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

Authors
Hoyles, Lesley 
Pontifex, Matthew G 
Rodriguez-Ramiro, Ildefonso 
Anis-Alavi, M Areeb 
Jelane, Khadija S 

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Article
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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. Video abstract.

Publication Date
2021-11-27
Online Publication Date
2021-11-27
Acceptance Date
2021-10-18
Keywords
Blood–brain barrier, Cognition, Trimethylamine, Trimethylamine N-oxide, Animals, Blood-Brain Barrier, Cognition, Mammals, Methylamines, Mice, Microbiota
Journal Title
Microbiome
Journal ISSN
2049-2618
2049-2618
Volume Title
9
Publisher
Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/L01632X/1)
Alzheimer's Research UK (ARUK-PPG2016B-6)
Solvo Biotechnology (ReACTS Program)
Imperial College London (Undergraduate Research Opportunities Programme)