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Hoyles, Lesley, Pontifex, Matthew G. 
ORCID: https://orcid.org/0000-0003-2174-2313, Rodriguez-Ramiro, Ildefonso, Anis-Alavi, M. Areeb, Jelane, Khadija S., Snelling, Tom, Solito, Egle, Fonseca, Sonia, Carvalho, Ana L., Carding, Simon R., Müller, Michael ORCID: https://orcid.org/0000-0002-5930-9905, Glen, Robert C., Vauzour, David ORCID: https://orcid.org/0000-0001-5952-8756 and McArthur, Simon
(2021)
Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide.
Microbiome, 9 (1).
ISSN 2049-2618
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Abstract
Background: Communication between the gut microbiota and the brain is primarily mediated via soluble microbe-derived metabolites, but the details of this pathway remain poorly defined. Methylamines produced by microbial metabolism of dietary choline and L-carnitine have received attention due to their proposed association with vascular disease, but their effects upon the cerebrovascular circulation have hitherto not been studied. Results: Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner. Conclusion: Our findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function.
| Item Type: | Article |
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| Additional Information: | Funding Information: This work was funded by Alzheimer’s Research UK Pilot Grant No. ARUK-PPG2016B-6. PREDEASY™ efflux transporter analysis kits were generously provided through the SOLVO Biotechnology Research and Academic Collaborative Transporter Studies (ReACTS) Program. This work used the computing resources of the UK MEDical BIOinformatics partnership—aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO), which was supported by the Medical Research Council (grant number MR/L01632X/1). SF was supported by Fundación Alfonso Martín Escudero. TS was supported by a bursary from the Imperial College London Undergraduate Research Opportunities Programme. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874583. This publication reflects only the authors’ view and the European Commission is not responsible for any use that may be made of the information it contains. |
| Uncontrolled Keywords: | blood–brain barrier,cognition,trimethylamine,trimethylamine n-oxide,microbiology,microbiology (medical) ,/dk/atira/pure/subjectarea/asjc/2400/2404 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
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| Depositing User: | LivePure Connector |
| Date Deposited: | 30 Nov 2021 01:43 |
| Last Modified: | 06 Jun 2024 15:17 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/82449 |
| DOI: | 10.1186/s40168-021-01181-z |
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