Francisco A. Tomás Barberán, PhD

Francisco A. Tomás Barberán, PhD

Biography

Francisco A. Tomás Barberán (1958) PhD. in Pharmacy and Research Professor of the Spanish Council for Scientific Research (CSIC) in the CEBAS Institute located in Murcia in the Spanish Mediterranean Region.

He is co-author of more than 200 scientific reports published in scientific journals and responsible for more than 80 research projects and contracts with food and pharmaceutical industries. He has produced a number of patents of which three have been licensed to companies. His main research activity has aimed to understanding the role of plant phenolic secondary metabolites in food quality and their health promoting properties.

His most recent research aims to the identification of those food constituents that are responsible for the health benefits, and the biochemical and physiological mechanisms for this activity as well as the evaluation of agronomic, genetic, processing and storage factors on these interesting compounds. He has conducted research stays in laboratories of the U.K., Switzerland, France and the USA (University of California, Davis). He has been recipient of the Rhone Poulenc Rorer Award (Phytochemical Society of Europe in 1997), for his research on food polyphenols, and more recently the Frial Award to Research on Food and Health in 2004 and the Danone Scientific Award to Research on Nutrition and Health in 2006.

Abstract

Exploring the Biological Activity of Berry Ellagitannins Metabolites: Urolithins

Francisco A. Tom’s-Barbern, Antonio Gonzalez-Sarras; Mar Larrosa; Mara T. Garcia-Conesa and Juan C. Espon.

Research Group on Quality, Safety and Bioactivity of Plant Foods. CEBAS (CSIC) P.O. Box 164, 30100, Espinardo, Murcia, Spain.
E-mail: fatomas@cebas.csic.es

Keywords: Urolithins; ellagic acid; polyphenols; metabolism; tissue distribution; antiinflammatory; chemopreventive; gene expression; strawberry; raspberry.

Ellagic acid and ellagitannins are polyphenols abundant in different berries including strawberry, blackberry and raspberry. They show high in vitro antioxidant activity and they have been associated to diverse beneficial health effects especially against cancers of the gastrointestinal tract. Previous studies in animals and humans have demonstrated a poor absorption for ellagic acid and ellagitannins as well as their metabolic transformation into urolithins by the gut microbiota. These metabolites are absorbed and circulate in plasma mostly as glucuronide and sulphate conjugates and persist in the body for a long time due to the entero-hepatic recirculation. Urolithins with different hydroxylation patterns have been found in the liver of animals feeding on ellagitannins.

Regarding tissue distribution of the urolithins and its conjugates, we have recently found that these molecules reach and enter the human prostate after consumption of ellagitannin rich foods1. The main metabolite detected was Urolithin A glucuronide (up to 2 ng/g tissue) together with traces of Urolithin B-glucuronide and ellagic acid-dimethyl ether. These metabolites were present only in a small number of the 63 patients studied which may be explained by rapid clearance of the compounds during pre-surgery fasting. This was confirmed in a parallel study with rats. These results show that urolithin glucuronides may be the actual molecules responsible for the beneficial effects previously attributed to ellagitannins and(or) ellagitannin-containing berries against prostate cancer.
We have investigated the bioactivity of urolithins using various in vitro and in vivo models. In a previous study we determined the estrogen-modulating activity of Urolithin A and B and showed that these molecules exhibit weak estrogenic and anti-estrogenic in vitro activity against human breast cancer cells2.

The effects of Urolithin A were also examined in an animal model of DSS-induced colon inflammation3. Oral administration of Urolithin A, at concentrations representative of those found in vivo in humans, preserved colonic architecture, decreased inflammation markers and modulated favourably the gut microbiota in rats. In addition, signalling pathways responsible for the inflammatory response were down-regulated whereas the G1 and S cell cycle pathways were up-regulated. These results suggest that Urolithin A may be a highly active anti-inflammatory compound derived form ellagitannin intake.

Urolithin A and Urolithin B also exert antiproliferative effects against colon cancer Caco-2 cells4 and are able to modulate phase I and phase II detoxifying enzymes in these cells at concentrations that are achievable in the colon after the intake of berries (mM range)5. These metabolites induced the expression and activity of CYP1A1 and UGT1A10 and inhibited several phenol sulphotransferases, favouring the synthesis of glucuronides over sulphated conjugates. Urolithins dissolved in an aqueous buffer were also able to induce CYP1A1 in situ in the rat colon. However, dissolving the compounds in oil abolished this effect. The results show that berry-derived urolithins may exert some blocking chemopreventive effects in the colon, but these effects are critically affected by interfering factors such as the food matrix 5.

Gonzalez-Sarras et al., Occurrence of urolithins, gut microbiota ellagic acid metabolites, and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice Mol. Nut. Food Res. 2009, in press.

Larrosa et al., Urolithins, ellagic acid-derived metabolites produced by human colonic microflora, exhibit estrogenic and antiestrogenic activities.J. Agric. Food Chem., 2006, 54,1611-20,.

Larrosa, et al., Anti-inflammatory properties of pomegranate extract and its metabolite Urolithin A in a colitis rat model and the effect of colon inflammation on the phenolic metabolism. J. Nut. Biochem., 2009, in press.

Gonzalez-Sarras et al. Gene Expression, Cell Cycle Arrest and MAPK Signaling Regulation in Caco-2 Cells Exposed to Ellagic Acid and its Metabolites, Urolithins, Mol. Nut. Food Res. 2009, in press.

Gonzalez-Sarras et al., Dissimilar in vitro and in vivo effects of ellagic acid and its microbiota-derived metabolites, urolithins, on the cytochrome P450 1A1J. Agric. Food Chem., 2009, in press.

Acknowledgements: The authors are grateful to the Spanish CICYT for financial support of this work (projects BFU2007-60576 and Consolider Ingenio 2010 CSD2007-0063)