The Gut Microbial Metabolite Trimethylamine-N-Oxide Is Present in Human Cerebrospinal Fluid
Open accessAbstract
Trimethylamine-N-oxide (TMAO) is a small organic molecule, derived from the intestinal and hepatic metabolism of dietary choline and carnitine. Although the involvement of TMAO in the framework of many chronic diseases has been recently described, no evidence on its putative role in the central nervous system has been provided. The aim of this study was to evaluate whether TMAO is present at detectable levels in human cerebrospinal fluid (CSF). CSF was collected for diagnostic purposes from 58 subjects by lumbar puncture and TMAO was quantified by using liquid chromatography coupled with multiple-reaction monitoring mass spectrometry. The molecule was detected in all samples, at concentrations ranging between 0.11 and 6.43 µmol/L. Further analysis on CSF revealed that a total of 22 subjects were affected by Alzheimer’s disease (AD), 16 were affected by non-AD related dementia, and 20 were affected by other neurological disorders. However, the stratification of TMAO levels according to the neurological diagnoses revealed no differences among the three groups. In conclusion, we provide the first evidence that TMAO can be assessed in human CSF, but the actual impact of this dietary metabolite in the patho-physiolgy of the central nervous system requires further study.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TMAO can be detected in human cerebrospinal fluid.
“A recent study evidenced that TMAO can be detected in human cerebrospinal fluid [30].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Human Intestinal Microbiome in Health and Disease
Lynch, S. V., & Pedersen, O. (2016) · New England Journal of Medicine · doi:10.1056/nejmra1600266 · Cited by 3,637 · cited 1× · see citing works
“It is now generally accepted that gut microbiota represents a major regulator of health and disease in humans, both contributing to the host metabolic and immune functions and potentially driving the onset of chronic diseases [1].”
BackgroundAdvancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria
Dubois, B., Feldman, H. H., Jacova, C., Hampel, H., Molinuevo, J. L., Blennow, K., DeKosky, S. T., Gauthier, S., Selkoe, D., Bateman, R., et al. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70090-0 · Cited by 3,321 · cited 1× · see citing works
“Alzheimer’s Disease (AD) (n = 22) and non-AD related dementia (non-AD) (n = 16) was diagnosed according to International Working Group (IWG)-2 criteria [7].”
MethodThe Gut Microbiome and the Brain
Galland, L. (2014) · Journal of Medicinal Food · doi:10.1089/jmf.2014.7000 · Cited by 648 · cited 1× · see citing works
“Up to now, only one work on lactic acid and short chain fatty acids have revealed how dietary-derived products may exert (potentially adverse) neurological effects [12].”
BackgroundLi, X. S., Obeid, S., Klingenberg, R., Gencer, B., Mach, F., Räber, L., Windecker, S., Rodondi, N., Nanchen, D., Muller, O., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehw582 · Cited by 479 · cited 1× · see citing works
“TMAO has been recently proposed as a novel prognostic marker of cardiovascular events, given the association of its plasma levels with indexes of atherosclerotic plaque vulnerability [8], major cardiac events [5], and death [9].”
BackgroundHUMAN FLAVIN-CONTAINING MONOOXYGENASES
Cashman, J. R., & Zhang, J. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141043 · Cited by 333 · cited 1× · see citing works
“The levels we detected are consistent with the hypothesis that a small fraction of liver-derived TMAO can cross the blood–brain barrier, but we cannot rule out that a fraction of the TMAO detected in CSF may derive from de novo synthesis, as expression of FMO3 has been detected in the adult brain [14].”
ResultVernetti, L. A., Gough, A., Baetz, N. W., Blutt, S. E., Broughman, J. R., Brown, J. A., Foulke-Abel, J. D., Hasan, N. M., In, J., Kelly, E. J., et al. (2017) · Scientific Reports · doi:10.1038/srep42296 · Cited by 274 · cited 1× · see citing works
“A recent work, based on an innovative microphysiology system hypothesized that TMAO could cross the blood–brain barrier [13], but this has never been demonstrated in vivo.”
BackgroundBae, S., Ulrich, C. M., Neuhouser, M. L., Malysheva, O., Bailey, L. B., Xiao, L., Brown, E. C., Cushing-Haugen, K. L., Zheng, Y., Cheng, T.-Y. D., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1835 · Cited by 253 · cited 1× · see citing works
“Similarly, it has been associated with other chronic diseases, such as diabetes [10] and cancer [11], further strengthening the pathological implications of this microbiota metabolite.”
BackgroundSenthong, V., Li, X. S., Hudec, T., Coughlin, J., Wu, Y., Levison, B., Wang, Z., Hazen, S. L., & Tang, W. H. W. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.03.546 · Cited by 242 · see citing works
Miller, C. A., Corbin, K. D., da Costa, K.-A., Zhang, S., Zhao, X., Galanko, J. A., Blevins, T., Bennett, B. J., O’Connor, A., & Zeisel, S. H. (2014) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.087692 · Cited by 240 · cited 1× · see citing works
“For TMAO quantification, before the analysis, each sample was added with TMAO-d9 as internal standard and then extracted with acidified acetonitrile, as previously described [6].”
MethodDiabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels
Dambrova, M., Latkovskis, G., Kuka, J., Strele, I., Konrade, I., Grinberga, S., Hartmane, D., Pugovics, O., Erglis, A., & Liepinsh, E. (2016) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-0035-1569330 · Cited by 229 · cited 1× · see citing works
“Similarly, it has been associated with other chronic diseases, such as diabetes [10] and cancer [11], further strengthening the pathological implications of this microbiota metabolite.”
BackgroundTrimethylamine- N -Oxide: Friend, Foe, or Simply Caught in the Cross-Fire?
Cho, C. E., & Caudill, M. A. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.10.005 · Cited by 218 · see citing works
Vernetti, L. A., Gough, A., Baetz, N. W., Blutt, S. E., Broughman, J. R., Brown, J. A., Foulke-Abel, J. D., Hasan, N. M., In, J., Kelly, E. J., et al. (2017) · Scientific Reports · doi:10.1038/srep44517 · Cited by 189 · see citing works
Trimethylamine <i>N</i> ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease
Senthong, V., Wang, Z., Fan, Y., Wu, Y., Hazen, S. L., & Tang, W. H. W. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.004237 · Cited by 175 · see citing works
Trimethylamine N-oxide and Risk Stratification after Acute Myocardial Infarction
Suzuki, T., Heaney, L. M., Jones, D. J. L., & Ng, L. L. (2016) · Clinical Chemistry · doi:10.1373/clinchem.2016.264853 · Cited by 144 · see citing works
Fu, Q., Zhao, M., Wang, D., Hu, H., Guo, C., Chen, W., Li, Q., Zheng, L., & Chen, B. (2016) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2016.07.071 · Cited by 76 · cited 1× · see citing works
“TMAO has been recently proposed as a novel prognostic marker of cardiovascular events, given the association of its plasma levels with indexes of atherosclerotic plaque vulnerability [8], major cardiac events [5], and death [9].”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Gut microbiota-derived metabolites as key actors in inflammatory bowel disease
Lavelle, A., & Sokol, H. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0258-z · Cited by 2,015 · see citing works
The gut-liver axis and the intersection with the microbiome
Tripathi, A., Debelius, J., Brenner, D. A., Karin, M., Loomba, R., Schnabl, B., & Knight, R. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0011-z · Cited by 1,480 · see citing works
Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health
Parker, A., Fonseca, S., & Carding, S. R. (2019) · Gut Microbes · doi:10.1080/19490976.2019.1638722 · Cited by 722 · see citing works
Janeiro, M., Ramírez, M., Milagro, F., Martínez, J., & Solas, M. (2018) · Nutrients · doi:10.3390/nu10101398 · Cited by 631 · see citing works
The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease
Vogt, N. M., Romano, K. A., Darst, B. F., Engelman, C. D., Johnson, S. C., Carlsson, C. M., Asthana, S., Blennow, K., Zetterberg, H., Bendlin, B. B., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0451-2 · Cited by 471 · see citing works
Feeding gut microbes to nourish the brain: unravelling the diet–microbiota–gut–brain axis
Schneider, E., O'Riordan, K. J., Clarke, G., & Cryan, J. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01108-6 · Cited by 258 · see citing works
“Studies have identified TMAO in the cerebrospinal fluid of both mice and humans, suggesting that circulating TMAO can influence the CNS 191 .”
InfluentialUnhealthy gut, unhealthy brain: The role of the intestinal microbiota in neurodegenerative diseases
Spielman, L. J., Gibson, D. L., & Klegeris, A. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.08.005 · Cited by 266 · see citing works
Gut Microbiota and Their Metabolites in Stroke: A Double-Edged Sword
Peh, A., O’Donnell, J. A., Broughton, B. R. S., & Marques, F. Z. (2022) · Stroke · doi:10.1161/strokeaha.121.036800 · Cited by 259 · see citing works
The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease
Tran, S. M.-S., & Mohajeri, M. H. (2021) · Nutrients · doi:10.3390/nu13030732 · Cited by 207 · see citing works
“Recent studies have detected TMAO in human cerebrospinal fluid (CSF), thus establishing its presence in the brain beyond the cerebrovascular system [188,189].”
BackgroundMicrobial-derived metabolites as a risk factor of age-related cognitive decline and dementia
Connell, E., Le Gall, G., Pontifex, M. G., Sami, S., Cryan, J. F., Clarke, G., Müller, M., & Vauzour, D. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00548-6 · Cited by 208 · see citing works
“TMAO and the brain In vivo studies have identified TMAO in the CSF of both mice and humans, implying that circulating TMAO can influence the CNS [147, 150].”
BackgroundBrunt, 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. (2021) · GeroScience · doi:10.1007/s11357-020-00257-2 · Cited by 197 · see citing works
Metabolome analysis for investigating host-gut microbiota interactions
Chen, M. X., Wang, S., Kuo, C., & Tsai, I. (2018) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2018.09.007 · Cited by 194 · see citing works
Implications of Gut Microbiota in Neurodegenerative Diseases
Zhang, H., Chen, Y., Wang, Z., Xie, G., Liu, M., Yuan, B., Chai, H., Wang, W., & Cheng, P. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.785644 · Cited by 157 · see citing works
Organ-on-chip in development: Towards a roadmap for organs-on-chip
partners, T. O., Mastrangeli, M., Millet, S., & Raaij, J. V. D. E. (2019) · ALTEX · doi:10.14573/altex.1908271 · Cited by 116 · see citing works
Microbiota–gut–brain axis: interplay between microbiota, barrier function and lymphatic system
Zhuang, M., Zhang, X., & Cai, J. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2387800 · Cited by 127 · see citing works
“73 Furthermore, certain strains of Lactobacillus and Bifidobacterium genera meta-bolize glutamate, the principal free amino acid and excitatory neurotransmitter in the brain, to yield γ-aminobutyric acid, a prominent inhibitory neurotransmitter.”
BackgroundBoundaries and integration between microbiota, the nervous system, and immunity
Macpherson, A. J., Pachnis, V., & Prinz, M. (2023) · Immunity · doi:10.1016/j.immuni.2023.07.011 · Cited by 117 · see citing works
Praveenraj, S. S., Sonali, S., Anand, N., Hediyal, T. A., Vichitra, C., Kalyan, M., Kanna, P. V., Chandana, K. A., Paneyala, S., Mahalakshmi, A. M., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02990-5 · Cited by 112 · see citing works
“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 * Meena Kishore Sakharkar meena.sakharkar@usask.ca * Saravana Babu Chidambaram babupublications@gmail.com 1 Department of Pharmacology, JSS College…”
BackgroundInfluentialYlilauri, M. P., Voutilainen, S., Lönnroos, E., Virtanen, H. E., Tuomainen, T., Salonen, J. T., & Virtanen, J. K. (2019) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz148 · Cited by 106 · 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
Du, D., Tang, W., Zhou, C., Sun, X., Wei, Z., Zhong, J., & Huang, Z. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/5816837 · Cited by 103 · see citing works
“Serum TMAO can cross the blood-brain barrier and lead to oxidative stress, causing damage in the brain [67, 68].”
BackgroundMetabolomics analysis of microbiota-gut-brain axis in neurodegenerative and psychiatric diseases
Konjevod, M., Perković, M. N., Sáiz, J., Štrac, D. Š., Barbas, C., & Rojo, D. (2020) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2020.113681 · Cited by 95 · see citing works
Medicinal Chemistry of Drugs with N-Oxide Functionalities
Kobus, M., Friedrich, T., Zorn, E., Burmeister, N., & Maison, W. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00254 · Cited by 84 · see citing works
Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health
Caradonna, E., Abate, F., Schiano, E., Paparella, F., Ferrara, F., Vanoli, E., Difruscolo, R., Goffredo, V. M., Amato, B., Setacci, C., et al. (2025) · Metabolites · doi:10.3390/metabo15040220 · Cited by 88 · see citing works
“At physiological levels (0.11 to 6.45 µ mol/L) [125], TMAO contributes to BBB stabilization and protection by promoting protein folding and hydration [126].”
InfluentialPreventive Role of L-Carnitine and Balanced Diet in Alzheimer’s Disease
Kępka, A., Ochocińska, A., Borzym‐Κluczyk, M., Skorupa, E., Stasiewicz‐Jarocka, B., Chojnowska, S., & Waszkiewicz, N. (2020) · Nutrients · doi:10.3390/nu12071987 · Cited by 77 · see citing works
“In a small tested groups of subjects, TMAO levels in the CSF were apparently unrelated to the diagnosis of neurological disorders such as AD [58].”
BackgroundInfluentialGut 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
Probiotics: Protecting Our Health from the Gut
Varela-Trinidad, G. U., Domínguez-Díaz, C., Solórzano-Castanedo, K., Íñiguez-Gutiérrez, L., Hernández-Flores, T. D. J., & Fafutis‐Morris, M. (2022) · Microorganisms · doi:10.3390/microorganisms10071428 · Cited by 78 · see citing works
“In animal models, changes in GM induced by endotoxin administration in C57BL/6J mice have been shown to promote Aβ production in the brain and also cause BBB dysregulation and cognitive decline in mice [51,52].”
BackgroundInfluentialChen, S., & Lin, C. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00839-6 · Cited by 81 · see citing works
Wasén, C., Beauchamp, L. C., Vincentini, J., Li, S., LeServe, D. S., Gauthier, C. D., Lopes, J. R., Moreira, T. G., Ekwudo, M. N., Yin, Z., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47683-w · Cited by 75 · see citing works
“Studies have shownthatbacterialmetabolitesthatoriginatefrombacteriainthegut can be found in cerebrospinal fl uid 40 and bacterial outer-membrane vesicles has been found in the brains of mice 42 .”
Ilyas, A., Wijayasinghe, Y. S., Khan, I., Samaloty, N. M. E., Adnan, M., Dar, T. A., Poddar, N. K., Singh, L. R., Sharma, H., & Khan, S. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.964624 · Cited by 71 · see citing works
The Brain–Gut Axis, an Important Player in Alzheimer and Parkinson Disease: A Narrative Review
Caradonna, E., Nemni, R., Bifone, A., Gandolfo, P., Costantino, L., Giordano, L., Mormone, E., Macula, A., Cuomo, M., Difruscolo, R., et al. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13144130 · Cited by 75 · see citing works
“The TMAO physiological values in cerebrospinal fluid range between 0.11 and 6.45 mol/L, and it appears to exert a stabilizing and protective action on the blood–brain barrier within these parameters [82].”
BackgroundInfluentialPublisher Correction: The gut–liver axis and the intersection with the microbiome
Tripathi, A., Debelius, J., Brenner, D. A., Karin, M., Loomba, R., Schnabl, B., & Knight, R. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0031-8 · Cited by 68 · see citing works
Meng, F., Li, N., Li, D., Song, B., & Li, L. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.111902 · Cited by 67 · see citing works
Mudimela, S., Vishwanath, N. K., Pillai, A., Morales, R., Marrelli, S. P., Barichello, T., & Giridharan, V. V. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.08.002 · Cited by 70 · see citing works
Yuan, J., Liu, X., Liu, C., Ang, A. F., Massaro, J., Devine, S. A., Auerbach, S. H., Blusztajn, J. K., Au, R., & Jacques, P. F. (2022) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqac193 · Cited by 61 · see citing works
Balancing the Equation: A Natural History of Trimethylamine and Trimethylamine-N-oxide
Loo, R. L., Chan, Q. M., Nicholson, J. K., & Holmes, E. C. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00851 · Cited by 60 · see citing works
Gut inflammation associated with age and Alzheimer’s disease pathology: a human cohort study
Heston, M. B., Hanslik, K. L., Zarbock, K. R., Harding, S. J., Davenport‐Sis, N. J., Kerby, R. L., Chin, N. A., Sun, Y., Hoeft, A., Deming, Y. K., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-45929-z · Cited by 64 · see citing works
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
The role of trimethylamine‐N‐Oxide in the development of Alzheimer's disease
Buawangpong, N., Pinyopornpanish, K., Siri‐Angkul, N., Chattipakorn, N., & Chattipakorn, S. C. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30646 · Cited by 58 · see citing works
Li, M., Guo, W., Dong, Y., Wang, W., Tian, C., Zhang, Z., Yu, T., Zhou, H., Yang, G., Xue, K., et al. (2022) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2022.05.002 · Cited by 58 · see citing works
Gut Microbiota and Neuroplasticity
Murciano-Brea, J., García-Montes, M. E., Geuna, S., & Herrera‐Rincon, C. (2021) · Cells · doi:10.3390/cells10082084 · Cited by 59 · see citing works
The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases
Ghezzi, L., Cantoni, C., Rotondo, E., & Galimberti, D. (2022) · Biomedicines · doi:10.3390/biomedicines10071486 · Cited by 58 · see citing works
“Besides acting locally, gut-derived metabolites can penetrate the CNS [108].”
BackgroundRiccio, P., & Rossano, R. (2019) · Nutrients · doi:10.3390/nu11112714 · Cited by 56 · see citing works
“TMAO may be associated with cardiovascular events [75], may also be present in human cerebrospinal fluid [76] and is elevated in Alzheimer’s disease [77].”
BackgroundAlzheimer’s disease and gut microbiota: does trimethylamine N-oxide (TMAO) play a role?
Arrona Cardoza, P., Spillane, M. B., & Morales Marroquin, E. (2022) · Nutrition Reviews · doi:10.1093/nutrit/nuab022 · Cited by 53 · see citing works
The gut microbiota is an emerging target for improving brain health during ageing
Boehme, M., Guzzetta, K. E., Wasén, C., & Cox, L. M. (2022) · Gut Microbiome · doi:10.1017/gmb.2022.11 · Cited by 56 · see citing works
“metabolite trimethylamine-N-oxide has been measured in human cerebrospinal fluid (Rio et al., 2017).”
Potential Role of L-Carnitine in Autism Spectrum Disorder
Kępka, A., Ochocińska, A., Chojnowska, S., Borzym‐Κluczyk, M., Skorupa, E., Knaś, M., & Waszkiewicz, N. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10061202 · Cited by 53 · see citing works
“In the small tested groups of subjects, TMNO levels in CSF were apparently unrelated to the diagnosed neurological disorders such as Alzheimer’s disease (AD) [60].”
BackgroundVascularized human brain organoid on-chip
Tan, S. Y., Feng, X., Cheng, L. K., & Wu, A. R. (2023) · Lab on a Chip · doi:10.1039/d2lc01109c · Cited by 52 · see citing works
Geerts, H., Wikswo, J. P., van der Graaf, P. H., Bai, J. P. F., Gaiteri, C., Bennett, D. A., Swalley, S. E., Schuck, E. L., Kaddurah‐Daouk, R., Tsaioun, K., et al. (2019) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12478 · Cited by 49 · see citing works
“systems might contribute to this understanding, it has been recently shown in vitro that a microbial metabolite trimethylamine, metabolized by the liver into trimethylamine-N-oxide, can transfer across the BBB,(128) which was subsequently confirmed with in vivo measurements of human CSF.(129)”
BackgroundDevelopmental Signatures of Microbiota-Derived Metabolites in the Mouse Brain
Swann, J. R., Spitzer, S. O., & Heijtz, R. D. (2020) · Metabolites · doi:10.3390/metabo10050172 · Cited by 52 · see citing works
Effects of gut microbiota on neurodegenerative diseases
Khatoon, S., Kalam, N., Rashid, S., & Bano, G. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1145241 · Cited by 51 · see citing works
Psychobiotics and the Microbiota–Gut–Brain Axis: Where Do We Go from Here?
Binda, S., Tremblay, A., Iqbal, U., Kassem, O., Barz, M. L., Thomas, V., Bronner, S., Perrot, T. S., Ismail, N., & Parker, J. A. (2024) · Microorganisms · doi:10.3390/microorganisms12040634 · Cited by 57 · see citing works
“Trimethylamine-n-oxide (TMAO), derived from the TMA produced by gut bacteria, has been also associated with NDDs. Del Rio et al. revealed the ability of this proinflammatory marker to cross the BBB as it was found in the cerebrospinal fluid of AD patients [54].”
BackgroundGut microbial metabolism in Alzheimer's disease and related dementias
Kang, J. W., Vemuganti, V., Kuehn, J. F., Ulland, T. K., Rey, F. E., & Bendlin, B. B. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00470 · Cited by 49 · see citing works
Deng, Y., Zou, J., Hong, Y., Peng, Q., Fu, X., Duan, R., Chen, J., & Chen, X. (2022) · Cells · doi:10.3390/cells11223650 · Cited by 48 · see citing works
Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias
Yassine, H. N., Self, W. K., Kerman, B. E., Santoni, G., Shanmugam, N. K. N., Abdullah, L. I., Golden, L. R., Fonteh, A. N., Harrington, M. G., Gräff, J., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12845 · Cited by 49 · see citing works
“151 TMAO also promotes vascular aging as well as impairment of mitochondrial function and increased oxidative stress.”
Zhao, L., Zhang, C., Cao, G., Dong, X., Li, D., & Jiang, L. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02868-4 · Cited by 46 · see citing works
Yadav, H., Jaldhi, Bhardwaj, R., Anamika, A., Bakshi, A., Gupta, S., & Maurya, S. K. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122022 · Cited by 46 · see citing works
Meinitzer, S., Baranyi, A., Holasek, S. J., Schnedl, W. J., Zelzer, S., Mangge, H., Herrmann, M., Meinitzer, A., & Enko, D. (2020) · Disease Markers · doi:10.1155/2020/7897240 · Cited by 44 · see citing works
“Since TMAO was shown to be present in human cerebrospinal fluid [24], it is hypothesized that TMAO could have the potential to cross the BBB [25].”
BackgroundGut microbial metabolite TMAO portends prognosis in acute ischemic stroke
Zhang, J., Wang, L., Cai, J., Lei, A., Liu, C., Lin, R., Li, J., & Fu, Y. (2021) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2021.577526 · Cited by 44 · see citing works
Nicolas, S., Dohm-Hansen, S., Lavelle, A., Bastiaanssen, T. F. S., English, J. A., Cryan, J. F., & Nolan, Y. M. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02904-0 · Cited by 47 · see citing works
Qiao, C.-M., Quan, W., Zhou, Y., Niu, G.-Y., Hong, H., Wu, J., Zhao, L.-P., Li, T., Cui, C., Zhao, W.-J., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03392-x · Cited by 45 · see citing works
Liu, G., Cheng, J., Zhang, T., Shao, Y., Chen, X., Han, L., Zhou, R., & Wu, B. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.856914 · Cited by 42 · see citing works
“TMAO can rapidly cross the blood–brain barrier (BBB) (Del Rio et al., 2017).”
BackgroundThe gut–immune axis during hypertension and cardiovascular diseases
Dinakis, E., O’Donnell, J. A., & Marques, F. Z. (2024) · Acta Physiologica · doi:10.1111/apha.14193 · Cited by 45 · see citing works
“Specifically, SCFAs are able to penetrate through the gut mucosal layer into the bloodstream and cross the BBB. 187 SCFAs exert physiological effects on the central nervous system primarily through receptor-mediated interactions.”
Role of metabolites derived from gut microbiota in inflammatory bowel disease
Zheng, L., Wen, X., & Duan, S.-L. (2022) · World Journal of Clinical Cases · doi:10.12998/wjcc.v10.i9.2660 · Cited by 43 · see citing works
Prajapati, S. K., Shah, R., Alford, N., Mishra, S. P., Jain, S., HANSEN, B. C., Sanberg, P. R., Molina, A. J. A., & Yadav, H. (2023) · The Journals of Gerontology Series A · doi:10.1093/gerona/glad226 · Cited by 42 · see citing works
Krueger, E. S., Lloyd, T. S., & Tessem, J. S. (2021) · Nutrients · doi:10.3390/nu13082873 · Cited by 40 · see citing works
Gut Microbiota at the Intersection of Alcohol, Brain, and the Liver
Gupta, H., Suk, K. T., & Kim, D. J. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10030541 · Cited by 40 · see citing works
“Additionally, liver overload with toxic metabolites leads to an increase in systemic load that reaches the brain via BBB alteration causing toxicity to brain cells [110].”
BackgroundInfluentialThe Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration
Borbolis, F., Mytilinaiou, E., & Palikaras, K. (2023) · Cells · doi:10.3390/cells12030429 · Cited by 39 · see citing works
Zhang, S., Jin, M., Ren, J., Sun, X., Zhang, Z., Luo, Y., & Sun, X. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114559 · Cited by 40 · see citing works
Bresciani, L., Dall’Asta, M., Favari, C., Calani, L., Rio, D. D., & Brighenti, F. (2018) · Food & Function · doi:10.1039/c8fo01778f · Cited by 38 · see citing works
Self-citationLi, C., Zhu, L., Dai, Y., Zhang, Z., Huang, L., Wang, T. J., Fu, P., Li, Y., Wang, J., & Jiang, C. Q. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/1599747 · Cited by 37 · see citing works
“Although the current understanding of TMAO’s role in the CNS is limited, evidence indicates that TMAO, a small organic molecule, could penetrate the blood-brain barrier (BBB) [69].”
Gut Microbiota Targeted Approach in the Management of Chronic Liver Diseases
Liu, J., Yang, D., Wang, X., Asare, P. T., Zhang, Q., Na, L., & Shao, L. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.774335 · Cited by 38 · see citing works
Hawkins, K. G., Casolaro, T. C., Brown, J. A., Edwards, D. A., & Wikswo, J. P. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1870 · Cited by 34 · see citing works
Wang, Q., Davis, P. B., Qi, X., Chen, S. G., Gurney, M. E., Perry, G. L., Doraiswamy, P. M., & Xu, R. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00917-1 · Cited by 35 · see citing works
Cracking Brain Diseases from Gut Microbes-Mediated Metabolites for Precise Treatment
Gong, Y., Chen, A., Zhang, G., Shen, Q., Zou, L., Li, J., Miao, Y., & Liu, W. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.85259 · Cited by 33 · see citing works
“Lumbar punctures were performed on 58 patients with different neurological disorders to obtain cerebrospinal fluid, which demonstrated that TMAO could be evaluated in cerebrospinal fluid, but its pathophysiological role in the central nervous system needs further study [39].”
BackgroundUceda, 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
“Moreover, the presence of TMAO in this fluid demonstrates that this metabolite has the capacity to reach the CNS and, therefore, could affect its function [71].”
BackgroundZhang, Q., Guo, X., Xie, C., Cao, Z., Wang, X., Liu, L., & Yang, P. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105884 · Cited by 33 · see citing works
Current Alzheimer disease research highlights: evidence for novel risk factors
Brenowitz, W. D., Xiang, Y., McEvoy, C. T., Yang, C., Yaffe, K. S., Le, W., & Leng, Y. (2021) · Chinese Medical Journal · doi:10.1097/cm9.0000000000001706 · Cited by 32 · see citing works
Gut microbiota–astrocyte axis: new insights into age-related cognitive decline
Zhang, L., Wei, J., Liu, X., Li, D., Pang, X., Chen, F., Cao, H., & Lei, P. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01776 · Cited by 28 · see citing works
“…be detected in human cerebrospinal fluid, and the key enzyme (FMO3) that converts TMA into TMAO is not expressed in the adult brain, indicating that TMAO could cross the BBB to play some role in the CNS (Janmohamed et al., 2004; Zhang and Cashman, 2006; Del Rio et al., 2017; Vogt et al., 2018).”
BackgroundResultBragazzi, N. L., Rio, D. D., Mayer, E. A., & Mena, P. R. (2024) · Advances in Nutrition · doi:10.1016/j.advnut.2024.100280 · Cited by 27 · see citing works
“…cardiovascular disease risk: red meat is rich in L -carnitine, transformed by the gut microbiome into tri-methylamine and metabolized by hepatic fl avin-containing-monooxygenase-3 into trimethylamine-N -oxide (TMAO), which has been shown to favor atherosclerosis in murine models [53, 54].”
BackgroundMechanisms by which microbiome-derived metabolites exert their impacts on neurodegeneration
Kern, L., Mastandrea, I., Melekhova, A., & Elinav, E. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.08.014 · Cited by 26 · see citing works
Trimethylamine N-oxide—a marker for atherosclerotic vascular disease
Xie, G., An, Y., Lin, P., Wang, Y., & Guo, L. (2021) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2203085 · Cited by 27 · see citing works
“TMAO can cross the blood-brain barrier and cause oxidative stress, thus potentially leading to brain damage [93, 94].”
BackgroundThe connection between gut microbiota and its metabolites with neurodegenerative diseases in humans
Fabi, J. P. (2024) · Metabolic Brain Disease · doi:10.1007/s11011-024-01369-w · Cited by 25 · see citing works
Tackling Current Biomedical Challenges With Frontier Biofabrication and Organ-On-A-Chip Technologies
Celikkin, N., Presutti, D., Maiullari, F., Fornetti, E., Agarwal, T., Paradiso, A., Volpi, M., Święszkowski, W., Bearzi, C., Barbetta, A., et al. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.732130 · Cited by 26 · see citing works
Obrenovich, M. E., Tabrez, S. S. M., Siddiqui, B., McCloskey, B., & Perry, G. L. (2020) · Microorganisms · doi:10.3390/microorganisms8040493 · Cited by 24 · see citing works
Gut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke
Li, Z., He, X., Fang, Q., & Yin, X. (2024) · Biomolecules · doi:10.3390/biom14111463 · Cited by 26 · see citing works
“Importantly, gut-microbiota-derived TMAO in the peripheral circulation can cross the blood–brain barrier, directly activate nerve cells, and modulate neuroinflammation, thus playing roles in a variety of neurological disease mechanisms [23,24].”
Baranyi, A., Enko, D., von Lewinski, D., Rothenhäusler, H., Amouzadeh-Ghadikolai, O., Harpf, H. H., Harpf, L., Traninger, H., Obermayer-Pietsch, B. M., Schweinzer, M., et al. (2021) · European Journal of Psychotraumatology · doi:10.1080/20008198.2021.1920201 · Cited by 24 · see citing works
Chen, X., Gu, M., Hong, Y., Duan, R., & Zhou, J. (2022) · Brain Sciences · doi:10.3390/brainsci12091203 · Cited by 23 · see citing works
“The presence of TMAO in the CSF might be hepatic-derived, as TMAO could cross the BBB [30], and high amounts of circulating TMAO might be linked to BBB disruption in vivo [31], yet de novo synthesis of TMAO could also be possible since FMO3 has been detected in the adult brain [32].”
BackgroundResultInfluentialGut Microbiome and the Role of Metabolites in the Study of Graves’ Disease
Liu, H., Liu, H., Liu, C., Shang, M., Wei, T., & Yin, P. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.841223 · Cited by 23 · see citing works
Gut Microbiota as a Hidden Player in the Pathogenesis of Alzheimer’s Disease
Choi, H., Lee, D., & Mook‐Jung, I. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215235 · Cited by 23 · see citing works
“The ability of gut metabolites to reach the CNS was confirmed by the detection of these metabolites in cerebrospinal fluid (CSF) [56].”
Zarbock, K. R., Han, J. H., Singh, A. P., Thomas, S. P., Bendlin, B. B., Denu, J. M., Yu, J. J., Rey, F. E., & Ulland, T. K. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220413 · Cited by 23 · see citing works
“This metabolite then enters vascular circulation – where it is detected at micromolar concentrations – eventually reaches the brain, and is cleared from the body primarily via the kidneys [9-10].”
BackgroundGut-Brain Axis and its Neuro-Psychiatric Effects: A Narrative Review
Shaik, L., Kashyap, R., Thotamgari, S. R., Singh, R., & Khanna, S. (2020) · Cureus · doi:10.7759/cureus.11131 · Cited by 22 · see citing works
The Role of the Gut Microbiota and Microbial Metabolites in the Pathogenesis of Alzheimer’s Disease
Wang, Y. (2022) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527321666220417005115 · Cited by 21 · see citing works
Relationship between Excreted Uremic Toxins and Degree of Disorder of Children with ASD
Osredkar, J., Gantar, B. Ž. B., Finderle, P., Bobrowska‐Korczak, B., Gątarek, P., Rosiak, A., Giebułtowicz, J., Vrhovšek, M. J., & Kałużna‐Czaplińska, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087078 · Cited by 19 · see citing works
You-on-a-chip’ for precision medicine
Low, L. A., & Tagle, D. A. (2018) · Expert Review of Precision Medicine and Drug Development · doi:10.1080/23808993.2018.1456333 · Cited by 18 · see citing works
“For example, recent work by Vernetti et al. [55] used multiple organ systems coupled through their media to predict the presence of trimethylamine-N-oxide, created in the gut, metabolized in the liver and later crossing the BBB and appearing inside the brain (which was subsequently confirmed from measurements in patie…”
MethodGetting on in Old Age: How the Gut Microbiota Interferes With Brain Innate Immunity
Mossad, O., & Blank, T. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.698126 · Cited by 18 · see citing works
“Since TMAO is found in the brain it is most likely able to cross the BBB (Del Rio et al., 2017).”
BackgroundTrimethylamine N-Oxide as a Mediator Linking Peripheral to Central Inflammation: An In Vitro Study
Janeiro, M. H., Solas, M., Orbe, J., Rodríguez, J. A., de Muniain, L. S., Escalada, P., Yip, P. K., & Ramírez, M. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417557 · Cited by 18 · see citing works
“…and on the concentration of TMAO used in vitro experiments in the literature for other cell lines [7,9,10,16,21,27,39,40], all of our experiments included the concentration of 200 µ M because recent epidemiological studies have shown that TMAO in plasma ranges widely from 0.08 to 250 µ M [41].”
MethodInfluentialPerspective on the Application of Microphysiological Systems to Drug Transporter Studies
Caetano-Pinto, P., & Stahl, S. H. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.118.082750 · Cited by 18 · see citing works
Zhang, Y., Zhang, C., Li, H., & Hou, J. (2019) · Inflammation · doi:10.1007/s10753-019-01090-2 · Cited by 17 · see citing works
Enko, D., Zelzer, S., Niedrist, T., Holasek, S. J., Baranyi, A., Schnedl, W. J., Herrmann, M., & Meinitzer, A. (2020) · EXCLI journal · doi:10.17179/excli2020-2763 · Cited by 17 · see citing works
TMAO 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
Wu, B., Liu, Y., Li, H., Zhu, L., Zeng, L., Zhang, Z., & Peng, W. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.391305 · Cited by 20 · see citing works
“Del Rio et al. (2017) determined the presence of TMAO in the CSF of patients with dementia and found that circulating TMAO can cross the BBB to reach the CNS. Optimal physiological concentrations of TMAO enhance the integrity of the BBB and protect it from inflammatory insults.”
Background
- Authors
- Del Rio, D., Zimetti, F., Caffarra, P., Tassotti, M., Bernini, F., Brighenti, F., Zini, A., & Zanotti, I.
- Affiliations
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
- University of Parma (IT)
- Azienda Ospedaliero-Universitaria di Modena (IT)
- Corresponding author
- Zanotti, Ilaria
- ORCID
- Venue
- Nutrients
- Publisher
- MDPI AG
- Published
- 2017-09-22
- Volume
- 9
- Issue
- 10
- Pages
- 1053
- ISSN
- 2072-6643 (ISSN-L)
- PMC
- PMC5691670
- OpenAlex
- W2759635061
- Cited by
- 172
- References
- 15
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 28 · 2023: 23 · 2022: 32 · 2021: 26 · 2020: 14 · 2019: 10 · 2018: 11
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nutrients (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Università degli Studi di Parma (FIL 2014)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- trimethylamine N-oxide, cerebrospinal fluid, gut microbiota metabolites, choline metabolism, carnitine metabolism, Alzheimer's disease, dementia, neurological disorders, central nervous system, biomarkers
- MeSH terms
- Gastrointestinal Microbiome, Aged, Aged, 80 and over, Alzheimer Disease, Bacteria, Chromatography, Liquid, Dementia, Female, Humans, Intestines, Male, Methylamines, Middle Aged, Predictive Value of Tests, Mass Spectrometry, Spinal Puncture
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
