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The Role of a Gut Microbial-Derived Metabolite, Trimethylamine N-Oxide (TMAO), in Neurological Disorders

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Abstract

Trimethylamine lyases are expressed in a wide range of intestinal microbiota which metabolize dietary nutrients like choline, betaine, and L-carnitine to form trimethylamine (TMA). Trimethylamine N-oxide (TMAO) is an oxidative product of trimethylamine (TMA) catalyzed by the action of flavin monooxygenases (FMO) in the liver. Higher levels of TMAO in the plasma and cerebrospinal fluid (CSF) have been shown to contribute to the development of risk factors and actively promote the pathogenesis of metabolic, cardiovascular, and cerebrovascular diseases. The investigations on the harmful effects of TMAO in the development and progression of neurodegenerative and sleep disorders are summarized in this manuscript. Clinical investigations on the role of TMAO in predicting risk factors and prognostic factors in patients with neurological disorders are also summarized. It is observed that the mechanisms underlying TMAO-mediated pathogenesis include activation of inflammatory signaling pathways such as nuclear factor kappa B (NF-κβ), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, and MAPK/JNK in the periphery and brain. Data suggests that TMAO levels increase with age-related cognitive dysfunction and also induce mitochondrial dysfunction, oxidative stress, neuronal senescence, and synaptic damage in the brain. Further research into the relationships between dietary food consumption and gut microbiota-dependent TMAO levels could provide novel therapeutic options for neurological illnesses.

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Data Availability

The data that support the findings of this study are available in standard research databases such as PubMed, Science Direct, or Google Scholar, and/or on public domains that can be searched with either key words or DOI numbers.

Abbreviations

Aβ:

Amyloid-beta

AD:

Alzheimer’s disease

ALC:

Acetyl L-carnitine

ALS:

Amyotrophic lateral sclerosis

BBB:

Blood-brain barrier

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CVD:

Cardiovascular diseases

EAE:

Experimental autoimmune encephalomyelitis

ETX:

Epsilon toxin

FMO:

Flavin-containing monooxygenases

FMT:

Fecal microbiota transplantation

HD:

Huntington’s disease

JNKs:

Jun N-terminal kinases

LPS:

Lipopolysaccharides

LTP:

Long term potentiation

MAPKs:

P38 mitogen-activated protein kinases

MCI:

Mild cognitive impairment

MS:

Multiple sclerosis

mTOR:

Mammalian target of rapamycin

NF-κβ:

Nuclear factor kappa B

NFTs:

Neurofibrillary tangles

NLRP3:

NOD-, LRR-, and pyrin domain-containing protein 3

OSAS:

Obstructive sleep apnea syndrome

PD:

Parkinson’s disease

PERK:

Protein kinase R-like endoplasmic reticulum kinase

PolyQ:

Polyglutamine

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

TDP43:

DNA-binding protein 43

TMA:

Trimethylamine

TMAO:

Trimethylamine N-oxide

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Acknowledgements

The authors thank their respective institutions for providing the facilities during the manuscript preparation. Figures are drawn using Adobe Photoshop and a few components used in the figures have been adapted and modified from Biorender.com (free trial version).

Funding

This work is supported by the “Public Health and Nutrition Division,” Department of Biotechnology, Ministry of Science and Technology, Govt of India. (BT/PR38038/PFN/20/1528/2020).

Author information

Authors and Affiliations

  1. Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, 570015, India

    Sankar Simla Praveenraj, Sharma Sonali, Hediyal Ahmed Tousif, Chandrasekaran Vichitra, Manjunath Kalyan, Perumalswamy Velumani Kanna, Kumar A. Chandana, Arehally M. Mahalakshmi & Saravana Babu Chidambaram

  2. Centre for Experimental Pharmacology & Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, 570015, India

    Sharma Sonali, Hediyal Ahmed Tousif, Chandrasekaran Vichitra & Saravana Babu Chidambaram

  3. Department of Pharmacology, American University of Antigua College of Medicine, P.O. Box W-1451, University Park, Jabberwock Beach Road, Coolidge, Antigua and Barbuda

    Nikhilesh Anand

  4. Department of Neurology, JSS Hospital, Mysuru, 570004, Karnataka, India

    Paneyala Shasthara

  5. SIG-Brain, Behaviour and Cognitive Neurosciences Research (BBRC), JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka, India

    Arehally M. Mahalakshmi & Saravana Babu Chidambaram

  6. Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada

    Jian Yang & Meena Kishore Sakharkar

  7. Somnogen Canada Inc, College Street, Toronto, ON, Canada

    Seithikurippu R. Pandi-Perumal

  8. Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India

    Seithikurippu R. Pandi-Perumal

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S.S.P., S.S., N.K., H.A.T., C.V., M.K., P.V.K., K.A.C., S.P., A.M.M., J.Y., S.R.P., M.K.S., and S.B.C. made a significant contribution to the work reported, whether that is in the conception, study design, execution, or the acquisition, analysis, or interpretation of data, or all these areas; took part in drafting, revising, or critically reviewing the article; and gave final approval of the version to be published. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Meena Kishore Sakharkar or Saravana Babu Chidambaram.

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Praveenraj, S.S., Sonali, S., Anand, N. et al. The Role of a Gut Microbial-Derived Metabolite, Trimethylamine N-Oxide (TMAO), in Neurological Disorders. Mol Neurobiol 59, 6684–6700 (2022). https://doi.org/10.1007/s12035-022-02990-5

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