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Gastrointestinal Simulation Model TWIN-SHIME Shows Differences This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Article pubs.acs.org/JAFC Gastrointestinal Simulation Model TWIN-SHIME Shows Differences between Human Urolithin-Metabotypes in Gut Microbiota Composition, Pomegranate Polyphenol Metabolism, and Transport along the Intestinal Tract † # § ∥ ⊥ # ‡ † † Rocío García-Villalba, , Hanne Vissenaekens, , , , Judit Pitart, María Romo-Vaquero, Juan C. Espín, § † ∥ ⊥ ‡ Charlotte Grootaert, María V. Selma, Katleen Raes, Guy Smagghe, Sam Possemiers, § † John Van Camp, and Francisco A. Tomas-Barberan*, † Research Group on Quality, Safety, and Bioactivity of Plant Foods, Laboratory of Food & Health, Department of Food Science and Technology, CEBAS-CSIC, 30100 Campus de Espinardo, Murcia Spain ‡ ProDigest BVBA, Ghent, Belgium § Department of Food Safety and Food Quality, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium ∥ Department of Industrial Biological Sciences, Faculty of Bioscience Engineering, Ghent University, Kortrijk, Belgium ⊥ Department of Crop Protection, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium *S Supporting Information ABSTRACT: A TWIN-SHIME system was used to compare the metabolism of pomegranate polyphenols by the gut microbiota from two individuals with different urolithin metabotypes. Gut microbiota, ellagitannin metabolism, short-chain fatty acids (SCFA), transport of metabolites, and phase II metabolism using Caco-2 cells were explored. The simulation reproduced the in vivo metabolic profiles for each metabotype. The study shows for the first time that microbial composition, metabolism of ellagitannins, and SCFA differ between metabotypes and along the large intestine. The assay also showed that pomegranate phenolics preserved intestinal cell integrity. Pomegranate polyphenols enhanced urolithin and propionate production, as well as Akkermansia and Gordonibacter prevalence with the highest effect in the descending colon. The system provides an insight into the mechanisms of pomegranate polyphenol gut microbiota metabolism and absorption through intestinal cells. The results obtained by the combined SHIME/Caco-2 cell system are consistent with previous human and animal studies and show that although urolithin metabolites are present along the gastrointestinal tract due to enterohepatic circulation, they are predominantly produced in the distal colon region. KEYWORDS: ellagic acid, urolithin, phenotypes, gut microbiota, intestinal cells Downloaded via CSIC on June 19, 2018 at 06:57:35 (UTC). ■ INTRODUCTION metabolites trigger different molecular and cell responses that may account, at least partially, for the antioxidant, anti- Dietary ellagitannins (ETs) and ellagic acid (EA) have been fl associated with important health effects and benefits in diseases in ammatory, anticancer, cardio-metabolic, and neuroprotec- 1,2 tive effects attributed to ETs and (or) to ET-containing including cardiovascular disease. They are present in dietary 2,5,12,13 See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. 3 foods. Therefore, the study of the mechanisms for sources in larger amounts than previously estimated. In fi fi humans, ETs are not absorbed as such, and the absorption of urolithin production, the identi cation of the speci c regions of EA is rather low.4 Both ETs and EA are catabolized by the gut the intestine where they are formed, and the gut microbiota microbiota leading to urolithin metabolites.5 The final involved are of special interest. After pomegranate polyphenols metabolites in this catabolic conversion are urolithin A (Uro- intake, several urolithins have been detected in human feces, urine, and also in biopsies taken from prostate and different A), urolithin B (Uro-B), and isourolithin A (Isouro-A) (Figure 14,15 1). Not all individuals have the appropriate gut microbiota to regions of the colon in cancer patients. In vitro production fi ff of urolithins from EA by human fecal microbiota from both produce the nal urolithin metabolites, and three di erent 16 urolithin metabotypes (UMs), UM-A, UM-B, and UM-0, have metabotypes A and B has also been described. However, the been reported.6 Species of the genus Gordonibacter have been gastrointestinal tract site for urolithin production, the stability, identified as gut microbiota constituents that are involved in the and absorption of the metabolites in the gut are still unknown. 7,8 fi conversion of EA into intermediary urolithins. Fecal To date, Gordonibacter levels have only been quanti ed in Gordonibacter concentrations correlate positively with uroli- thin-A content in feces and urine,9 although other unknown Received: May 3, 2017 bacterial species are needed to produce the final urolithin Revised: June 13, 2017 metabolites. Urolithins reach concentrations within the micro- Accepted: June 15, 2017 molar range in human plasma,10,11 and these bioavailable Published: June 15, 2017 © 2017 American Chemical Society 5480 DOI: 10.1021/acs.jafc.7b02049 J. Agric. Food Chem. 2017, 65, 5480−5493 Journal of Agricultural and Food Chemistry Article Figure 1. Gut microbiota catabolism of pomegranate ETs (punicalagin) to urolithin metabolites, and differences between metabotypes A and B. In blue, urolithin metabolites derived from ellagic acid. In red, transient intermediate metabolite not detected. Compound numbers as in the chromatograms of Figure 2. human fecal samples, but its distribution throughout the subjected to a stomach and small intestine (SI) digestion to digestive tract and its role in urolithin production are still estimate the bioavailability of native polyphenols and their unknown. Fecal Gordonibacter levels are higher in urolithin catabolism in the upper part of the gastrointestinal tract. Long- metabotype A (UM-A) individuals than in those with urolithin term microbial colon fermentation was also investigated in the 17 metabotype B (UM-B) and urolithin metabotype 0 (UM-0). TWIN-SHIME, thus determining the gut microbiota metabo- Modulation of some human fecal bacteria by consumption of lism of ETs in the colon, the urolithin production pathway, the ET- rich food such as pomegranate has recently been sites of transformation, and the metabolite profile of (poly)- described,18,19 and the increase of fecal Gordonibacter levels phenolics which have potential to be absorbed. The production was highlighted.19 However, modulation of Gordonibacter and of specific SCFA was also evaluated, as well as the modulation other bacterial groups by ET-rich foods along the digestive tract as well as their differences between metabotypes has not been of gut microbiota. The intestinal transport and cell metabolism explored and requires further research. of the (poly)phenolics were also evaluated through direct In the present study, a simulator of the human intestinal addition of diluted phenolics-containing SHIME matrix to microbial ecosystem (TWIN-SHIME) was used to shed light Caco-2-cells. Overall, our results are of interest to validate this on ET gut microbiota metabolism in the different regions of the system when compared with the results previously obtained in intestine. A pomegranate extract (PE) supplement was vivo. 5481 DOI: 10.1021/acs.jafc.7b02049 J. Agric. Food Chem. 2017, 65, 5480−5493 Journal of Agricultural and Food Chemistry Article ■ MATERIALS AND METHODS the limits of detection and quantification using this matrix (SHIME medium) (Suppl. Table 1). Pomegranate Extract (PE) and Chemicals. Characterized PE SCFA Analysis. TWIN-SHIME samples were analyzed as was provided by Laboratorios Admira S.L. (Alcantarilla, Murcia, 24 fl 19 previously described. Brie y, SCFA were extracted from the samples Spain). EA, punicalagin and 6,7-dihydroxycoumarin (DHC) were with diethyl ether, after the addition of 2-methyl hexanoic acid as an from Sigma-Aldrich (St. Louis, MO, USA). Urolithins were obtained 3 internal standard. Extracts were analyzed using a GC-2014 gas as previously described. Purity was higher than 95% for all tested chromatograph (Shimadzu, Hertogenbosch, The Netherlands), compounds. Organic solvents such as methanol, acetone, and equipped with a capillary fatty acid-free EC-1000 Econo-Cap column acetonitrile were from Merck (Darmstadt, Germany). All chemicals (dimensions, 25 mm × 0.53 mm; film thickness, 1.2 mM; Alltech, and reagents were of analytical grade. Laarne, Belgium), a flame ionization detector, and a split injector. The fi Volunteer Strati cation and Characterization. To select the injection volume was 1 mL, and the temperature profile was set from fecal donors for UM-A and UM-B, 13 individuals consumed 30 g 110 to 160 °C, with a temperature increase of 6 °C/min. The carrier walnuts/day for 3 days, and urine samples were collected on the third gas was nitrogen, and the temperature of the injector and detector was day. Urolithin production and metabolic profiles were evaluated using 100 and 220 °C, respectively. 20 HPLC-DAD-MS, and eight individuals were stratified as UM-A, four DNA Extraction and Microbial Analysis. Powerfecal DNA as UM-B, and one as UM-0. This distribution is consistent with isolation kit (Mo-Bio Laboratories, Carlsbad, CA, USA) was used to normal values as previously reported.20,6 Representatives of UM-A and isolate total DNA from different SHIME samples. An additional step UM-B were selected as fecal donors for the assay of ET metabolism in was done consisting of vigorous shaking using a FastPrep
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