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

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 the...

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Autores principales: 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, Glen, Robert C., Vauzour, David, McArthur, Simon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626999/
https://www.ncbi.nlm.nih.gov/pubmed/34836554
http://dx.doi.org/10.1186/s40168-021-01181-z
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author 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
Glen, Robert C.
Vauzour, David
McArthur, Simon
author_facet 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
Glen, Robert C.
Vauzour, David
McArthur, Simon
author_sort Hoyles, Lesley
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01181-z.
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spelling pubmed-86269992021-11-30 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 Glen, Robert C. Vauzour, David McArthur, Simon Microbiome Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40168-021-01181-z. BioMed Central 2021-11-27 /pmc/articles/PMC8626999/ /pubmed/34836554 http://dx.doi.org/10.1186/s40168-021-01181-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
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
Glen, Robert C.
Vauzour, David
McArthur, Simon
Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
title Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
title_full Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
title_fullStr Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
title_full_unstemmed Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
title_short Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
title_sort regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine n-oxide
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626999/
https://www.ncbi.nlm.nih.gov/pubmed/34836554
http://dx.doi.org/10.1186/s40168-021-01181-z
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