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Cited by 197Neuroinflammation and Neurodegeneration MechanismsTryptophan and brain disordersGut microbiota and health

The gut microbiome–derived metabolite trimethylamine N-oxide modulates neuroinflammation and cognitive function with aging

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Brunt, Vienna E., LaRocca, Thomas J., Bazzoni, Amy E., Sapinsley, Zachary J., Miyamoto-Ditmon, Jill, Gioscia-Ryan, Rachel A., Neilson, Andrew P., Link, Christopher D. +1 more·2021·GeroScience
DOI 10.1007/s11357-020-00257-2PMC PMC8050157
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Abstract

Aging is associated with declines in cognitive performance, which are mediated in part by neuroinflammation, characterized by astrocyte activation and higher levels of pro-inflammatory cytokines; however, the upstream drivers are unknown. We investigated the potential role of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) in modulating neuroinflammation and cognitive function with aging. Study 1: In middle-aged and older humans (65 ± 7 years), plasma TMAO levels were inversely related to performance on NIH Toolbox Cognition Battery tests of memory and fluid cognition (both r 2 = 0.07, p < 0.05). Study 2: In mice, TMAO concentrations in plasma and the brain increased in parallel with aging (r 2 = 0.60), suggesting TMAO crosses the blood-brain barrier. The greater TMAO concentrations in old mice (27 months) were associated with higher brain pro-inflammatory cytokines and markers of astrocyte activation vs. young adult mice (6 months). Study 3: To determine if TMAO independently induces an "aging-like" decline in cognitive function, young mice (6 months) were supplemented with TMAO in chow for 6 months. Compared with controls, TMAO-supplemented mice performed worse on the novel object recognition test, indicating impaired memory and learning, and had increased neuroinflammation and markers of astrocyte activation. Study 4: Human astrocytes cultured with TMAO vs. control media exhibited changes in cellular morphology and protein markers consistent with astrocyte activation, indicating TMAO directly acts on these cells. Our results provide translational insight into a novel pathway that modulates neuroinflammation and cognitive function with aging, and suggest that TMAO might be a promising target for prevention of neuroinflammation and cognitive decline with aging.

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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 [411]

  • 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 [411]

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Authors
Brunt, V. E., LaRocca, T. J., Bazzoni, A. E., Sapinsley, Z. J., Miyamoto-Ditmon, J., Gioscia-Ryan, R. A., Neilson, A. P., Link, C. D., & Seals, D. R.
Affiliations
  • University of Colorado Boulder (US)
  • North Carolina State University (US)
Corresponding author
Seals, Douglas R.
ORCID
Venue
GeroScience
Publisher
Springer Science and Business Media LLC
Published
2020-08-29
Volume
43
Issue
1
Pages
377-394
ISSN
  • 2152-4041 (ISSN-L)
  • 2509-2715
  • 2509-2723
DOI
10.1007/s11357-020-00257-2
PMC
PMC8050157
OpenAlex
W3082564026
Cited by
197
References
73
Citations by year
2026: 32 · 2025: 38 · 2024: 46 · 2023: 36 · 2022: 30 · 2021: 15
FWCI
7.92
Type
journal article
Language
en
Open access
Licence
Locations
  • GeroScience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01 HL134887, F32 HL140875)
  • National Center for Advancing Translational Sciences (UL1 TR002535)
  • National Institute of Neurological Disorders and Stroke (R01 NS063964, Administrative Supplement to NS063964)
  • National Institute of Food and Agriculture (Hatch Program)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
trimethylamine N-oxide, gut microbiota, neuroinflammation, cognitive aging, cognitive decline, astrocyte activation, inflammatory cytokines, blood-brain barrier, memory impairment, novel object recognition, brain aging
MeSH terms
Gastrointestinal Microbiome, Aging, Animals, Cognition, Methylamines, Mice

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