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

Lesley Hoyles, Matthew G. Pontifex, Ildefonso Rodriguez-Ramiro, M. Areeb Anis-Alavi, Khadija S. Jelane, Tom Snelling, Egle Solito, Sonia Fonseca, Ana L. Carvalho, Simon R. Carding, Michael Müller, Robert C. Glen, David Vauzour, Simon McArthur

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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.
Original languageEnglish
Article number235
JournalMicrobiome
Volume9
Issue number1
DOIs
Publication statusPublished - 27 Nov 2021

Keywords

  • Blood–brain barrier
  • Cognition
  • Trimethylamine
  • Trimethylamine N-oxide

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