Gene expression changes in colon tissues from colorectal cancer patients following the intake of an ellagitannin-containing pomegranate extract: a randomized clinical trial.
The clinical evidence of dietary polyphenols as colorectal cancer (CRC) chemopreventive compounds is very weak. Verification in humans of tissue-specific molecular regulation by the intake of polyphenols requires complex clinical trials that allow for the procurement of sufficient pre- and postsupplementation tissue samples. Ellagitannins (ETs), ellagic acid (EA) and their gut microbiota-derived metabolites, the urolithins, modify gene expression in colon normal and cancer cultured cells. We conducted here the first clinical trial with 35 CRC patients daily supplemented with 900 mg of an ET-containing pomegranate extract (PE) and evaluated the expression of various CRC-related genes in normal and cancerous colon tissues before (biopsies) and after (surgical specimens) 5-35 days of supplementation. Tissues were also obtained from 10 control patients (no supplementation) that confirmed a large, gene- and tissue-specific interindividual variability and impact of the experimental protocol on gene expression, with some genes induced (MYC, CD44, CDKN1A, CTNNB1), some repressed (CASP3) and others not affected (KRAS). Despite these issues, the consumption of the PE was significantly associated with a counterbalance effect in the expression of CD44, CTNNB1, CDKN1A, EGFR and TYMs, suggesting that the intake of this PE modulated the impact of the protocol on gene expression in a gene- and tissue-specific manner. These effects were not associated with the individuals' capacity to produce specific urolithins (i.e., metabotypes) or the levels of urolithins and EA in the colon tissues and did not reproduce in vitro effects evidencing the difficulty of demonstrating in vivo the in vitro results.
Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain.
María A
MA
Nuñez-Sánchez
Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain.
Antonio
A
González-Sarrías
Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain.
Rocío
R
García-Villalba
Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain; Nutrition, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Tamara
T
Monedero-Saiz
Nutrition, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Noelia V
NV
García-Talavera
Nutrition, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
María B
MB
Gómez-Sánchez
Nutrition, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Carmen
C
Sánchez-Álvarez
Digestive, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Ana M
AM
García-Albert
Digestive, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Francisco J
FJ
Rodríguez-Gil
Surgery, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Miguel
M
Ruiz-Marín
Anatomical Pathology Services, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Francisco A
FA
Pastor-Quirante
Anatomical Pathology Services, Hospital Reina Sofía, Avda. Intendente Jorge Palacios s/n, 30003 Murcia, Spain.
Francisco
F
Martínez-Díaz
Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain.
Francisco A
FA
Tomás-Barberán
Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain. Electronic address: jcespin@cebas.csic.es.
Juan Carlos
JC
Espín
Research Group on Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, P.O. Box 164, 30100 Campus de Espinardo, Murcia, Spain. Electronic address: mtconesa@cebas.csic.es.
María-Teresa
MT
García-Conesa
D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000178:diet therapy* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D029561:Lythraceae / Q000737:chemistry*; D008297:Male; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D015203:Reproducibility of Results
D047348:Hydrolyzable Tannins; D010936:Plant Extracts; C013515:ellagitannin
Clinical trial; Colon tissues; Ellagitannins; Gene expression; Interindividual variability; Pomegranate extract; Urolithins