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Identification of Novel Urolithin Metabolites in Human Feces And 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 Cite This: J. Agric. Food Chem. 2019, 67, 11099−11107 pubs.acs.org/JAFC Identification of Novel Urolithin Metabolites in Human Feces and Urine after the Intake of a Pomegranate Extract Rocío García-Villalba, María V. Selma, Juan C. Espín, and Francisco A. Tomas-Barberá ń* Laboratory of Food & Health, Research Group on Quality, Safety, and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, Murcia 30100, Spain *S Supporting Information ABSTRACT: Urolithins are bioactive gut microbiota metabolites of ellagic acid. Here, we have identified four unknown urolithins in human feces after the intake of a pomegranate extract. The new metabolites occurred only in 19% of the subjects. 4,8,9,10-Tetrahydroxy urolithin, (urolithin M6R), was unambiguously identified by 1H NMR, UV, and HRMS. Three metabolites were tentatively identified by the UV, HRMS, and chromatographic behavior, as 4,8,10-trihydroxy (urolithin M7R), 4,8,9-trihydroxy (urolithin CR), and 4,8-dihydroxy (urolithin AR) urolithins. Phase II conjugates of the novel urolithins were detected in urine and confirmed their absorption, circulation, and urinary excretion. The production of the new urolithins was not specific of any of the known urolithin metabotypes A and B. The new metabolites needed a bacterial 3-dehydroxylase activity for their production, and this is a novel feature as all the previously known urolithins maintained the hydroxyl at 3 position. The ability of production of these “R” urolithins can be considered an additional metabolic feature for volunteer stratification. KEYWORDS: ellagitannin metabolism, gut microbiota, urolithins, interindividual variability, metabotypes ■ INTRODUCTION samples from some volunteers showed that several unknown Urolithins (hydroxylated dibenzo[b,d]-pyran-6-one-deriva- metabolites with the mass of tetrahydroxy-, trihydroxy-, and dihydroxy-urolithins were present together with the main tives) are produced in vivo by the gut microbiota of humans metabolite, urolithin A, although in smaller amounts. This and different animals after the intake of ellagitannins and 1−4 prompted us to characterize these new urolithin metabolites, ellagic acid. The main final metabolites found in plasma, although this was a challenging task because of the small tissues, and excreted in urine and feces, include urolithin A, amount present and their presence in a very complex matrix as urolithin B, and isourolithin A, and their corresponding phase- it is feces. II conjugates. Other intermediate metabolites have been fi identi ed and they follow the sequential loss of hydroxyls MATERIALS AND METHODS from the pentahydroxy urolithin (urolithin M5) which is the ■ fi Chemicals. The internal standard 6,7-dihydroxycoumarin was Downloaded via CSIC on October 10, 2019 at 10:26:33 (UTC). rst urolithin produced by opening one of the two lactone 5 from Sigma-Aldrich (St. Louis, MO, USA). Urolithin standards were rings of ellagic acid and its subsequent decarboxylation. These 16 final urolithin metabolites are much better absorbed than the obtained as previously described. Purity was higher than 95% for all 6 tested compounds. Organic solvents such as methanol and acetonitrile ellagitannins and ellagic acid found in food products, reaching were from Baker (Deventer, The Netherlands). Formic acid and HCl fi 2,3 signi cant concentrations in blood and urine. were obtained from Panreac (Barcelona, Spain). The Milli-Q system Urolithin metabolites also show different biological activities (Millipore Corp., Bedford, MA) ultrapure water was used throughout See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. and have been suggested to be responsible for the health the study. All chemicals and reagents were of analytical grade. effects observed after the intake of ellagitannin-rich foods such Human Study Design. This trial (“The POMEcardio study”) was as pomegranates, walnuts, and berries.4,7,8 This has fueled the conformed to ethical guidelines outlined in the Declaration of studies to understand the production of urolithins in the gut Helsinki and its amendments. The protocol included in the − and the mechanisms behind their biological effects.8 11 BACCHUS Project (FP7-KBBE-2012) was approved by the Spanish National Research Council’s Bioethics Committee (Spain) and Urolithins have also been suggested as biomarkers for the 4,12 registered at clinicaltrials.gov (NCT02061098). Protocol details intake of ellagic acid-containing foods. As the production of were reported elsewhere.15 Briefly, 49 overweight-obese healthy urolithins in our body depends on the occurrence in the gut of individuals (32 men and 17 women) aged between 40 and 65 years specific bacteria,10 and because of the known large variability participated in a double-blind, crossover, dose−response, randomized, of gut microbiota composition between individuals, it is and placebo-controlled trial.15 In the first phase, they consumed daily expected that not all subjects produce the same urolithins and one capsule of PE (160 mg phenolics) for 3 weeks, and after a in the same quantity.13 Thus, three different consistent washout period, they consumed daily four capsules of PE (640 mg urolithin metabotypes, A, B, and 0 have been described after the analysis of these metabolites in human urine.14 Received: July 15, 2019 Under a previous human intervention study with a Revised: September 6, 2019 pomegranate extract (PE) rich in ellagitannins and ellagic Accepted: September 8, 2019 acid,15 the HPLC−DAD−MS analysis of urolithins in fecal Published: September 8, 2019 © 2019 American Chemical Society 11099 DOI: 10.1021/acs.jafc.9b04435 J. Agric. Food Chem. 2019, 67, 11099−11107 Journal of Agricultural and Food Chemistry Article phenolics).15 Feces and urine samples were collected after each phase (NMR) analysis. Finally, the whole 500 μL was transferred to a 5 and were frozen at −80 °C until further analysis. In a previous study, mm standard NMR tube. urolithins were identified in feces samples, and volunteers were 1H NMR Analysis. For the identification of the new urolithin stratified as metabotype A (UM-A) (production of urolithin A metabolites, a Bruker AVANCE III HD spectrometer equipped with derivatives), metabotype B (UM-B) (production of isourolithin A an Ascend TM magnet, 11.7 T (1H operating frequency 500 MHz) and/or urolithin B in addition to urolithin A), and metabotype 0 and a cryoprobe (Cryoplatform Prodigy BBO) for increased (UM-0) (urolithins were not detected).15 sensitivity was used. One of the new metabolites was isolated in Sample Clean-up for LC Analyses. Feces samples (1 g) were enough amount to allow the 1H NMR analysis. The isolated new 1 defrosted and homogenized with 10 mL of MeOH/DMSO/H2O tetrahydroxy-urolithin was analyzed by H NMR (500 MHz in δ (40:40:20) with 0.1% HCl using an Ultra-Turrax for 1 min at 24 000 DMSO-d6) with chemical shift values ( ) in ppm: 6.78 (d; 1H, J = 8.2 rpm. The mixture was centrifuged at 5000×g for 10 min at room Hz, H-3); 6.96 (t, 1H, JH3−H2 = 8.20 Hz; JH1−H2 = 8.53 Hz, H-2); 7.03 temperature, and the supernatant was filtered through a 0.22 μm (s, 1H, H-7); 8.33 (d, 1H, JH2−H1 = 8.53 Hz, H-1) (Supporting PVDF filter before analysis. Information Figure S1). HPLC−DAD−ESI MS and UPLC−QTOF−MS Analyses. Ur- olithins were analyzed in feces as explained elsewhere.16 The analyses ■ RESULTS AND DISCUSSION were performed using an high-performance liquid chromatography Urolithin Analysis in Fecal Samples after the Intake (HPLC) system (1200 Series, Agilent Technologies) equipped with a of a PE. photodiode-array detector and a single quadrupole mass spectrometer The urolithin metabolites present in fecal samples (n = 47) after the intake of an ellagitannin-rich PE were analyzed detector in series (6120 Quadrupole, Agilent Technologies). − − The chromatographic separation was carried out on a Poroshell by HPLC DAD MS. As previously reported, the urolithin 120 EC-C18 column (3 × 100 mm, 2.7 μm) (Agilent Technologies) base level in biological samples prior to pomegranate intake using water with 0.5% formic acid (A) and acetonitrile (B) as the was negligible for most volunteers because of the dietary mobile phases with a flow rate of 0.5 mL/min. The gradient profile restriction of ellagitannin-containing foods.15 The metabolites was: 0−7 min, 5−18% B, 7−17 min, 18−28% B, 17−22 min, 28−50% identified in previous studies16,17 were easily detected with the B, 22−27 min, and 50−90% B, and this percentage was maintained specificdifferences for the characteristic metabotypes.14 In for 1 min and then came back to the initial conditions. A volume of 5 μ some volunteers, however, new metabolites with UV spectra L of sample was injected onto the column operating at room similar to those of urolithins and consistent masses were also temperature. Ultraviolet (UV) chromatograms were recorded at 360 and 305 nm. detected (Figure 1). In this case, one unknown metabolite with MS in selective ion-monitoring mode and negative polarity was used to confirm the identification. Optimal electrospray ionization (ESI) parameters using nitrogen as nebulizer gas were: capillary voltage 3500 V; drying gas flow 10 L/min; nebulizer pressure 45 psi, and drying T 300 °C. Metabolites were identified using their UV spectral properties and molecular mass, and whenever possible by comparison with authentic standards. To help in the identification of the new urolithins detected, some fecal samples were analyzed in an Agilent 1290 Infinity UPLC system coupled to a 6550 Accurate-Mass Quadrupole time-of-flight (UPLC- QTOF-MS) using the methodology previously reported.16 QTOF- MS provides the possible molecular formulae for the compounds based on the accurate mass and isotopic pattern.
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