5-(Hydroxyphenyl)-y-valerolactone-sulfate, a key microbial metabolite of flavan-3-ols, is able to reach the brain: evidence from different in silico, in vitro and in vivo experimental models

Authors: ANGELINO, DONATO - University Of Parma; CARREGORA, DIOGO - Universidade Nova De Lisboa; DOMENECH-COCA, CRISTINA - Collaborator; SAVI, MONIA - University Of Parma; FIGUEIRA, INES - Instituto De Tecnologia Quimica E Biologica; BRINDANI, NICOLETTA - University Of Parma; JANG, SAEBYEOL - Former ARS Employee; Lakshman, Sukla; Molokin, Aleksey; Urban, Joseph; DAVIES, CINDY - National Cancer Institute (NCI, NIH); BRITTO, M - National Institute On Aging (NIA, NIH); KIM, K - University Of Parma; BRIGHENTI, FURIO - University Of Parma; CURTI, CLAUDIO - University Of Parma; BLADE, CINTA - University Rovira I Virgili; DEL BAS, JOSEP - University Rovira I Virgili; STILLI, DONATELLA - University Of Parma; Solano-Aguilar, Gloria; NUNES DEL SANTOS, CLAUDIA - Universidade Nova De Lisboa; DEL RIO, DANIELE - University Of Parma; MENA, PEDRO - University Of Parma

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/24/2019
Publication Date: 11/5/2019
Citation: Angelino, D., Carregora, D., Domenech-Coca, C., Savi, M., Figueira, I., Brindani, N., Jang, S., Lakshman, S., Molokin, A., Urban Jr, J.F., Davies, C.D., Britto, M.A., Kim, K.S., Brighenti, F., Curti, C., Blade, C., Del Bas, J.M., Stilli, D., Solano Aguilar, G., Nunes Del Santos, C., Del Rio, D., Mena, P. 2019. 5-(Hydroxyphenyl)-y-valerolactone-sulfate, a key microbial metabolite of flavan-3-ols, is able to reach the brain: evidence from different in silico, in vitro and in vivo experimental models. Nutrients. 11(11). pii: E2678. https://doi.org/10.3390/nu11112678.
DOI: https://doi.org/10.3390/nu11112678

Interpretive Summary: Phenolic compounds have been recognized as promising compounds for the prevention of chronic diseases, including neurodegenerative ones. However, certain phenolics (ie. flavan-3-ols (F3O) are poorly absorbed along the gastrointestinal tract and need to be modified by host intestinal microbiota to produce smaller and more polar metabolites like phenyl--valerolactones, phenylvaleric acids and their conjugates. which can be absorbed. The present work investigated the ability of phenolic compounds like F3O-derived metabolites to cross the blood-brain barrier (BBB) using five experimental in vitro and in vivo models. First, an in silico study examined the physical-chemical characteristics of F3O metabolites to predict those who most likely will cross the BBB. Some of these candidates' metabolites were then tested at physiological concentrations to cross the luminal and abluminal membranes of brain microvascular endothelial cells, cultured in vitro. Finally, three different in vivo studies in rats injected with pure 5-(3',4'-dihydroxyphenyl)--valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)--valerolactone-sulfate (3',4' isomer) in the brain. This work highlighted, using different experimental models, the BBB permeability of one of the main F3O-derived metabolites. This information is helpful to support the neuroprotective effects of phenolic-rich foods.

Technical Abstract: Phenolic compounds have been recognized as promising compounds for the prevention of chronic diseases, including neurodegenerative ones. However, phenolics like flavan-3-ols (F3O) are poorly absorbed along the gastrointestinal tract and structurally rearranged by gut microbiota, yielding smaller and more polar metabolites like phenyl--valerolactones, phenylvaleric acids and their conjugates. The present work investigated the ability of F3O-derived metabolites to cross the blood-brain barrier (BBB), by linking five experimental models with increasing realism. First, an in silico study examined the physical-chemical characteristics of F3O metabolites to predict those most likely to cross the BBB. Some of these metabolites were then tested at physiological concentrations to cross the luminal and abluminal membranes of brain microvascular endothelial cells, cultured in vitro. Finally, three different in vivo studies in rats injected with pure 5-(3',4'-dihydroxyphenyl)--valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)--valerolactone-sulfate (3',4' isomer) in the brain. This work highlighted, with different experimental models, the BBB permeability of one of the main F3O-derived metabolites. It may support the neuroprotective effects of phenolic-rich foods in the frame of the “gut-brain axis”.