Orally Induced High Serum Level of Trimethylamine N-oxide Worsened Glial Reaction and Neuroinflammation on MPTP-Induced Acute Parkinson’s Disease Model Mice
Abstract
Neuroinflammation mediated by brain glial cells is one of the pathological drivers of Parkinson's disease (PD). Recent studies have shown that higher circulating trimethylamine N-oxide (TMAO, a gut microbiota-derived metabolite) can induce neuroinflammation and are strongly related to a variety of central nervous system diseases and adverse brain events. Herein, we explored the effect of pre-existing higher circulating TMAO on dopamine system and neuroinflammation in acute PD model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). TMAO pretreatment was given by adding 3% (w/v) TMAO to drinking water of mice for 21 days to induce higher circulating TMAO status, then mice were administered with MPTP (20 mg/kg, i.p) for four times in one day to construct an acute PD model mice and treated with TMAO continuously until the end of the experiment. Results demonstrated that TMAO treatment significantly increased serum TMAO levels. Moreover, high serum TMAO significantly increased activation of microglia and astrocytes both in striatum and in substantia nigra. And strikingly, high serum TMAO significantly promoted the metabolism of striatal dopamine (DA) of PD model mice, although it had no significant effect on the number of dopaminergic neurons or the content of DA. Furthermore, immunofluorescence, ELISA, and RT-qPCR results of the hippocampus also showed that high serum TMAO significantly promoted the activation of microglia and astrocytes in the dentate gyrus, increased the levels of TNF-α and IL-1β, and upregulated gene expression of M1 microglia-related markers (including CD16, CD32, and iNOS) and A2 astrocyte-related markers (including S100a10, Ptx3, and Emp1) in mRNA levels. In summary, we found that pre-existing high serum levels of TMAO worsened the PD-related brain pathology by promoting DA metabolism, aggravating neuroinflammation and regulating glial cell polarization.
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TMAO levels are elevated in plasma and cerebrospinal fluid of individuals with mild cognitive impairment and Alzheimer's disease, and TMAO can traverse the blood-brain barrier and contribute to neurodegeneration by inducing microglial and astrocytic activation.
“Importantly, elevated levels of TMAO have been observed in the plasma and cerebrospinal fluid (CSF) of individuals with MCI and AD.409,410 Several studies have shown that TMAO has the ability to traverse the BBB and contribute to neurodegeneration by inducing microglial and astrocytic activation.411–414”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [412]
TMAO is associated with neuroinflammation by inducing microglial and astrocytic activation.
“TMAO is also associated with neuroinflammation by inducing microglial and astrocytic activation.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [412]
Cites
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,402 · see citing works
Tang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223 · see citing works
Susceptibility of Human Metabolic Phenotypes to Dietary Modulation
Stella, C., Beckwith-Hall, B., Cloarec, O., Holmes, E., Lindon, J. C., Powell, J., van der Ouderaa, F., Bingham, S., Cross, A. J., & Nicholson, J. K. (2006) · Journal of Proteome Research · doi:10.1021/pr060265y · Cited by 376 · see citing works
Wang, Y., Tong, Q., Ma, S.-R., Zhao, Z.-X., Pan, L.-B., Cong, L., Han, P., Peng, R., Yu, H., Lin, Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00456-5 · Cited by 319 · see citing works
Trimethylamine‐<i>N</i>‐oxide promotes brain aging and cognitive impairment in mice
Li, D., Ke, Y., Zhan, R., Liu, C., Zhao, M., Zeng, A., Shi, X., Ji, L., Cheng, S., Pan, B., et al. (2018) · Aging Cell · doi:10.1111/acel.12768 · Cited by 304 · see citing works
Self-citationBrunt, V. E., Gioscia‐Ryan, R. A., Richey, J. J., Zigler, M. C., Cuevas, L. M., Gonzalez, A., Vázquez‐Baeza, Y., Battson, M. L., Smithson, A. T., Gilley, A. D., et al. (2019) · The Journal of Physiology · doi:10.1113/jp277336 · Cited by 182 · see citing works
The Gut Microbial Metabolite Trimethylamine-N-Oxide Is Present in Human Cerebrospinal Fluid
Del Rio, D., Zimetti, F., Caffarra, P., Tassotti, M., Bernini, F., Brighenti, F., Zini, A., & Zanotti, I. (2017) · Nutrients · doi:10.3390/nu9101053 · Cited by 172 · see citing works
Trimethylamine N‐oxide: breathe new life
Subramaniam, S., & Fletcher, C. (2018) · British Journal of Pharmacology · doi:10.1111/bph.13959 · Cited by 171 · see citing works
Sankowski, B., Księżarczyk, K., Raćkowska, E., Szlufik, S., Koziorowski, D., & Giebułtowicz, J. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.10.038 · Cited by 105 · see citing works
Neuroprotective effects of short-chain fatty acids in MPTP induced mice model of Parkinson's disease
Hou, Y., Li, X., Liu, C., Zhang, M., Zhang, X., Ge, S., & Zhao, L. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111376 · Cited by 101 · see citing works
Self-citationGut Microbiota-Derived Metabolite Trimethylamine N-Oxide as a Biomarker in Early Parkinson’s Disease
Chung, S. J., Rim, J. H., Ji, D., Lee, S., Yoo, H. S., Jung, J. H., Baik, K., Choi, Y., Ye, B. S., Sohn, Y. H., et al. (2021) · Nutrition · doi:10.1016/j.nut.2020.111090 · Cited by 74 · see citing works
Cui, C., Hong, H., Shi, Y., Zhou, Y., Qiao, C.-M., Zhao, W.-J., Zhao, L.-P., Wu, J., Quan, W., Niu, G.-Y., et al. (2023) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10047-y · Cited by 45 · see citing works
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
The expression of immune related genes and potential regulatory mechanisms in schizophrenia
Yu, S., Qu, Y., Du, Z., Ou, M., Lu, R., Yuan, J., Jiang, Y., & Zhu, H. (2024) · Schizophrenia Research · doi:10.1016/j.schres.2023.11.007 · Cited by 17 · see citing works
- Authors
- Qiao, C.-M., Quan, W., Zhou, Y., Niu, G.-Y., Hong, H., Wu, J., Zhao, L.-P., Li, T., Cui, C., Zhao, W.-J., & Shen, Y.-Q.
- Affiliations
- Jiangnan University (CN)
- Corresponding author
- Shen, Yan-Qin
- Venue
- Molecular Neurobiology
- Published
- 2023-06-02
- Volume
- 60
- Issue
- 9
- Pages
- 5137-5154
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W4379094985
- Cited by
- 45
- References
- 12
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 11 · 2023: 1
- FWCI
- 4.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81771384, 82171429)
- Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX22_2436)
- the Youth Foundation of Basic Research Program of Jiangnan University (JUSRP121063)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- trimethylamine N-oxide, Parkinson's disease, MPTP-induced neurotoxicity, neuroinflammation, glial activation, microglia, astrocytes, dopamine metabolism, gut microbiota metabolites, M1 microglia, A2 astrocytes, TNF-α, IL-1β, striatum, substantia nigra, hippocampus
- MeSH terms
- Neuroinflammatory Diseases, Animals, Disease Models, Animal, Dopamine, Methylamines, Mice, Inbred C57BL, Parkinson Disease, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Microglia, MPTP Poisoning, Mice, Dopaminergic Neurons
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