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The health benefits associated with the consumption of polyphenol-rich foods have been studied in depth, however, the full mechanism of action remains unknown. One of the proposed mechanisms is through microbiota interaction. In the present study, we aimed to explore the relationship between changes in fecal microbiota and changes in urinary phenolic metabolites after wine interventions. Nine participants followed a randomized, crossover, controlled interventional trial. After the washout period, they received red wine, dealcoholized red wine or gin for 20 days each. Polyphenol metabolites (n > 60) in urine were identified and quantified by UPLC-MS/MS and the microbial content of fecal samples was quantified by real-time quantitative PCR. Interventions with both red wine and dealcoholized red wine increased the fecal concentration of Bifidobacterium, Enterococcus and Eggerthella lenta, compared to gin intervention and baseline. When participants were categorized in tertiles of changes in fecal bacteria, those in the highest tertile of Bifidobacteria had higher urinary concentration changes in syringic acid, p-coumaric acid, 4-hydroxybenzoic acid and homovanillic acid (all anthocyanin metabolites) than those in tertile 1 (P < 0.05, all). In addition, changes of Bifidobacteria correlated positively with changes of these metabolites (r = 0.5-0.7, P < 0.05, all). Finally, the 68.5% changes in Bifidobacteria can be predicted by syringic acid and 4-hydroxybenzoic acid changes. This study confirms the important role of polyphenols as bacterial substrates and their modulatory capacity as an important field in the research of new products with prebiotic and probiotic characteristics for the food industry.

Scope: Knowledge of in vivo polyphenol metabolites derived from the consumption of red wine could be key to understanding its health benefits. This work aimed to predict the wine polyphenol metabolic space in biofluids by using all available data compiled in the Phenol-Explorer database., Methods and Results: A search strategy was developed for Phenol-Explorer to obtain the widest range of metabolites related to wine consumption. A total of 97 metabolites have been described in intervention studies with wine and related products (n = 37), and after consumption of pure compounds known to be wine constituents (n = 90). These 97 metabolites, derived from host and microbial metabolism of several classes of polyphenols, were found in plasma and urine samples and some of them have demonstrated higher or lower biological activities than the parent compound in in vitro studies. The metabolites have been linked to generate, for the first time, a global pathway map of wine in vivo polyphenol metabolism., Conclusion: The retrieval of the widest range of metabolites so far described and their assembly as a metabolic pathway map could aid the identification of possible biomarkers of wine consumption and improve current understanding of the health effects of wine consumption., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The regular consumption of dealcoholized red wine (DRW) has demonstrated benefits in cardiovascular risk factors. The analysis of phenolic metabolites formed in the organism, especially those that could come from microbiota metabolism, would help to understand these benefits. The aim of this study was to determine the widest urinary metabolomic fingerprinting of phenolics and microbial-derived phenolic acids (n = 61) after regular intake of DRW in men at high cardiovascular risk by UPLC-MS/MS using a targeted approach. Up to 49 metabolites, including phase II and microbial phenolic metabolites, increased after DRW consumption compared to baseline (P < 0.05). The highest percentage of increase was found for microbial metabolites from anthocyanin degradation such as syringic, p-coumaric, gallic acids and pyrogallol and from flavan-3-ols degradation such as hydroxyphenylvalerolactones and (epi)catechins. These findings provide the most complete metabolic fingerprinting after wine consumption, amplifying the spectrum of microbial derived metabolites and their potential bioactivity related with health benefits.

Background & Aims: Epidemiological data suggest that moderate red wine consumption reduces cardiovascular mortality and the incidence of diabetes. However, whether these effects are due to ethanol or to non-alcoholic components of red wine still remains unknown. The aim of the present study was to compare the effects of moderate consumption of red wine, dealcoholized red wine, and gin on glucose metabolism and the lipid profile., Methods: Sixty-seven men at high cardiovascular risk were randomized in a crossover trial. After a run-in period, all received each of red wine (30 g alcohol/d), the equivalent amount of dealcoholized red wine, and gin (30 g alcohol/d) for 4 week periods, in a randomized order. Fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance (HOMA-IR), plasma lipoproteins, apolipoproteins and adipokines were determined at baseline and after each intervention., Results: Fasting glucose remained constant throughout the study, while mean adjusted plasma insulin and HOMA-IR decreased after red wine and dealcoholized red wine. HDL cholesterol, Apolipoprotein A-I and A-II increased after red wine and gin. Lipoprotein(a) decreased after the red wine intervention., Conclusions: These results support a beneficial effect of the non-alcoholic fraction of red wine (mainly polyphenols) on insulin resistance, conferring greater protective effects on cardiovascular disease to red wine than other alcoholic beverages. www.isrctn.org: ISRCTN88720134., (Copyright © 2012. Published by Elsevier Ltd.)

Resveratrol exerts a variety of biological and pharmacological activities, which are observed despite its extremely low bioavailability and rapid clearance from the circulation due to extensive sulfation and glucuronidation in the intestine and liver. In order to more accurately quantify all known resveratrol metabolites, a sensitive and optimized analytical assay was developed and validated by pure standards. Methodology improvements aimed to the chromatographic detection of disulfates and sulfoglucuronides, improving resolution of sulfates, by using a buffered solution, with recovery values of resveratrol and its metabolites, even of sulfates, of 99%. The adapted methodology was then applied to a clinical study with high cardiovascular risk subjects, after the moderate consumption of red wine (RW) or dealcoholized red wine (DRW) for 28 days. Up to 21 resveratrol metabolites, including those formed by gut and microbial metabolism, were identified in 24-h urine samples. Interestingly, after long-term consumption of RW and DRW, resveratrol metabolite concentration significantly increased in urine with no differences between the two interventions, indicating that bioavailability and biotransformation of resveratrol is not affected by the alcoholic matrix of wine. In summary, we established a sensitive analytical assay for the quantification of a wide resveratrol metabolic profile in human urine, also regarding gut microbial-derived metabolites, which may also be applied to blood and tissue samples. The resveratrol metabolic pattern might therefore act as an excellent marker for the efficacy of resveratrol in clinical and epidemiological studies for the study of the beneficial effects of grape product consumption. In this sense, having a more precise concentration value of all the resveratrol metabolites in target tissues would finally lead to a better interpretation of the obtained results., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A pharmacokinetic study of the metabolic profile of resveratrol has been performed in healthy men after moderate red wine (RW) consumption. The bioavailability of resveratrol is highly influenced by several factors such as the food matrix and, therefore, this study has been compared with a pilot study in which men ingested grape extract (GE) tablets as a nutraceutical, containing similar total amounts of resveratrol than RW. Blood and urine samples were taken before and at several time points after intervention and then analyzed by SPE and LC-ESI-MS/MS. Up to 17 resveratrol and piceid derivatives were identified, including those formed by the intestinal microbiota. Resveratrol glucosides were found in plasma as intact forms and reached the lowest maximum concentrations 1h after both interventions. Higher plasma concentrations and longer times (t(max)) were observed for resveratrol glucuronides due to phase II metabolism and even higher values for conjugates derived from microbiota, such as dihydroresveratrol-glucuronides. The same trend was observed for total excreted amounts in urine samples. When both treatments were compared, statistically significant differences for some metabolites were obtained, which may be due to the different composition of resveratrol and piceid in both sources. However, GE formulation seems to delay resveratrol absorption, staying longer in the gut where could be metabolized to a greater degree, since 2.1-3.6-fold higher urinary concentrations of microbial metabolites were observed after GE intervention at 12-24h urinary fraction. Therefore, supplement intake could be also a way to bring resveratrol benefits to human health., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Rationale: Experimental studies have shown a potential blood pressure (BP) lowering effect of red wine polyphenols, whereas the effects of ethanol and polyphenols on BP in humans are not yet clear., Objective: The aim of the present work was to evaluate the effects of red wine fractions (alcoholic and nonalcoholic) on BP and plasma nitric oxide (NO) in subjects at high cardiovascular risk., Methods and Results: Sixty-seven men at high cardiovascular risk were studied. After a 2-week run-in period, subjects were randomized into 3 treatment periods in a crossover clinical trial, with a common background diet plus red wine (30g alcohol/day), the equivalent amount of dealcoholized red wine, or gin (30g alcohol/day), lasting 4 weeks each intervention. At baseline and after each intervention, anthropometrical parameters, BP and plasma NO were measured. Systolic and diastolic BP decreased significantly after the dealcoholized red wine intervention and these changes correlated with increases in plasma NO., Conclusions: Dealcoholized red wine decreases systolic and diastolic BP. Our results point out through an NO-mediated mechanism. The daily consumption of dealcoholized red wine could be useful for the prevention of low to moderate hypertension. Trial registered at controlled-trials.com: ISRCTN88720134.

Moderate wine consumption has been shown to reduce cardiovascular (CV) risk, due to alcohol and polyphenolic compounds, such as resveratrol. We investigated the associations between total urinary resveratrol metabolites (TRMs) as biomarkers of wine and resveratrol consumption and CV risk factors in a large cross-sectional study including high CV risk individuals in Spain. We studied 1000 participants in the PREDIMED Study in whom TRMs were analyzed by LC-MS/MS with a previous solid phase extraction. Multiple linear regression of TRMs (biomarker of wine consumption) improved the mean (95% CI) of HDL [0.168 (0.027-0.309); P=0.02] and triglyceride [-1.012 (-1.797 to -0.227); P=0.012] plasma concentrations and heart rate [-0.259 (-0.412 to -0.107); P<0.001]. Models of TRMs adjusted for alcohol (biomarker of resveratrol intake) decreased fasting blood glucose [-0.533 (-1.034 to -0.033); P=0.037] and triglyceride [-1.014 (-1.998 to -0.029); P=0.044] concentrations, and heart rate [-0.277 (-0.467 to -0.087); P=0.004]. Both resveratrol and wine intake, evaluated as TRMs, were associated with beneficial changes in blood lipid profiles, fasting blood glucose (only resveratrol) and heart rate, suggesting that resveratrol intake via wine consumption might help to decrease CV risk factors., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Few clinical studies have focused on the alcohol-independent cardiovascular effects of the phenolic compounds of red wine (RW)., Objective: We aimed to evaluate the effects of ethanol and phenolic compounds of RW on the expression of inflammatory biomarkers related to atherosclerosis in subjects at high risk of cardiovascular disease., Design: Sixty-seven high-risk, male volunteers were included in a randomized, crossover consumption trial. After a washout period, all subjects received RW (30 g alcohol/d), the equivalent amount of dealcoholized red wine (DRW), or gin (30 g alcohol/d) for 4 wk. Before and after each intervention period, 7 cellular and 18 serum inflammatory biomarkers were evaluated., Results: Alcohol increased IL-10 and decreased macrophage-derived chemokine concentrations, whereas the phenolic compounds of RW decreased serum concentrations of intercellular adhesion molecule-1, E-selectin, and IL-6 and inhibited the expression of lymphocyte function-associated antigen 1 in T lymphocytes and macrophage-1 receptor, Sialil-Lewis X, and C-C chemokine receptor type 2 expression in monocytes. Both ethanol and phenolic compounds of RW downregulated serum concentrations of CD40 antigen, CD40 ligand, IL-16, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1., Conclusion: The results suggest that the phenolic content of RW may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of RW may modulate soluble inflammatory mediators in high-risk patients. The trial was registered in the International Standard Randomized Controlled Trial Number Register at http://www.isrctn.org/ as ISRCTN88720134.

Background: Nutritional biomarkers are alternatives to traditional dietary assessment tools. We sought to develop a method for nutritional analysis of resveratrol, a phenolic compound with purported health-promoting properties, and to determine all resveratrol metabolites., Methods: We obtained LDL and urine samples from 11 healthy male volunteers who had consumed 250 mL of Merlot red wine. We measured resveratrol and its metabolites with 96-well solid-phase extraction plates coupled with HPLC-tandem mass spectrometry. Hexestrol was used as the internal standard. Gradient chromatography in multiple reaction monitoring mode was performed on a Luna C(18) column, maintained at 40 degrees C; m/z transitions were as follows: resveratrol, 227/185; resveratrol glucosides, 389/227; resveratrol glucuronides, 403/227; resveratrol sulfates, 307/227; taxifolin, 303/285; and hexestrol, 269/134., Results: Standard calibration curves were linear at 4.4-3289.5 nmol/L. Residual analyses were 100% (3.2) for trans-resveratrol and 100% (11.1) for trans-piceid. In both matrices, imprecision (CV) was <10.8% at all concentrations. Detection limits for resveratrol were 0.2 nmol/L (LDL), 0.3 nmol/L (synthetic urine), and 4.0 nmol/L (blank urine). Resveratrol and metabolites were checked for stability, and no degradation was observed., Conclusions: The HPLC-tandem mass spectrometry method enabled us to identify resveratrol sulfates in human LDL and to characterize the complete profile of resveratrol metabolism in human LDL and urine. This method provides an accurate index of exposure to resveratrol and its metabolites, which can be used as nutritional biomarkers for evaluating the biological effects of moderate wine intake on human health.

Abstract: Beer is one of the most commonly consumed undistilled alcoholic beverages in many countries. In recent studies, the stilbenes resveratrol and piceid have been found in some hop varieties which are used in the production of beer. Therefore, they could be transferred to beer. The aim of the present work was to validate a method to study the potential content of trans- and cis-resveratrol and piceid in 110 commercial beers from around the world. The resveratrol and piceid contents of 110 beers were analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) after a solid-phase extraction (SPE) using optimized and validated procedures for the beer matrix. The beer matrix effect was also studied. Stilbenes were found in quantifiable amounts in 92 beers, while concentrations below the limit of quantification (LOQ) were found in 18 beers. Resveratrol was found in the range of 1.34–77.0μg/L in 79% of the beers analyzed, and piceid was found in the range of 1.80–27.3μg/L in only 33% of them. The mean of total resveratrol in all the beers was 14.7±20.5μg/L. The content of resveratrol has been compared with other resveratrol containing foods. A serving of beer contains similar amounts of stilbenes as berries, less than chocolate and grape products but more than pistachios, peanuts or tomatoes. Overall, beer is one of the products with the lowest levels of total resveratrol (μg/L), and despite its high consumption it should not be considered as a representative source of resveratrol. [ABSTRACT FROM AUTHOR]