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 Santos & 2 others Daniele Del Rio, Pedro Mena

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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
Article number2678
JournalNutrients
Volume11
Issue number11
DOIs
Publication statusPublished - 1 Nov 2019

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flavanols
Blood-Brain Barrier
Computer Simulation
Sulfates
sulfates
Theoretical Models
blood-brain barrier
metabolites
brain
Brain
Vitis
Neuroprotective Agents
Gastrointestinal Tract
Permeability
Chronic Disease
Swine
Endothelial Cells
neuroprotective effect
rats
Food

Keywords

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

Cite this

Angelino, Donato ; Carregosa, Diogo ; Domenech-Coca, Cristina ; Savi, Monia ; Figueira, Inês ; Brindani, Nicoletta ; Jang, Saebyeol ; Lakshman, Sukla ; Molokin, Aleksey ; Urban, Joseph F. ; Davis, Cindy D. ; Brito, Maria Alexandra ; Kim, Kwang Sik ; Brighenti, Furio ; Curti, Claudio ; Bladé, Cinta ; Del Bas, Josep M. ; Stilli, Donatella ; Solano-Aguilar, Gloria I. ; Dos Santos, Claudia Nunes ; Del Rio, Daniele ; Mena, Pedro. / 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. In: Nutrients. 2019 ; Vol. 11, No. 11.
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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”.",
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author = "Donato Angelino and Diogo Carregosa and Cristina Domenech-Coca and Monia Savi and In{\^e}s Figueira and Nicoletta Brindani and Saebyeol Jang and Sukla Lakshman and Aleksey Molokin and Urban, {Joseph F.} and Davis, {Cindy D.} and Brito, {Maria Alexandra} and Kim, {Kwang Sik} and Furio Brighenti and Claudio Curti and Cinta Blad{\'e} and {Del Bas}, {Josep M.} and Donatella Stilli and Solano-Aguilar, {Gloria I.} and {Dos Santos}, {Claudia Nunes} and {Del Rio}, Daniele and Pedro Mena",
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Angelino, D, Carregosa, D, Domenech-Coca, C, Savi, M, Figueira, I, Brindani, N, Jang, S, Lakshman, S, Molokin, A, Urban, JF, Davis, CD, Brito, MA, Kim, KS, Brighenti, F, Curti, C, Bladé, C, Del Bas, JM, Stilli, D, Solano-Aguilar, GI, Dos Santos, CN, Del Rio, D & 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, vol. 11, no. 11, 2678. https://doi.org/10.3390/nu11112678

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

In: Nutrients, Vol. 11, No. 11, 2678, 01.11.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 5-(Hydroxyphenyl)-γ-valerolactone-sulfate, a key microbial metabolite of flavan-3-ols, is able to reach the brain

T2 - Evidence from different in silico, in vitro and in vivo experimental models

AU - Angelino, Donato

AU - Carregosa, Diogo

AU - Domenech-Coca, Cristina

AU - Savi, Monia

AU - Figueira, Inês

AU - Brindani, Nicoletta

AU - Jang, Saebyeol

AU - Lakshman, Sukla

AU - Molokin, Aleksey

AU - Urban, Joseph F.

AU - Davis, Cindy D.

AU - Brito, Maria Alexandra

AU - Kim, Kwang Sik

AU - Brighenti, Furio

AU - Curti, Claudio

AU - Bladé, Cinta

AU - Del Bas, Josep M.

AU - Stilli, Donatella

AU - Solano-Aguilar, Gloria I.

AU - Dos Santos, Claudia Nunes

AU - Del Rio, Daniele

AU - Mena, Pedro

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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”.

AB - 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”.

KW - Blood brain barrier

KW - Catechin

KW - Flavan-3-ol

KW - Gut

KW - Metabolites

KW - Neurodegenerative disease

KW - Permeability

KW - Polyphenols

KW - Proanthocyanidin

KW - Valerolactone

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U2 - 10.3390/nu11112678

DO - 10.3390/nu11112678

M3 - Article

VL - 11

JO - Nutrients

JF - Nutrients

SN - 1422-8599

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ER -