Abstract
BackgroundCommunication 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.ResultsHere, 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.ConclusionOur findings demonstrate the mechanisms through which microbiome-associated methylamines directly interact with the mammalian BBB, with consequences for cerebrovascular and cognitive function.24wuPkhfjSm7S4zaEcHM79Video abstract
Highlights
As the role of the gut microbiota in host physiology and disease is categorised, novel pathways through which these interactions are mediated continue to emerge
To provide an initial assessment of the effects of the methylamines TMA and TMAO upon the blood-brain barrier (BBB) we used a well-established in vitro BBB model, hCMEC/ D3 immortalised human cerebromicrovascular cell monolayers grown under polarising conditions on a Transwell filter, examining two key barrier properties: paracellular permeability to a protein-sized tracer and transendothelial electrical resistance (TEER)
The actions of TMAO are mediated through annexin A1 signalling Of the four BBB-associated genes identified as upregulated by TMAO, ANXA1 is of particular interest as we have previously shown this protein to regulate BBB tightness in vitro and in vivo through modulation of the actin cytoskeleton [54]
Summary
As the role of the gut microbiota in host physiology and disease is categorised, novel pathways through which these interactions are mediated continue to emerge. SCFAs represent just one Dietary methylamines, such as choline, phosphatidylcholine, betaine and trimethylamine-N-oxide (TMAO), are a class of metabolites receiving considerable attention as modulators of vascular function [3, 4], the mechanism(s) by which they affect human physiology remain poorly understood. Communication between the gut microbiota and the brain is primarily mediated via soluble microbederived 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
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