title: Iberian pig as a model to clarify obscure points in the bioavailability and metabolism of ellagitannins in humans.
abstract: Ellagitannin-containing foods (strawberries, walnuts, pomegranate, raspberries, oak-aged wine, etc.) have attracted attention due to their cancer chemopreventive, cardioprotective, and antioxidant effects. Ellagitannins (ETs) are not absorbed as such but are metabolized by the intestinal flora to yield urolithins (hydroxydibenzopyran-6-one derivatives). In this study, Iberian pig is used as a model to clarify human ET metabolism. Pigs were fed either cereal fodder or acorns, a rich source of ETs. Plasma, urine, bile, lumen and intestinal tissues (jejunum and colon), feces, liver, kidney, heart, brain, lung, muscle, and subcutaneous fat tissue were analyzed. The results demonstrate that acorn ETs release ellagic acid (EA) in the jejunum, then the intestinal flora metabolizes EA sequentially to yield tetrahydroxy- (urolithin D), trihydroxy- (urolithin C), dihydroxy- (urolithin A), and monohydroxy- (urolithin B) dibenzopyran-6-one metabolites, which were absorbed preferentially when their lipophilicity increased. Thirty-one ET-derived metabolites were detected, including 25 urolithin and 6 EA derivatives. Twenty-six extensively conjugated metabolites were detected in bile, glucuronides and methyl glucuronides of EA and particularly urolithin A, C, and D derivatives, confirming a very active enterohepatic circulation. Urolithins A and B as well as dimethyl-EA-glucuronide were detected in peripheral plasma. The presence of EA metabolites in bile and in urine and its absence in intestinal tissues suggested its absorption in the stomach. Urolithin A was the only metabolite detected in feces and together with its glucuronide was the most abundant metabolite in urine. No metabolites accumulated in any organ analyzed. The whole metabolism of ETs is shown for the first time, confirming previous studies in humans and explaining the long persistency of urolithin metabolites in the body mediated by an active enterohepatic circulation.
authors.affiliation: Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Espín
authors.forename: Rocío
authors.initials: R
authors.lastname: González-Barrio
authors.forename: Begoña
authors.initials: B
authors.lastname: Cerdá
authors.forename: Clemente
authors.initials: C
authors.lastname: López-Bote
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rey
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Tomás-Barberán
mesh_terms: D000818:Animals; D001682:Biological Availability; D001826:Body Fluids / Q000737:chemistry; D003374:Coumarins / Q000378:metabolism / Q000493:pharmacokinetics*; D004032:Diet; D002523:Edible Grain / Q000737:chemistry; D006801:Humans; D047348:Hydrolyzable Tannins / Q000378:metabolism / Q000493:pharmacokinetics*; D023421:Models, Animal; D029963:Quercus; D012639:Seeds / Q000737:chemistry; D013552:Swine / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D003374:Coumarins; D047348:Hydrolyzable Tannins; C000595063:urolithin D