The full consensus on the role of dietary polyphenols as human‐health‐promoting compounds remains elusive. The two‐way interaction between polyphenols and gut microbiota (GM) (i.e., modulation of GM ...by polyphenols and their catabolism by the GM) is determinant in polyphenols’ effects. The identification of human metabotypes associated with a differential gut microbial metabolism of polyphenols has opened new research scenarios to explain the inter‐individual variability upon polyphenols consumption. The metabotypes unequivocally identified so far are those involved in the metabolism of isoflavones (equol and(or) O‐desmethylangolesin producers versus non‐producers) and ellagic acid (urolithin metabotypes, including producers of only urolithin‐A (UM‐A), producers of urolithin‐A, isourolithin‐A, and urolithin‐B (UM‐B), and non‐producers (UM‐0)). In addition, the microbial metabolites (phenolic‐derived postbiotics) such as equol, urolithins, valerolactones, enterolactone, and enterodiol, and 8‐prenylnaringenin, among others, can exert differential health effects. The knowledge is updated and position is taken here on i) the two‐way interaction between GM and polyphenols, ii) the evidence between phenolic‐derived postbiotics and health, iii) the role of metabotypes as biomarkers of GM and the clustering of individuals depending on their metabotypes (metabotyping) to explain polyphenols’ effects, and iv) the gut microbial metabolism of catecholamines to illustrate the intersection between personalized nutrition and precision medicine.
Human metabotypes (HMs) are at the crossroads of polyphenols' (PPs) health effects. HMs, associated with a differential gut microbial metabolism of PPs, have opened new scenarios to explain the inter‐individual variability upon PPs intake. The two‐way interaction between gut microbiota (GM) and PPs, the phenolic postbiotics, the metabotyping, and HMs as biomarkers of GM participate in this complex cocktail.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Urolithins, metabolites produced by the gut microbiota from the polyphenols ellagitannins and ellagic acid, are discovered by the research group in humans almost 20 years ago. Pioneering research ...suggests urolithins as pleiotropic bioactive contributors to explain the health benefits after consuming ellagitannin‐rich sources (pomegranates, walnuts, strawberries, etc.). Here, this study comprehensively updates the knowledge on urolithins, emphasizing the review of the literature published during the last 5 years. To date, 13 urolithins and their corresponding conjugated metabolites (glucuronides, sulfates, etc.) have been described and, depending on the urolithin, detected in different human fluids and tissues (urine, blood, feces, breastmilk, prostate, colon, and breast tissues). There has been a substantial advance in the research on microorganisms involved in urolithin production, along with the compositional and functional characterization of the gut microbiota associated with urolithins metabolism that gives rise to the so‐called urolithin metabotypes (UM‐A, UM‐B, and UM‐0), relevant in human health. The design of in vitro studies using physiologically relevant assay conditions (molecular forms and concentrations) is still a pending subject, making some reported urolithin activities questionable. In contrast, remarkable progress has been made in the research on the safety, bioactivity, and associated mechanisms of urolithin A, including the first human interventions.
About 20 years ago, urolithins are discovered as bioavailable metabolites produced by the human gut microbiota from ellagitannins and ellagic acid. Pioneering investigations suggested pleiotropic effects for urolithins that growing evidence confirms, especially for urolithin A. Here, we update the knowledge on urolithins metabolism, bioactivity, and associated gut microbiota, emphasizing the literature published in the last 5 years.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Display omitted
(Poly)phenols (PPs) constitute a large family of phytochemicals with high chemical diversity that are known to be active principles of plant-derived nutraceuticals and herbal ...medicinal products. Their pharmacological activity, however, is difficult to demonstrate due to their mild physiological effects, and to the large inter-individual variability observed. Many PPs have little bioavailability and reach the colon almost unaltered. There they encounter the gut microbes resulting in a two-way interaction in which PPs modulate the gut microbiota composition, and the intestinal microbes catabolize the ingested PPs to release metabolites that are often more active and better absorbed than the native phenolic compounds. The type and quantity of the PP metabolites produced in humans depend on the gut microbiota composition and function, and different metabotypes have been identified. However, not all the metabolites have the same biological activity, and therefore the final health effects of dietary PPs depend on the gut microbiota composition. Stratification in clinical trials according to individuals’ metabotypes is necessary to fully understand the health effects of PPs. In this review, we present and discuss the most significant and updated knowledge regarding the reciprocal interrelation of the gut microbiota with dietary PPs as a key factor that modulates the health effects of these compounds. The review will focus in those PPs that are known to be metabolized by gut microbiota resulting in bioactive metabolites.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Urolithins are dibenzob,dpyran‐6‐one derivatives that are produced by the human gut microbiota from ellagitannins and ellagic acid (EA). These metabolites are much better absorbed than their ...precursors and have been suggested to be responsible for the health effects attributed to ellagitannins and EA that occur in food products as berries and nuts. In the present review, the role and potential of urolithins in human health are critically reviewed, and a perspective of the research approach needed to demonstrate these health effects is presented, based on the existing knowledge. The analytical methods available for urolithin analysis, their occurrence in different tissues and biological fluids, and their metabolism by human gut microbiota are considered. In addition, the interindividual variability observed for the production of urolithins (metabotypes) and its relationship with health status and dysbiosis are also reviewed. The potential mechanisms of action of urolithins are also critically discussed, paying attention to the concentration and the type of metabolites used in the in vitro and in vivo assays and the physiological significance of the results obtained. The gut microbiota metabolism of EA to urolithins and that of daidzein to equol, their individual variations, and the effects on health are also compared.
The role of urolithins in human health after the consumption of dietary ellagitannins (ETs) is reviewed. The review shows preclinical evidence and in vitro mechanistic studies indicating that ETs can have anti‐inflammatory effects. However, no clinical studies have confirmed this effect yet. The recent finding that urolithins can reach the brain has increased the relevance of preclinical studies indicating that urolithins might have a role in protecting against neurodegenerative diseases.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Scope
The pomegranate lipid‐lowering properties remain controversial, probably due to the interindividual variability in polyphenol (ellagitannins) metabolism.
Objective
We aimed at investigating ...whether the microbially derived ellagitannin‐metabolizing phenotypes, i.e. urolithin metabotypes A, (UM‐A), B (UM‐B), and 0 (UM‐0), influence the effects of pomegranate extract (PE) consumption on 18 cardiovascular risk biomarkers in healthy overweight‐obese individuals.
Methods and results
A double‐blind, crossover, dose–response, randomized, placebo‐controlled trial was conducted. The study (POMEcardio) consisted of two test phases (dose‐1 and dose‐2, lasting 3 weeks each) and a 3‐week washout period between each phase. Forty‐nine participants (BMI > 27 kg/m2) daily consumed one (dose‐1, 160 mg phenolics/day) or four (dose‐2, 640 mg phenolics/day) PE or placebo capsules. Notably, UM‐B individuals showed the highest baseline cardiovascular risk. After dose‐2, total cholesterol (–15.5 ± 3.7%), LDL‐cholesterol (–14.9 ± 2.1%), small LDL‐cholesterol (–47 ± 7%), non‐HDL‐cholesterol (–11.3 ± 2.5%), apolipoprotein‐B (–12 ± 2.2%), and oxidized LDL‐cholesterol –24 ± 2.5%) dose dependently decreased (P < 0.05) but only in UM‐B subjects. These effects were partially correlated with urolithin production and the increase in Gordonibacter levels. Three (50%) nonproducers (UM‐0) became producers following PE consumption.
Conclusions
UM clustering suggests a personalized effect of ellagitannin‐containing foods and could explain the controversial pomegranate benefits. Research on the specific role of urolithins and the microbiota associated with each UM is warranted.
The high interindividual variability prevents the improvement of serum cardiovascular disease risk markers in healthy overweight‐obese subjects following pomegranate supplementation. However, urolithin metabotype clustering reveales a significant improvement of the blood lipid profile only in urolithin metabotype B individuals. This suggests a personalized effect of ellagitannin‐containing foods and could explain the controversial pomegranate benefits and the lack of European Food Safety Authority related health claims.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Scope
Gut microbiota dysbiosis, intestinal barrier failure, obesity, metabolic endotoxemia, and pro‐inflammatory status promote cardiovascular risk. However, the modulation of the gut microbiome to ...prevent endotoxemia in obesity has been scarcely studied. We investigated the association between gut microbiota modulation and plasma lipopolysaccharide‐binding protein (LBP), a surrogate marker of endotoxemia, in overweight‐obese individuals.
Methods and results
In a randomized trial, 49 overweight‐obese subjects (body mass index> 27 kg m−2) with mild hypelipidemia daily consumed, in a cross‐over fashion, two doses (D1 and D2, lasting 3 weeks each) of pomegranate extract (PE) or placebo alternating with 3 weeks of wash‐out periods. A significant decrease (p < 0.05) of plasma LBP and a marginal decrease (p = 0.054) of high‐sensitivity C‐reactive protein were observed, but only after PE‐D2 administration (656 mg phenolics). 16S rDNA sequencing analyses revealed the increase of microorganisms important for maintaining normal balance of gut microbiota and gut barrier function, particularly Bacteroides, Faecalibacterium, Butyricicoccus, Odoribacter, and Butyricimonas. PE‐D2 also decreased pro‐inflammatory microorganisms including Parvimonas, Methanobrevibacter, and Methanosphaera. Remarkably, plasma LBP reduction was significantly associated (p < 0.05) with both Faecalibacterium and Odoribacter increase and Parvimonas decrease.
Conclusions
Consumption of PE decreased endotoxemia in overweight‐obese individuals by reshaping the gut microbiota, mainly through the modulation of Faecalibacterium, Odoribacter, and Parvimonas.
Gut microbiota dysbiosis, intestinal barrier failure, obesity, metabolic endotoxemia, and pro‐inflammatory status promote cardiovascular risk. Consumption of a polyphenol‐rich pomegranate extract decreased plasma lipopolysaccharide‐binding protein (LBP), a marker of endotoxemia, in mild hyperlipidemic overweight‐obese subjects. This was mediated by a gut microbiota reshaping, determined by 16S rDNA sequencing, mainly through both Faecalibacterium and Odoribacter increase and Parvimonas decrease.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Scope
Recent evidence demonstrates that resveratrol (RSV) metabolites, but not free RSV, reach malignant tumors (MT) in breast cancer (BC) patients. Since these metabolites, as detected in MT, do not ...exert short‐term antiproliferative or estrogenic/antiestrogenic activities, long‐term tumor‐senescent chemoprevention has been hypothesized. Consequently, here, for the first time, whether physiologically relevant RSV metabolites can induce senescence in BC cells is investigated.
Methods and Results
Human BC MCF‐7 (wild‐type p53) and MDA‐MB‐231 (mutant p53), and non‐tumorigenic MCF‐10A cells are treated with free RSV and physiological‐derived metabolites (RSV 3‐O‐glucuronide, RSV 3‐O‐sulfate, RSV 4′‐O‐sulfate, dihydroresveratrol (DH‐RSV), and DH‐RSV 3‐Oglucuronide). Cellular senescence is measured by SA‐β‐gal activity and senescence‐associated markers (p53, p21Cip1/Waf1, p16INK4a, and phosphorylation status of retinoblastoma (pRb/tRb)). Although no effect is observed in MDA‐MB‐231 and normal cells, RSV metabolites induce cellular senescence in MCF‐7 cells by reducing their clonogenic capacity and arresting cell cycle at G2M/S phase, but do not induce apoptosis. Senescence is induced through the p53/p21Cip1/Waf1 and p16INK4a/Rb pathways, depending on the RSV metabolite, and requires ABC transporters, but not estrogen receptors.
Conclusions
These data suggest that RSV metabolites, as found in MT from BC patients, are not de‐conjugated to release free RSV, but enter the cells and may exert long‐term tumor‐senescent chemoprevention.
Physiologically relevant resveratrol (RSV) metabolites, as found in malignant tissues from breast cancer (BC) patients, induce cellular senescence in BC cells but not in non‐tumorigenic cells. Senescence is induced through the p53/p21 and p16/Rb pathways, depending on the RSV‐metabolite, and requires ABC transporters but not estrogen receptors. This mechanism might be involved in BC chemoprevention upon consumption of RSV‐containing foods.
.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Scope
Some polyphenol‐derived metabolites reach human breast cancer (BC) tissues at concentrations that induce cell senescence. However, this is unknown for isoflavones, curcuminoids, and lignans. ...Here, their metabolic profiling in normal (NT) and malignant (MT) mammary tissues of newly‐diagnosed BC patients and the tissue‐occurring metabolites’ anticancer activity are evaluated.
Methods and results
Patients (n = 26) consumed 3 capsules/day (turmeric, red clover, and flaxseed extracts plus resveratrol; 296.4 mg phenolics/capsule) from biopsy‐confirmed diagnosis to surgery (5 ± 2 days) or did not consume capsules (n = 13). NT and MT, blood, and urine are analyzed by UPLC‐QTOF‐MS using targeted metabolomics. Anticancer activity was tested in MCF‐7 and MDA‐MB‐231 BC cells. Mainly phase‐II metabolites were detected (108, 84, 49, and 47 in urine, plasma, NT, and MT, respectively). Total metabolite concentrations reached 10.7 ± 11.1 and 2.5 ± 2.4 µmol L–1 in NT and MT, respectively. Free curcumin, but not its glucuronide, was detected in the tissues (1.1 ± 1.8 and 0.2 ± 0.2 µmol L–1 in NT and MT, respectively). Breast tissue‐occurring metabolites’ antiproliferation was mainly exerted in p53‐wild‐type MCF‐7 cells by curcuminoids through cell cycle arrest, senescence, and apoptosis induction via p53/p21 induction, while isoflavone‐derived metabolites exerted estrogenic‐like activity.
Conclusion
Curcuminoids could be coadjuvants that might help fight BC upon regular consumption.
A total of 47 curcuminoid, isoflavone, resveratrol, and lignan‐derived metabolites, mostly conjugated, were detected in malignant mammary tissues of breast cancer patients. However, free curcumin, but not its glucuronide, was detected at micromolar concentration, likely due to a glucuronidation‐saturation process. Breast tissue‐occurring metabolites, mainly, curcuminoids, induced cell cycle arrest, senescence, and apoptosis via p53/p21, while isoflavone metabolites exerted estrogenic activity.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Several epidemiological studies have linked flavonols with decreased risk of cardiovascular disease (CVD). However, some heterogeneity in the individual physiological ...responses to the consumption of these compounds has been identified. This meta-analysis aimed to study the effect of flavonol supplementation on biomarkers of CVD risk such as, blood lipids, blood pressure and plasma glucose, as well as factors affecting their inter-individual variability. Data from 18 human randomized controlled trials were pooled and the effect was estimated using fixed or random effects meta-analysis model and reported as difference in means (DM). Variability in the response of blood lipids to supplementation with flavonols was assessed by stratifying various population subgroups: age, sex, country, and health status. Results showed significant reductions in total cholesterol (DM = -0.10 mmol/L; 95% CI: -0.20, -0.01), LDL cholesterol (DM = -0.14 mmol/L; Nutrients 2017, 9, 117 2 of 21 95% CI: -0.21, 0.07), and triacylglycerol (DM = -0.10 mmol/L; 95% CI: -0.18, 0.03), and a significant increase in HDL cholesterol (DM = 0.05 mmol/L; 95% CI: 0.02, 0.07). A significant reduction was also observed in fasting plasma glucose (DM = -0.18 mmol/L; 95%CI: -0.29, -0.08), and in blood pressure (SBP: DM = -4.84 mmHg; 95% CI: -5.64, -4.04; DBP: DM = -3.32 mmHg; 95% CI: -4.09, -2.55). Subgroup analysis showed a more pronounced effect of flavonol intake in participants from Asian countries and in participants with diagnosed disease or dyslipidemia, compared to healthy and normal baseline values. In conclusion, flavonol consumption improved biomarkers of CVD risk, however, country of origin and health status may influence the effect of flavonol intake on blood lipid levels.
Scope
Dietary polyphenols may protect against breast cancer. However, it is unknown whether polyphenols reach human malignant breast tumors in molecular forms and(or) at concentrations likely to act ...against cancer.
Methods and Results
Ninteen breast cancer patients consumed three capsules daily from biopsy‐confirmed diagnosis to surgery (6 ± 2 days). The capsules contained pomegranate, orange, lemon, olive, cocoa, and grapeseed extracts plus resveratrol, providing 37 different phenolics (473.7 mg), theobromine and caffeine (19.7 mg). A total of 101 metabolites are identified in urine, 69 in plasma, 39 in normal (NT), and 33 in malignant (MT) tissues by UPLC‐ESI‐QTOF‐MS. Eight control patients did not consume extracts. Phenolic‐derived metabolites in MT and NT are mainly glucuronidated and(or) sulfated. Some representative metabolites detected in MT (median and range, pmol g−1) are urolithin‐A‐3‐O‐glucuronide (26.2; 3.2−66.5), 2,5‐dihydroxybenzoic acid (40.2; 27.7−52.2), resveratrol‐3‐O‐sulfate (86.4; 7.8−224.4), dihydroresveratrol‐3‐O‐glucuronide (109.9; 10.3−229.4), and theobromine (715.0; 153.9−3,216). Metabolites, as detected in breast tissues, do not exert antiproliferative or estrogenic/antiestrogenic activities in MCF‐7 breast cancer cells.
Conclusion
This is the first study that describes the metabolic profiling of dietary phenolics and methylxanthines in MT and NT comprehensively. Although phase‐II conjugation might hamper a direct anticancer activity, long‐term tumor‐senescent chemoprevention cannot be discarded.
The first comprehensive metabolic profiling of dietary phenolics and methylxanthines in normal and malignant mammary tissues from newly diagnosed breast cancer patients is reported. The pool of metabolites, as detected in malignant tissues, do not exert antiproliferative or estrogenic/antiestrogenic activities in the MCF‐7 breast cancer model. Although phase‐II conjugation may hamper anticancer activity, long‐term tumor‐senescent chemoprevention cannot be discarded.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
