Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide

Hoyles, Lesley, Pontifex, Matthew G., 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:, Glen, Robert C., Vauzour, David ORCID: 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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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
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
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Depositing User: LivePure Connector
Date Deposited: 30 Nov 2021 01:43
Last Modified: 22 Oct 2022 16:31
DOI: 10.1186/s40168-021-01181-z

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