5-(Hydroxyphenyl)-γ-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

Donato Angelino, Diogo Carregosa, Cristina Domenech-Coca, Monia Savi, Inês Figueira, Nicoletta Brindani, Saebyeol Jang, Sukla Lakshman, Aleksey Molokin, Joseph F. Urban, Cindy D. Davis, Maria Alexandra Brito, Kwang Sik Kim, Furio Brighenti, Claudio Curti, Cinta Bladé, Josep M. Del Bas, Donatella Stilli, Gloria I. Solano-Aguilar, Claudia Nunes Dos SantosDaniele Del Rio, Pedro Mena

Research output: Contribution to journalArticle

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-γ-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)-γ-valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)-γ-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”.

Original languageEnglish (US)
Article number2678
JournalNutrients
Volume11
Issue number11
DOIs
StatePublished - Nov 2019

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Keywords

  • Blood brain barrier
  • Catechin
  • Flavan-3-ol
  • Gut
  • Metabolites
  • Neurodegenerative disease
  • Permeability
  • Polyphenols
  • Proanthocyanidin
  • Valerolactone

ASJC Scopus subject areas

  • Food Science
  • Nutrition and Dietetics

Cite this

Angelino, D., Carregosa, D., Domenech-Coca, C., Savi, M., Figueira, I., Brindani, N., Jang, S., Lakshman, S., Molokin, A., Urban, J. F., Davis, C. D., Brito, M. A., Kim, K. S., Brighenti, F., Curti, C., Bladé, C., Del Bas, J. M., Stilli, D., Solano-Aguilar, G. I., ... Mena, P. (2019). 5-(Hydroxyphenyl)-γ-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), [2678]. https://doi.org/10.3390/nu11112678