{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T15:53:12Z","timestamp":1778773992844,"version":"3.51.4"},"reference-count":36,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,5]],"date-time":"2019-11-05T00:00:00Z","timestamp":1572912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"iNOVA4Health Research Unit","award":["LISBOA-01-0145-FEDER-007344"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-007344"]}]},{"DOI":"10.13039\/501100007512","name":"Universitat Rovira i Virgili","doi-asserted-by":"publisher","award":["2014PMF-PIPF-48"],"award-info":[{"award-number":["2014PMF-PIPF-48"]}],"id":[{"id":"10.13039\/501100007512","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000199","name":"U.S. Department of Agriculture","doi-asserted-by":"publisher","award":["8040-51530-056-00"],"award-info":[{"award-number":["8040-51530-056-00"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Inter Agency Agreement","award":["8040-51530-056-13"],"award-info":[{"award-number":["8040-51530-056-13"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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-\u03b3-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\u2032,4\u2032-dihydroxyphenyl)-\u03b3-valerolactone, and rats and pigs fed grapes or a F3O-rich cocoa extract, respectively, confirmed the presence of 5-(hydroxyphenyl)-\u03b3-valerolactone-sulfate (3\u2032,4\u2032 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 \u201cgut-brain axis\u201d.<\/jats:p>","DOI":"10.3390\/nu11112678","type":"journal-article","created":{"date-parts":[[2019,11,7]],"date-time":"2019-11-07T02:48:31Z","timestamp":1573094911000},"page":"2678","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["5-(Hydroxyphenyl)-\u03b3-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"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5436-7428","authenticated-orcid":false,"given":"Donato","family":"Angelino","sequence":"first","affiliation":[{"name":"Human Nutrition Unit, Department of Veterinary Medicine, University of Parma, 43125 Parma, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1396-3039","authenticated-orcid":false,"given":"Diogo","family":"Carregosa","sequence":"additional","affiliation":[{"name":"CEDOC, NOVA Medical School, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1589-4556","authenticated-orcid":false,"given":"Cristina","family":"Domenech-Coca","sequence":"additional","affiliation":[{"name":"Unitat de Nutrici\u00f3 i Salut, Centre Tecnol\u00f2gic de Catalunya, Eurecat, 43204 Reus, Spain"},{"name":"Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Universitat Rovira i Virgili, 43007 Tarragona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7895-7756","authenticated-orcid":false,"given":"Monia","family":"Savi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy"}]},{"given":"In\u00eas","family":"Figueira","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u0131\u0301mica e Biol\u00f3gica\u2013Ant\u00f3nio Xavier, Universidade Nova de Lisboa, EAN, 2781-901 Oeiras, Portugal"}]},{"given":"Nicoletta","family":"Brindani","sequence":"additional","affiliation":[{"name":"Human Nutrition Unit, Department of Food and Drug, University of Parma, 43125 Parma, Italy"},{"name":"Department of Food and Drug, University of Parma, 43125 Parma, Italy"}]},{"given":"Saebyeol","family":"Jang","sequence":"additional","affiliation":[{"name":"U.S. Department of Agriculture, Northeast Area, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD 20705, USA"}]},{"given":"Sukla","family":"Lakshman","sequence":"additional","affiliation":[{"name":"U.S. Department of Agriculture, Northeast Area, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD 20705, USA"}]},{"given":"Aleksey","family":"Molokin","sequence":"additional","affiliation":[{"name":"U.S. Department of Agriculture, Northeast Area, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD 20705, USA"}]},{"suffix":"Jr.","given":"Joseph F.","family":"Urban","sequence":"additional","affiliation":[{"name":"U.S. Department of Agriculture, Northeast Area, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD 20705, USA"}]},{"given":"Cindy D.","family":"Davis","sequence":"additional","affiliation":[{"name":"Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20892, USA"}]},{"given":"Maria Alexandra","family":"Brito","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Kwang Sik","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8441-4611","authenticated-orcid":false,"given":"Furio","family":"Brighenti","sequence":"additional","affiliation":[{"name":"Human Nutrition Unit, Department of Food and Drug, University of Parma, 43125 Parma, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6117-1503","authenticated-orcid":false,"given":"Claudio","family":"Curti","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, 43125 Parma, Italy"}]},{"given":"Cinta","family":"Blad\u00e9","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Nutrigenomics Research Group, Universitat Rovira i Virgili, 43007 Tarragona, Spain"}]},{"given":"Josep M.","family":"del Bas","sequence":"additional","affiliation":[{"name":"Unitat de Nutrici\u00f3 i Salut, Centre Tecnol\u00f2gic de Catalunya, Eurecat, 43204 Reus, Spain"}]},{"given":"Donatella","family":"Stilli","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-7102","authenticated-orcid":false,"given":"Gloria I.","family":"Solano-Aguilar","sequence":"additional","affiliation":[{"name":"U.S. Department of Agriculture, Northeast Area, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet Genomics and Immunology Laboratory, Beltsville, MD 20705, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5809-1924","authenticated-orcid":false,"given":"Claudia Nunes 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