Alzheimer’s disease and gut microbiota: does trimethylamine N-oxide (TMAO) play a role?
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that affects memory and cognitive function. Clinical evidence has put into question our current understanding of AD development, propelling researchers to look into further avenues. Gut microbiota has emerged as a potential player in AD pathophysiology. Lifestyle factors, such as diet, can have negative effects on the gut microbiota and thus host health. A Western-type diet has been highlighted as a risk factor for both gut microbiota alteration as well as AD development. The gut-derived trimethylamine N-oxide (TMAO) has been previously implied in the development of cardiovascular diseases with recent evidence suggesting a plausible role of TMAO in AD development. Therefore, the main goal of the present review is to provide the reader with potential mechanisms of action through which consumption of a Western-type diet could increase AD risk, by acting through microbiota-produced TMAO. Although a link between TMAO and AD is far from definitive, this review will serve as a call for research into this new area of research.
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TMAO is implicated in oxidative stress enhancement, blood-brain barrier disruption, mitochondria dysfunction, brain aging and neurodegeneration.
“TMAO is an amine oxide product of the bacterial metabolism that has been implicated in oxidative stress enhancement, BBB disruption, mitochondria dysfunction, brain aging and neurodegeneration [105,106,107]”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [105]
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Dietary Regulation of Gut-Brain Axis in Alzheimer’s Disease: Importance of Microbiota Metabolites
Frausto, D. M., Forsyth, C. B., Keshavarzian, A., & Voigt, R. M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.736814 · Cited by 61 · see citing works
Microglia and gut microbiota: A double-edged sword in Alzheimer's disease
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Insulin resistance in Alzheimer’s disease: The genetics and metabolomics links
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“Strategies aimed at restoring gut microbiota homeostasis represent a promising avenue for mitigating the effects of neurode-generation explore microbiome-targeted”
Wang, F., Gu, Y., Xu, C., Du, K., Zhao, C., Zhao, Y., & Liu, X. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.858130 · Cited by 39 · see citing works
Effect of a Vegan Diet on Alzheimer’s Disease
Katonová, A., Sheardová, K., Amlerová, J., Angelucci, F., & Hort, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314924 · Cited by 39 · see citing works
Ji, X., Tian, L., Niu, S., Yao, S., & Qu, C. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.963876 · Cited by 38 · see citing works
Plasma Trimethylamine N-Oxide (TMAO): Associations with Cognition, Neuroimaging, and Dementia
Yaqub, A., Vojinovic, D., Vernooij, M. W., Slagboom, P. E., Ghanbari, M., Beekman, M., van der Grond, J., Hankemeier, T., van Duijn, C. M., Ikram, M. A., et al. (2024) · Alzheimer's Research & Therapy · doi:10.1186/s13195-024-01480-1 · Cited by 37 · see citing works
“Thus far, evidence on the detrimental effects of TMAO on the brain largely derives from animal studies or small-scale clinical samples [13], whilst population-based evidence on the association between TMAO and dementia is limited.”
BackgroundZhou, S., Liu, J., Sun, Y., Xu, P., Liu, J. L., Sun, S., Zhu, B., & Wu, H. (2023) · Food & Function · doi:10.1039/d2fo03874a · Cited by 34 · see citing works
Uceda, S., Echeverry‐Alzate, V., Reiriz, M., Miguel, E. M., Pérez-Curiel, A., Gómez-Senent, S., & Beltrán-Velasco, A. I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713294 · Cited by 35 · see citing works
“Trimethylamine-N-oxide (TMAO) is a bacterial derivate metabolite of choline, lcarnitine, and betaine, among others, which is related to the AD apparition [69,70].”
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Zhan, Y., Al‐Nusaif, M., Ding, C., Zhao, L., & Dong, C. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1130730 · Cited by 30 · see citing works
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The emerging role of the microbiome in Alzheimer's disease
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Czarnik, W., Fularski, P., Gajewska, A., Jakubowska, P., Uszok, Z., Młynarska, E., Rysz, J., & Franczyk, B. (2024) · Nutrients · doi:10.3390/nu16020308 · Cited by 24 · see citing works
“Hence, it can be inferred that a diet rich in TMAO precursors, such as red meat, fish, and eggs, may lead to an elevated concentration of this protein in the bloodstream [55].”
BackgroundConsensus statement on exploring the Nexus between nutrition, brain health and dementia prevention
Johnstone, A. M., Albanese, E., Crabtree, D. R., Dalile, B., Grabrucker, S., Gregory, J. M., Grosso, G., Holliday, A., Hughes, C., Itsiopoulos, C., et al. (2025) · Nutrition & Metabolism · doi:10.1186/s12986-025-00981-6 · Cited by 21 · see citing works
“Among the most studied gut metabolites is trimeth-ylamine N-oxide (TMAO), produced from seafood, egg, and whole-grain products [44], and its relationship with AD, with elevated TMAO levels correlating with increased AD risk [45].”
Luo, S., Pan, M., Fu, G., Meng, X., Zhao, Z., Yu, H., Yue, G.-X., & Lei, T. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107974 · Cited by 19 · see citing works
Trimethylamine N-oxide: role in cell senescence and age-related diseases
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A Review on the Protective Effects of Probiotics against Alzheimer’s Disease
Mishra, V., Yadav, D., Solanki, K. S., Koul, B., & Song, M. (2023) · Biology · doi:10.3390/biology13010008 · Cited by 19 · see citing works
“CSF TMNO promotes tau protein hyperphosphorylation, which plays a significant role in the pathology of AD [113,114].”
BackgroundTMAO promotes dementia progression by mediating the PI3K/Akt/mTOR pathway
Hu, X., Zhang, Y., Gu, C., Gu, C., Yao, Y., Yao, Y., Luo, L., & Zhang, Y. (2023) · Tissue and Cell · doi:10.1016/j.tice.2023.102034 · Cited by 17 · see citing works
Gut microbiota-generated metabolites: missing puzzles to hosts’ health, diseases, and aging
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Unveiling Selected Influences on Chronic Kidney Disease Development and Progression
Fularski, P., Czarnik, W., Frankenstein, H., Gąsior, M., Młynarska, E., Rysz, J., & Franczyk, B. (2024) · Cells · doi:10.3390/cells13090751 · Cited by 19 · see citing works
“Foods particularly rich in TMAO precursors include red meat, fish, and eggs [73,74].”
BackgroundThe Gut-Brain Axis in Alzheimer’s Disease: Exploring Microbial Influences and Therapeutic Strategies
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Oral Health and Cognitive Decline: A Systematic Review of the Periodontitis–Alzheimer’s Connection
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Microbiome Alterations and Alzheimer’s Disease: Modeling Strategies with Transgenic Mice
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Bu, L., Wang, C., Bai, J., Song, J., Zhang, Y., Chen, H., & Suo, H. (2024) · Food & Function · doi:10.1039/d3fo02307a · Cited by 13 · see citing works
Citicoline for Supporting Memory in Aging Humans
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“A promising area of research focuses on gut microbi-ota-derived metabolites, particularly Trimethylamine N-oxide (TMAO), which is elevated in the plasma and cerebrospinal fluid of AD patients [7, 8].”
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Insulin resistance: fueling oxidative stress and neurodegeneration
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Investigating the Role of Gut-Derived Neurotoxin TMAO in PTSD Risk Following Traumatic Brain Injury
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“[ 30] found a strong correlation between increased TMAO levels and Alzheimer’s disease (AD).”
The complex of gut microbial metabolites and sex hormones in Alzheimer’s disease
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The Microbiome Epoch: Cracking the Cardiovascular-Neurodegenerative Disorder Code
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Yaqub, A., Vojinović, D., Vernooij, M. W., Slagboom, P. E., Ghanbari, M., Beekman, M., van der Grond, J., Hankemeier, T., van Duijn, C. M., Ikram, M. A., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25865060
Chronic stress, gut dysbiosis, and cholesterol metabolism: Implications for Alzheimer's disease
Das, A., Navya, P., Chowdhury, D., Das, A., Manna, R., & Bodakhe, S. H. (2026) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2026.578853
Peng, L., Wu, Z., Yuan, X., Zhou, C., & Fu, H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1910604
“In AD, elevated TMAO, derived from microbial metabolism of dietary choline, L-carnitine, and phosphatidylcholine, has been associated with two core pathological hallmarks: A b plaque deposition and tau hyperphosphorylation (78, 79).”
Shao, Y., Zhang, R. F., Wang, Z., Gan, J., Jiang, X. J., & Yang, L. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-06213-z
“Furthermore, interventions targeting specific metabolites, such as SCFA supplementation and TMAO inhibition, provide additional evidence supporting a bidirectional causal relationship between GM-metabolite-AD interactions [91, 92].”
- Authors
- Arrona Cardoza, P., Spillane, M. B., & Morales Marroquin, E.
- Affiliations
- Tecnológico de Monterrey, School of Medicine and Health Science, Monterrey, Nuevo Leon, Mexico
- H.C. Drew School of Health and Human Performance, McNeese State University, Lake Charles, Louisiana, USA
- School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
- Venue
- Nutrition Reviews
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-05-03
- Volume
- 80
- Issue
- 2
- Pages
- 271-281
- ISSN
- 0029-6643 (ISSN-L)
- 1753-4887
- OpenAlex
- W3157088902
- Cited by
- 53
- References
- 192
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 13 · 2023: 8 · 2022: 12 · 2021: 2
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Nutrition Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, gut microbiota, trimethylamine N-oxide, Western diet, neurodegeneration, gut-brain axis, dietary risk factors, cardiovascular risk
- MeSH terms
- Gastrointestinal Microbiome, Alzheimer Disease, Humans, Methylamines, Neurodegenerative Diseases
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