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

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.

A host–gut microbial co-metabolite of aromatic amino acids, p-cresol glucuronide, promotes blood–brain barrier integrity in vivo

“…Sample sizes were calculated to detect differences of 15% or more with a power of 0.85 and α set at 5%, calculations being informed by previously published data [2,17]. Experimental data are expressed as mean ± SEM, with n = 6-9 independent experiments for all studies.…”

“…Processing of mouse brain samples (taken at 2 h) and RNA extraction were performed as described previously [2]. RNA samples (n=6 pCG, n=6 control) were sent to Macrogen Inc.…”

“…Three pCG-treated and three saline controls produced data of poor quality so were excluded from analyses after quality checks and consideration of Macrogen quality reports; as such, samples SG1, SG3, SG5, CG2, CG5 and CG6 were used for all analyses described from hereon. Raw RNAseq (fastq) sequence data were processed in house as described previously [2]. Entrez gene identifiers were converted to gene symbols using Mus musculus annotations downloaded from NCBI on 4 January 2021; only those genes with valid Entrez gene identifiers were retained in analyses.…”

“…That communication between the gut microbiota and the brain can occur is now well established, with increasing evidence indicating a central role for microbe-derived metabolites acting primarily through three routes: directly on enteric and gut extrinsic neural pathways, by modification of enteroendocrine signalling or, as we and others have shown, via the circulation and interactions with the blood-brain barrier (BBB) [1,2]. Notably, while many microbe-derived metabolites circulate in their native form, many others are subjected to host metabolic enzymemediated biotransformation, thereby altering their biological activities.…”

The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer’s Disease

“…Behavioural tests were performed as previously described [ 48 , 49 ] on mice aged to 14 months old. Objects and arenas were cleaned with 70% ( v/v ) ethanol in between each trial.…”