Skip to main content

Advertisement

SpringerLink
Log in

An Alternative Explanation for Alzheimer’s Disease and Parkinson’s Disease Initiation from Specific Antibiotics, Gut Microbiota Dysbiosis and Neurotoxins

  • Review
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The late onset neuropathologies, including Alzheimer’s disease and Parkinson’s disease, have become increasingly prevalent. Their causation has been linked to genetics, gut microbiota dysbiosis (gut dysbiosis), autoimmune diseases, pathogens and exposures to neurotoxins. An alternative explanatory hypothesis is provided for their pathogenesis. Virtually everyone has pervasive daily exposures to neurotoxins, through inhalation, skin contact, direct blood transmission and through the gastrointestinal tract by ingestion. As a result, every individual has substantial and fluctuating neurotoxin blood levels. Two major barriers to neurotoxin entry into the central nervous system are the blood–brain barrier and the intestinal wall, in the absence of gut dysbiosis. Inflammation from gut dysbiosis, induced by antibiotic usage, can increase the intestinal wall permeability for neurotoxins to reach the bloodstream, and also increase the blood–brain barrier permeability to neurotoxins. Gut dysbiosis, including gut dysbiosis caused by antibiotic treatments, is an especially high risk for neurotoxin entry into the brain to cause late onset neuropathologies. Gut dysbiosis has far-reaching immune system and central nervous system effects, and even a transient gut dysbiosis can act in combination with neurotoxins, such as aluminum, mercury, lead, arsenic, cadmium, selenium, manganese, organophosphate pesticides and organochlorines, to reach neurotoxin blood levels that can initiate a late onset neuropathology, depending on an individual’s age and genetic vulnerability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

Not applicable.

Code Availability

Not applicable.

Abbreviations

SNCA:

Synuclein, Alpha

GI:

Gastrointestinal

CNS:

Central nervous system

HPA:

Hypothalamic–pituitary–adrenal

GABA:

γ-Aminobutyric acid

IgG:

Immunoglobulin G

CD4:

Cluster of differentiation 4

TH1:

Helper 1 T cells

TH17:

Helper 17 T cells

IL-1:

Interleukin-1

IL-6:

Interleukin-6

IL-17:

Interleukin-17

TNF-α:

Tumor necrosis factor-α

eNOS:

Endothelial nitric oxide synthase

BBB:

Blood–brain barrier

ROS:

Reactive oxygen species

GSH:

Glutathione

NO:

Nitric oxide

NOS:

Nitric oxygen synthase

iNOS:

Inducible nitric oxygen synthase

DDT:

Dichlorodiphenyltrichloroethane

DDE:

Dichlorodiphenyldichloroethylene

References

  1. Morris G, Puri BK, Frye RE (2017) The putative role of environmental aluminum in the development of chronic neuropathology in adults and children. How strong is the evidence and what could be the mechanisms involved? Metab Brain Dis 32(5):1335–1335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Alasfar RH, Isaifan RJ (2021) Aluminum environmental pollution: the silent killer. Environ Sci Pollut Res Int 28(33):44587–44597. https://doi.org/10.1007/s11356-021-14700-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cryan JF, O’riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG et al (2019) The microbiota-gut-brain axis. Physiol Rev 99:1877–2013

    Article  CAS  PubMed  Google Scholar 

  4. Zhu S, Jiang Y, Xu K, Cui M, Ye W, Zhao G, Jin L, Chen X (2020) The progress of gut microbiome research related to brain disorders. J Neuroinflammation 17(1):25. https://doi.org/10.1186/s12974-020-1705-z

    Article  PubMed  PubMed Central  Google Scholar 

  5. Skjærbæk C, Knudsen K, Horsager J, Borghammer P (2021) Gastrointestinal dysfunction in Parkinson’s disease. J Clin Med 10(3):493. https://doi.org/10.3390/jcm10030493

    Article  PubMed  PubMed Central  Google Scholar 

  6. Liu B, Fang F, Pedersen NL, Tillander A, Ludvigsson JF, Ekbom A, Svenningsson P, Chen H, Wirdefeldt K (2017) Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology 88(21):1996–2002. https://doi.org/10.1212/WNL.0000000000003961

    Article  PubMed  PubMed Central  Google Scholar 

  7. Van Den Berge N, Ferreira N, Gram H, Mikkelsen TW, Alstrup AKO, Casadei N, Tsung-Pin P, Riess O, Nyengaard JR, Tamgüney G, Jensen PH, Borghammer P (2019) Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats. Acta Neuropathol 138(4):535–550. https://doi.org/10.1007/s00401-019-02040-w

    Article  CAS  Google Scholar 

  8. Rolli-Derkinderen M, Leclair-Visonneau L, Bourreille A, Coron E, Neunlist M, Derkinderen P (2020) Is Parkinson’s disease a chronic low-grade inflammatory bowel disease? J Neurol 267:2207–2213. https://doi.org/10.1007/s00415-019-09321-0

    Article  PubMed  Google Scholar 

  9. Ramirez J, Guarner F, Bustos Fernandez L, Maruy A, Sdepanian VL, Cohen H (2020) Antibiotics as major disruptors of gut microbiota. Front Cell Infect Microbiol 10:572912. https://doi.org/10.3389/fcimb.2020.572912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Antonini M, Conte M, Sorini C, Falcone M (2019) How the interplay between the commensal microbiota, gut barrier integrity, and mucosal immunity regulates brain autoimmunity. Front Immunol 10:1937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lau WL, Savoj J, Nakata MB, Vaziri ND (2018) Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins. Clin Sci 132(5):509–522

    Article  CAS  Google Scholar 

  12. Obrenovich MEM (2018) Leaky gut, leaky brain? Microorganisms 6(4):107

    Article  CAS  PubMed Central  Google Scholar 

  13. Coelho-Santos V, Shih AY (2020) Postnatal development of cerbrovascular structure and neurogliovascular unit. Wiley Interdiscip Rev Dev Biol 9(2):e363

    Article  PubMed  Google Scholar 

  14. Galea I (2021) The blood-brain barrier in systemic infection and inflammation. Cell Mol Immunol. https://doi.org/10.1038/s41423-021-00757-x

    Article  PubMed  PubMed Central  Google Scholar 

  15. Profaci CP, Munji RN, Pulido RS, Daneman R (2020) The blood-brain barrier in health and disease: important unanswered questions. J Exp Med 217(4):e20190062. https://doi.org/10.1084/jem.20190062

    Article  PubMed  PubMed Central  Google Scholar 

  16. Hussain B, Fang C, Chang J (2021) Blood-brain barrier breakdown: an emerging biomarker of cognitive impairment in normal aging and dementia. Front Neurosci 15:688090. https://doi.org/10.3389/fnins.2021.688090

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kern JK, Geier DA, Homme KG, King PG, Bjorklund G, Chirumbolo S, Geier MR (2017) Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males. Acta Neurobiol Exp 77(4):269–296

    Google Scholar 

  18. Gershon MD, Margolis KG (2021) The gut, its microbiome, and the brain: connections and communications. J Clin Invest 131(18):e143768. https://doi.org/10.1172/JCI143768

    Article  CAS  Google Scholar 

  19. Jacobson A, Yang D, Vella M, Chiu IM (2021) The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes. Mucosal Immunol 14(3):555–565. https://doi.org/10.1038/s41385-020-00368-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Janakiraman M, Krishnamoorthy G (2018) Emerging role of diet and microbiota interactions in neuroinflammation. Front Immunol 9:2067

    Article  PubMed  PubMed Central  Google Scholar 

  21. Eshraghi RS, Davies C, Iyengar R, Perez L, Mittal R, Eshraghi AA (2021) Gut-Induced inflammation during development may compromise the blood-brain barrier and predispose to autism spectrum disorder. J Clin Med 10(1):27. https://doi.org/10.3390/jcm10010027

    Article  CAS  Google Scholar 

  22. Fukui H (2016) Increased intestinal permeability and decrease barrier function: does it really influence the risk of inflammation? Inflamm Intest Dis 1(3):135–145

    Article  PubMed  PubMed Central  Google Scholar 

  23. Igbokwe IO, Igwenagu E, Igbokwe NA (2019) Aluminum toxicosis; a review of toxic actions and effects. Interdiscip Toxicol 12(2):45–70

    Article  CAS  PubMed  Google Scholar 

  24. Tietz T, Lenzner A, Kolbaum AE, Zellmer S, Riebeling C, Gürtler R, Jung C, Kappenstein O, Tentschert J, Giulbudagian M, Merkel S, Pirow R, Lindtner O, Tralau T, Schäfer B, Laux P, Greiner M, Lampen A, Luch A, Wittkowski R, Hensel A (2019) Aggregated aluminium exposure: risk assessment for the general population. Arch Toxicol 93(12):3503–3521. https://doi.org/10.1007/s00204-019-02599-z

    Article  CAS  PubMed  Google Scholar 

  25. Bondy SC (2016) Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer’s disease and age-related neurodegeneration. Neurotoxicology 52:222–229. https://doi.org/10.1016/j.neuro.2015.12.002

    Article  CAS  PubMed  Google Scholar 

  26. Skalny AV, Aschner M, Jiang Y, Gluhcheva YG, Tizabi Y, Lobinski R, Tinkov AA (2021) Molecular mechanisms of aluminum neurotoxicity: update on adverse effects and therapeutic strategies. Adv Neurotoxicol 5:1–34. https://doi.org/10.1016/bs.ant.2020.12.001

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tremblay MÈ (2021) Microglial functional alteration and increased diversity in the challenged brain: insights into novel targets for intervention. Brain Behav Immun Health 16:100301. https://doi.org/10.1016/j.bbih.2021.100301

    Article  PubMed  PubMed Central  Google Scholar 

  28. Anderson SR, Vetter ML (2019) Developmental roles of microglia: a window into mechanisms of disease. Dev Dyn 248(1):98–117. https://doi.org/10.1002/dvdy.1

    Article  PubMed  Google Scholar 

  29. Hoeijmakers L, Heinen Y, van Dam AM, Lucassen PJ, Korosi A (2016) Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics? Front Hum Neurosci 10:398

    Article  PubMed  PubMed Central  Google Scholar 

  30. Edmonson CA, Ziats MN, Rennert OM (2016) A non-inflammatory role for microglia in autism spectrum disorders. Front Neurol 7:9

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nutma E, van Gent D, Amor S, Peferoen LAN (2020) Astrocyte and oligodendrocyte cross-talk in the central nervous system. Cells 9(3):600. https://doi.org/10.3390/cells9030600

    Article  CAS  PubMed Central  Google Scholar 

  32. Verkhratsky A, Parpura V (2016) Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis 85:254–261

    Article  PubMed  Google Scholar 

  33. Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18(7):942–952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Siblerud R, Mutter J, Moore E, Naumann J, Walach H (2019) A hypothesis and evidence that mercury may be an etiological factor in Alzheimer’s disease. Int J Environ Res Public Health 16(24):5152

    Article  CAS  PubMed Central  Google Scholar 

  35. Genchi G, Sinicropi MS, Carocci A, Lauria G, Catalono A (2017) Mercury exposure and heart diseases. Int J Environ Res Public Health 14(1):74

    Article  PubMed Central  Google Scholar 

  36. Drevnick PE, Lamborg CH, Horgan MJ (2015) Increase in mercury in Pacific yellow fin tuna. Environ Toxicol Chem 34:931–934

    Article  CAS  PubMed  Google Scholar 

  37. Bengtsson UG, Hylander LD (2017) Increased mercury emissions from modern dental amalgams. Biometals 30(2):277–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jirau-Colón H, González-Parrilla L, Martinez-Jiménez J, Adam W, Jiménez-Velez B (2019) Rethinking the dental amalgam dilemma: an integrated toxicological approach. Int J Environ Res Public Health 16(6):1036

    Article  PubMed Central  Google Scholar 

  39. Akushevich I, Kravchenko J, Yashkin AP, Yashin AI (2018) Time trends in the prevalence of cancer and non-cancer diseases among older U.S. adults: medicare-based analysis. Exp Gerontol 110:267–276

    Article  PubMed  PubMed Central  Google Scholar 

  40. Garza-Lombó C, Posadas Y, Quintanar L, Gonsebatt ME, Franco R (2018) Neurotoxicity linked to dysfunctional metal ion homeostatis and xenobiotic metal exposure: redox signaling and oxidative stress. Antioxid Redox Signal 28(18):1669–1703

    Article  PubMed  PubMed Central  Google Scholar 

  41. Schofield K (2017) The metal neurotoxins: an important role in current human neural epidemics? Int J Environ Res Public Health 14(12):1511

    Article  PubMed Central  Google Scholar 

  42. Misra S, Boylan M, Selvam A, Spallholz JE, Björnstedt M (2015) Redox-active selenium compounds—from toxicity and cell death to cancer treatment. Nutrients 7(5):3536–3556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vinceti M, Filippini T, Wise LA (2018) Environmental selenium and human health: an update. Curr Environ Health Rep 5(4):464–485. https://doi.org/10.1007/s40572-018-0213-0

    Article  PubMed  Google Scholar 

  44. Prasad EM, Hung SY (2020) Behavioral tests in neurotoxin-induced animal models of Parkinson’s disease. Antioxidants 9(10):1007

    Article  CAS  PubMed Central  Google Scholar 

  45. Yeung AWK, Georgieva MG, Atanasov AG, Tzvetkov NT (2019) Monamine oxidases (MAOs) as privileged molecular targets in neuroscience: research literature analysis. Front Mol Neurosci 12:143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Powers R, Lei S, Anandhan A, Marshall DD, Worley B, Cerny RL, Dodds ED, Huang Y, Panayiotidis MI, Pappa A, Franco R (2017) Metabolic investigations of the molecular mechanisms associated with Parkinson’s disease. Metabolities 7(2):22

    Article  Google Scholar 

  47. Nandipati S, Litvan I (2016) Environmental exposures and Parkinson’s disease. Int J Environ Res Public Health 13(9):881

    Article  PubMed Central  Google Scholar 

  48. Kamel F, Tanner CM, Umbach DM, Hoppin JA, Alavanja MCR, Blair A, Comyns K et al (2007) Pesticide exposure and self-reported Parkinson’s disease in the agricultural health study. Am J Epidemiol 165(4):364–374

    Article  CAS  PubMed  Google Scholar 

  49. Prasuhn J, Davis RL, Kumar KR (2021) Targeting mitochondrial impairment in Parkinson’s disease: challenges and opportunities. Front Cell Dev Biol 5(8):615461. https://doi.org/10.3389/fcell.2020.615461

    Article  Google Scholar 

  50. Minakaki G, Krainc D, Burbulla LF (2020) The convergence of alpha-synuclein, mitochondrial, and lysosomal pathways in vulnerability of midbrain dopaminergic neurons in Parkinson’s disease. Front Cell Dev Biol 8:580634. https://doi.org/10.3389/fcell.2020.580634

    Article  PubMed  PubMed Central  Google Scholar 

  51. Bentea E, Verbruggen L, Massie A (2017) The proteasome inhibition model of Parkinson’s disease. J Parkinsons Dis 7(1):31–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ureshino RP, Erustes AG, Bassani TB, Wachilewski P, Guarache GC, Nascimento AC, Costa AJ, Smaili SS, Pereira GJDS (2019) The interplay between Ca2+ signaling pathways and neurodegeneration. Int J Mol Sci 20(23):6004. https://doi.org/10.3390/ijms20236004

    Article  CAS  PubMed Central  Google Scholar 

  53. Zaman V, Shields DC, Shams R, Drasites KP, Matzelle D, Haque A, Banik NL (2021) Cellular and molecular pathophysiology in the progression of Parkinson’s disease. Metab Brain Dis 36(5):815–827. https://doi.org/10.1007/s11011-021-00689-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Henderson MX, Trojanowski JQ, Lee VM-Y (2019) α-Synuclein pathology in Parkinson’s disease and related α-synucleinopathies. Neurosci Lett 709:134316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Trist BG, Hare DJ, Double KL (2019) Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell 18(6):e13031. https://doi.org/10.1111/acel.13031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rudyk CA, McNeill J, Prowse N, Dwyer Z, Farmer K, Litteljohn D, Caldwell W, Hayley S (2017) Age and chronicity of administration dramatically influenced the impact of low dose paraquat exposure on behavior and hypothalmic-pituitary-adrenal activity. Front Aging Neurosci 9:222

    Article  PubMed  PubMed Central  Google Scholar 

  57. Rudyk C, Dwyer Z, McNeill J, Salmaso N, Farmer K, Prowse N, Hayley S (2019) Chronic unpredictable stress influenced the behavioral but not the neurodegenerative impact of paraquat. Neurobiol Stress 11:100179

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

There are no acknowledgements.

Funding

No funding was received for this article.

Author information

Authors and Affiliations

  1. San Jose, CA, USA

    Kevin Roe

Authors
  1. Kevin Roe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Kevin Roe is the sole author of all contributions.

Corresponding author

Correspondence to Kevin Roe.

Ethics declarations

Conflict of interest

The author has no potential conflicts of interest.

Ethical Approval

Not applicable.

Consent for Publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Kevin Roe—Retired.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roe, K. An Alternative Explanation for Alzheimer’s Disease and Parkinson’s Disease Initiation from Specific Antibiotics, Gut Microbiota Dysbiosis and Neurotoxins. Neurochem Res 47, 517–530 (2022). https://doi.org/10.1007/s11064-021-03467-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-021-03467-y

Keywords

Search

Navigation