele E, Nazer Y, Kortebi I, Casasbuenas DL, Fan Y, Trinh M, et al. Oral probiotic therapy improves motor function in a rodent model of sensorimotor stroke. Exp Brain Res. 2023;241:1931–43. [DOI] [PubMed]

56.

Han Y, Xu H, Tao S, Zhu Y, Wei ZZ, Zhao Y, et al. Bifico Ameliorates Neurological Deficits After Ischemic Stroke in Mice: Transcriptome Profiling. In Vivo. 2024;38:699–709. [DOI] [PubMed] [PMC]

57.

Li T, Chu C, Yu L, Zhai Q, Wang S, Zhao J, et al. Neuroprotective Effects of Bifidobacterium breve CCFM1067 in MPTP-Induced Mouse Models of Parkinson’s Disease. Nutrients. 2022;14:4678. [DOI] [PubMed] [PMC]

58.

Park S, Jung S, Lee G, Lee E, Black R, Hong J, et al. Self-Nourishing and Armored Probiotics via Egg-Inspired Encapsulation. Adv Healthc Mater. 2025;14:e2405219. [DOI] [PubMed]

59.

Yang J, Ma Y, Li T, Pang Y, Zhang H, Xie Y, et al. Ameliorative Effects of Bifidobacterium animalis subsp. lactis J-12 on Hyperglycemia in Pregnancy and Pregnancy Outcomes in a High-Fat-Diet/Streptozotocin-Induced Rat Model. Nutrients. 2022;15:170. [DOI] [PubMed] [PMC]

60.

Mindrescu NM, Guja C, Jinga V, Ispas S, Curici A, Twakor AN, et al. Interactions between Gut Microbiota and Oral Antihyperglycemic Drugs: A Systematic Review. Int J Mol Sci. 2024;25:3540. [DOI] [PubMed] [PMC]