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.
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SCOPE: Chlorogenic acid (3‐O‐caffeoyl‐quinic acid, C‐QA), the caffeic ester of quinic acid, is one of the most abundant phenolic acids in Western diet. The majority of C‐QA escapes absorption in the ...small intestine and reaches the colon, where the resident microbiota transforms it into several metabolites. C‐QA conversion by the gut microbiota from nine subjects was compared to evaluate the variability of bacterial metabolism. It was investigated whether a potentially probiotic Bifidobacterium strain, capable of C‐QA hydrolysis, could affect C‐QA fate. METHODS AND RESULTS: Bioconversion experiments exploiting the microbiota from diverse subjects revealed that C‐QA was metabolized through a succession of hydrogenation, dexydroxylation and ester hydrolysis, occurring in different order among the subjects. Transformation may proceed also through quinic acid residue breakdown, since caffeoyl‐glycerol intermediates were identified (HPLC‐MS/MS, Q‐TOF). All the pathways converged on 3‐(3‐hydroxyphenyl)‐propanoic acid, which was transformed to hydroxyphenyl‐ethanol and/or phenylacetic acid in few subjects. A strain of Bifidobacterium animalis able to hydrolyze C‐QA was added to microbiota cultures. It affected microbial composition but not to such an extent that C‐QA metabolism was modified. CONCLUSION: A picture of the variability of microbiota C‐QA transformations among subjects is provided. The transformation route through caffeoyl‐glycerol intermediates is described for the first time.
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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.
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Ellagic acid (EA) is converted to urolithins by gut microbiota. Urolithins have beneficial biological effects in humans, but differences in urolithin production capacity among individuals have been ...shown. Therefore, the identification of the urolithin production pathways and the microorganisms implicated is of high interest. EA was incubated with gut microbiota from two volunteers able to produce urolithins but with different in vivo urolithin profiles (urolithin A and isourolithin A producers). The metabolic capabilities observed in vivo were retained in vitro. Both individuals showed a much higher abundance of Clostridium leptum group of Firmicutes phylum than Bacteroides/Prevotella. EA was either dissolved in DMSO or suspended in water. DMSO increased EA solubility but decreased urolithin production rate due to a delay in growth of some microbial groups, principally, Clostridium coccoides. This allowed the detection of catabolic intermediates urolithins M-5, M-6, M-7, C, and 2,3,8,10-tetrahydroxy urolithin (urolithin E). Bacteria from C. coccoides group (or genera co-occurring in vivo with this group) seem to be involved in production of different urolithins.
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Three phenotypes for urolithin production after ellagitannin and ellagic acid intake are consistently observed in different human intervention trials. Subjects can be stratified into three ...urolithin-producing groups. “Phenotype A” produced only urolithin A conjugates, which included between 25 and 80% of the volunteers in the different trials. “Phenotype B” produced isourolithin A and/or urolithin B in addition to urolithin A, this being the second relevant group (10–50%). “Phenotype 0” (5–25%) was that in which these urolithins were not detected. The three phenotypes were observed independently of the volunteers’ health status and demographic characteristics (age, gender, body mass index (BMI)) and of the amount or type of ellagitannin food source ingested (walnuts and other nuts, strawberries, raspberries, and other berries or pomegranates). Interestingly, a higher percentage of phenotype B was observed in those volunteers with chronic illness (metabolic syndrome or colorectal cancer) associated with gut microbial imbalance (dysbiosis). These urolithin phenotypes could show differences in the human gut microbiota and should be considered in intervention trials dealing with health benefits of ellagitannins or ellagic acid. Whether this phenotypic variation could be a biomarker related to differential health benefits or illness predisposition deserves further research.
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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.
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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.
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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.
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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.
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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.
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