Circulating (poly)phenol metabolites in the brain: unveiling in vitro and in vivo blood-brain barrier transport

Abstract

Circulating metabolites resulting from colonic metabolism of dietary (poly)phenols are highly abundant in the bloodstream, though still marginally explored, particularly concerning their brain accessibility. Our goal is to disclose (poly)phenol metabolites’ blood-brain barrier (BBB) transport,in vivoandin vitro, as well as their role at BBB level.For three selected metabolites, pyrogallol-O-sulfate (Pyr-sulf), phloroglucinol-O-sulfate (Phlo-sulf), and resorcinol-O-sulfate (Res-sulf), BBB transport was assessed in human brain microvascular endothelial cells (HBMEC). Their potential in modulatingin vitroBBB properties at circulating concentrations was also studied. Metabolites’ fate towards the brain, liver, kidney, urine, and blood was disclosed in Wistar rats upon injection.Transport kinetics in HBMEC highlighted different BBB permeability rates, where Pyr-sulf emerged as the mostin vitroBBB permeable metabolite. Pyr-sulf was also the most potent regarding BBB properties improvement, namely increased β-catenin membrane expression and reduction of zonula occludens-1 membrane gaps. Whereas no differences were observed for transferrin, increased expression of caveolin-1 upon Pyr-sulf and Res-sulf treatments was found. Pyr-sulf was also capable of modulating gene and protein expression of some solute carrier transporters. Notably, each of the injected metabolites exhibited a unique tissue distributionin vivo, with the remarkable ability to almost immediately reach the brain.