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

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Title: Regulation of blood brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
Authors: Hoyles, L
Pontifex, MG
Rodriguez-Ramiro, I
Anis-Alavi, MA
Jelane, KS
Snelling, T
Solito, E
Fonseca, S
Carvalho, AL
Carding, SR
Muller, M
Glen, RC
Vauzour, D
McArthur, S
Item Type: Journal Article
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.
Issue Date: 27-Nov-2021
Date of Acceptance: 18-Oct-2021
URI: http://hdl.handle.net/10044/1/92852
DOI: 10.1186/s40168-021-01181-z
ISSN: 2049-2618
Publisher: BioMed Central
Start Page: 1
End Page: 21
Journal / Book Title: Microbiome
Volume: 9
Issue: 1
Copyright Statement: © The Author(s). 2021 Open Access This 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/. The Creative Commons Public Domain Dedication waiver (http://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.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Alzheimer's Research UK
Funder's Grant Number: MR/L01632X/1
MR/L01632X/1
ARUK-PPG2016B-6
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Trimethylamine N-oxide
Trimethylamine
Blood-brain barrier
Cognition
ANNEXIN A1
TRANSGENIC MICE
DIETARY CHOLINE
FATTY-ACIDS
PERFORMANCE
DISRUPTION
METABOLITE
IDENTIFICATION
ACCUMULATION
INVOLVEMENT
Blood–brain barrier
Cognition
Trimethylamine
Trimethylamine N-oxide
Science & Technology
Life Sciences & Biomedicine
Microbiology
Trimethylamine N-oxide
Trimethylamine
Blood-brain barrier
Cognition
ANNEXIN A1
TRANSGENIC MICE
DIETARY CHOLINE
FATTY-ACIDS
PERFORMANCE
DISRUPTION
METABOLITE
IDENTIFICATION
ACCUMULATION
INVOLVEMENT
0602 Ecology
0605 Microbiology
1108 Medical Microbiology
Publication Status: Published
Open Access location: https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-021-01181-z
Article Number: ARTN 235
Online Publication Date: 2021-11-27
Appears in Collections:Department of Surgery and Cancer



This item is licensed under a Creative Commons License Creative Commons