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

Microbiome

Lesley Hoyles¹  Robert C. Glen²  Tom Snelling²  M. Areeb Anis-Alavi³  Khadija S. Jelane³  Simon McArthur³  Michael Müller⁴  Ildefonso Rodriguez-Ramiro⁴  Matthew G. Pontifex⁴  Simon R. Carding⁴  David Vauzour⁴  Sonia Fonseca⁵  Ana L. Carvalho⁵  Egle Solito⁶ 

[1] Department of Biosciences, School of Science and Technology, Nottingham Trent University;Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London;Institute of Dentistry, Faculty of Medicine & Dentistry, Queen Mary University of London;Norwich Medical School, University of East Anglia;The Gut Microbes and Health Research Programme, The Quadram Institute;William Harvey Research Institute, Faculty of Medicine & Dentistry, Queen Mary University of London;

关键词: Trimethylamine N-oxide;    Trimethylamine;    Blood–brain barrier;    Cognition;   

DOI  :  10.1186/s40168-021-01181-z

来源: DOAJ

【 摘 要 】

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

【 授权许可】

Unknown