Untargeted metabolomics identified urinary biomarkers able to discriminate between the intake of fresh hand-squeezed and industrially processed orange juices. Processing led to an upregulation in the ...excretion of hydroxy-polymethoxyflavone sulfates, abscisic acid, and sinapic acid 4′-glucuronide. The demethylated polymethoxyflavone metabolites were produced with a significant interindividual variability suggesting that they could originate from gut microbiota metabolism. No correlation between the excretion levels of flavanone and polymethoxyflavone metabolites was observed, showing that gut microbiota metabolism differences could be behind the interindividual variability. Subjects with a high excretion level of hesperetin conjugates could be low or high polymethoxyflavone excretors. Flavanone phase II metabolites were primarily glucuronides, while those of demethylated polymethoxyflavones were mainly sulfates. A comparative study with the available demethylated polymethoxyflavone standards suggested that the metabolites produced in humans could be tentatively 4′-hydroxy- and/or 3′-hydroxy-polymethoxyflavone sulfates. This study is the first to describe the bioavailability and metabolism of citrus juice polymethoxyflavones in humans.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
SCOPE: MicroRNAs (miRs) are proposed as colorectal cancer (CRC) biomarkers. Pomegranate ellagic acid and their microbiota metabolites urolithins exert anticancer effects in preclinical CRC models, ...and target normal and malignant colon tissues in CRC patients. Herein, we investigated whether the intake of pomegranate extract (PE) modified miRs expression in surgical colon tissues versus biopsies from CRC patients. METHODS AND RESULTS: We conducted a randomized, double‐blind, controlled trial. Thirty‐five CRC patients consumed 900 mg PE daily before surgery. Control CRC patients (no PE intake, n = 10) were included. Our results revealed: (1) significant differences for specific miRs between malignant and normal tissues modifiable by the surgical protocols; (2) opposed trends between ‐5p and ‐3p isomolecules; (3) general induction of miRs attributable to the surgery; (4) moderate modulation of various miRs following the PE intake, and (5) no association between tissue urolithins and the observed miRs changes. CONCLUSION: PE consumption appears to affect specific colon tissue miRs but surgery critically alters miRs levels hindering the discrimination of significant changes caused by dietary factors and the establishment of genuine differences between malignant and normal tissues as biomarkers. The components responsible for the PE effects and the clinical relevance of these observations deserve further research.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Colorectal cancer (CRC) remains a major cause of cancer death worldwide. Over 70% of CRC cases are sporadic and related to lifestyle. Epidemiological studies inversely correlate CRC incidence with ...the intake of fruits and vegetables but not with their phenolic content. Preclinical studies using in vitro (cell lines) and animal models of CRC have reported anticancer effects for dietary phenolics through the regulation of different markers and signaling pathways. Herein, we review and contrast the evidence between preclinical studies and clinical trials (patients with CRC or at risk, familial adenopolyposis or aberrant crypt foci) investigating the protective effects of curcumin, resveratrol, isoflavones, green tea extracts (epigallocatechin gallate), black raspberry powder (anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger extracts (gingerol derivatives), and pomegranate extracts (ellagitannins and ellagic acid). To date, curcumin is the most promising polyphenol as possible future adjuvant in CRC management. Overall, the clinical evidence of dietary phenolics against CRC is still weak and the amounts needed to exert some effects largely exceed common dietary doses. We discuss here the possible reasons behind the gap between preclinical and clinical research (inconsistence of results, lack of clinical endpoints, etc.), and provide an outlook and a roadmap to approach this topic.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Urolithins are intestinal microbial metabolites produced from ellagitannin- and ellagic acid-containing foods such as walnuts, strawberries, and pomegranates. These metabolites, better absorbed than ...their precursors, can contribute significantly to the beneficial properties attributed to the polyphenols ellagitannins and ellagic acid (EA). However, both the ability of producing the final metabolites in this catabolism (urolithins A, B and isourolithin A) and the health benefits associated with ellagitannin consumption differ considerably among individuals depending on their gut microbiota composition. Three human urolithin metabotypes have been previously described, i.e., metabotype 0 (urolithin non-producers), metabotype A (production of urolithin A as unique final urolithin) and metabotype B (urolithin B and/or isourolithin A are produced besides urolithin A). Although production of some intermediary urolithins has been recently attributed to intestinal species from
family named
and
, the identification of the microorganisms responsible for the complete transformation of EA into the final urolithins, especially those related to metabotype B, are still unknown. In the present research we illustrate the isolation of urolithin-producing strains from human feces of a healthy adult and their ability to transform EA into different urolithin metabolites, including isourolithin A. The isolates belong to a new genus from
family. EA transformation and urolithin production arisen during the stationary phase of the growth of the bacteria under anaerobic conditions. The HPLC-DAD-MS analyses demonstrated the sequential appearance of 3,8,9,10-tetrahydroxy-urolithin (urolithin M6), 3,8,9-trihydroxy-urolithin (urolithin C) and 3,9-dihydroxy-urolithin (isourolithin A) while 3,8-dihydroxy-urolithin (urolithin A) and 3-hydroxy-urolithin (urolithin B) were not detected. For the first time isourolithin A production capacity of pure strains has been described. The biological activity attributed to urolithins A and B and isourolithin A (anti-inflammatory, anti-carcinogenic, cardioprotective, and neuroprotective properties) explains the relevance of identifying these urolithin-producing bacteria as potential novel probiotics with applications in the development of functional foods and nutraceuticals. Their human administration could improve the health benefits upon ellagitannin consumption, especially in metabotype 0 individuals. However, further research is necessary to probe well-established beneficial effects on the host and safety requirements before being considered among the next-generation probiotics.
Primary prevention of cardiovascular disease (CVD) aims to avoid a first event in subjects that are at risk but have not yet been diagnosed with heart disease. Secondary prevention of CVD aims to ...avoid new events in patients with established heart disease. Both approaches involve clinical intervention and implementation of healthy lifestyles. The grape and wine polyphenol resveratrol (3,5,4′‐trihydroxy‐trans‐stilbene) has shown cardioprotective benefits in humans. Most of these approaches deal with rather high doses and short follow‐ups, and do not address the issue of long‐term resveratrol consumption safety, especially in medicated individuals. Here, we review the trials conducted with resveratrol in patients at risk for or with established CVD, focusing on the two longest human clinical trials reported so far (1‐year follow‐up). We also discuss the expectations for resveratrol from a dietary and clinical perspective in relation to CVD. However, statistically significant changes in CVD‐risk markers do not necessarily equal clinical significance in the daily care of patients.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
PURPOSE OF REVIEWDietary (poly)phenolic compounds have received attention over the last 20 years as antioxidants with preventive properties against chronic diseases. However, the evidence of these ...effects in clinical trials is weak, mainly because of a considerable interindividual variability. Polyphenols bioavailability is low, and gut microbiota metabolize them into simpler metabolites. As gut microbiota vary among individuals, such interindividual variability should be considered as a moderating factor in clinical trials. In this review, we show evidence of interactions with gut microbiota that help understanding polyphenols’ health effects.
RECENT FINDINGSRecent studies indicate that dietary polyphenols are relevant in the modulation of gut microbiota and that these microorganisms convert polyphenols into active and bioavailable metabolites; hence, variations in gut microbiota can affect polyphenol activity.
SUMMARYThe results show that study participants’ stratification by their polyphenol-metabolizing phenotypes would be necessary for clinical trials as specific metabotypes produce the bioactive metabolites responsible for the health effects. Metabotypes can also reflect the gut microbiota composition and metabolic status, and could be biomarkers of the potential polyphenol health effects mediated through gut microbiota.
The metabolism of phenolic compounds is a key factor in the development of wound-induced enzymatic browning of fresh-cut lettuce. In the present study, the lettuce midribs discriminant metabolites, ...selected in a previous untargeted metabolomics study, were thoroughly identified. Our results showed that their basal contents correlated with browning developed after 5 days of storage. 5-trans-Chlorogenic acid and 5-cis-chlorogenic acid were positively correlated with browning, while sinapaldehyde and its 4-β-d-glucoside and 4-(6′-malonyl)-β-d-glucoside conjugates were negatively correlated. Using targeted metabolomics, the metabolites were analyzed in lettuce heads with different degrees of development and different browning susceptibility and these biomarkers were confirmed. Despite the large variability in the browning process of lettuce, the chlorogenic acids/sinapaldehyde derivatives ratio showed a linear correlation (r 2 = 0.79) with the fresh-cut lettuce browning developed in 24 Romaine lettuce cultivars, validating the relevance of these biomarkers. These results show that the analysis of the basal content of these metabolites could be used in lettuce breeding programs to select cultivars that are more appropriate for the fresh-cut industry.
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Low–glycemic index diets have demonstrated health benefits associated with a reduced risk of developing type 2 diabetes.
We tested whether pomegranate polyphenols could lower the glycemic response of ...a high–glycemic index food when consumed together and the mechanism by which this might occur.
We compared the acute effect of a pomegranate juice and a polyphenol-rich extract from pomegranate (supplement) on the bread-derived postprandial blood glucose concentration in 2 randomized, crossover, controlled studies (double-blinded for the supplements), each on 16 healthy volunteers. An additional randomized, crossover, controlled study on 16 volunteers consuming constituent fruit acids in a pH-balanced solution (same pH as pomegranate) and bread was conducted to determine any contributions to postprandial responses caused by acidic beverages.
As primary outcome, the incremental area under the curve for bread-derived blood glucose (−33.1% ± 18.1%, P = 0.000005) and peak blood glucose (25.4% ± 19.3%, P = 0.0004) were attenuated by pomegranate juice, compared with a control solution containing the equivalent amount of sugars. In contrast, the pomegranate supplement, or a solution containing the malic and citric acid components of the juice, was ineffective. The pomegranate polyphenol punicalagin was a very effective inhibitor of human α-amylase in vitro, comparable to the drug acarbose. Neither the pomegranate extract nor the individual component polyphenols inhibited 14C-D-glucose transport across differentiated Caco-2/TC7 cell monolayers, but they inhibited uptake of 14C-glucose into Xenopus oocytes expressing the human glucose transporter type 2. Further, some of the predicted pomegranate gut microbiota metabolites modulated 14C-D-glucose and 14C-deoxy-D-glucose uptake into hepatic HepG2 cells.
These data indicate that pomegranate polyphenols, when present in a beverage but not in a supplement, can reduce the postprandial glycemic response of bread, whereas microbial metabolites from pomegranate polyphenols exhibit the potential to further modulate sugar metabolism much later in the postprandial period. This trial was registered at clinicaltrials.gov as NCT02486978, NCT02624609, and NCT03242876.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pomegranate (Punica granatum L.) is a well-known source of bioactive phenolic compounds such as ellagitannins, anthocyanins, and flavanols. Punicalagin, one of the main constituents of pomegranate, ...needs to be biodegraded by bacteria to yield metabolites of medicinal interest. In this work, we tested 30 lactic acid bacteria (LAB) and their capacity to transform punicalagin from a punicalagin-rich pomegranate extract into smaller bioactive molecules, namely, ellagic acid and urolithins. These were identified and quantified by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS2). Further, we evaluated the molecular mechanism governing this transformation through label-free comparative MS-based proteomics. All tested LAB strains were capable of transforming punicalagin into ellagic acid, while the biosynthesis of urolithins was not observed. Proteomic analysis revealed an increase of generic transglycosylases that might have a hydrolytic role in the target phenolic molecule, coupled with an increase in the quantity of ATP-binding cassette (ABC) transporters, which might play a relevant role in transporting the resulting byproducts in and out of the cell.
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The relevance of environmental triggers in Crohn's disease remains poorly explored, despite the well‐known association between industrialization and disease onset/progression. We have aimed at ...evaluating the influence of endocrine disrupting chemicals in CD patients. We performed a prospective observational study on consecutive patients diagnosed of CD. Serum levels of endocrine disruptors, short‐chain fatty acids, tryptophan and cytokines were measured. Bacterial‐DNA and serum endotoxin levels were also evaluated. Gene expression of ER‐α, ER‐β and GPER was measured in PBMCs. All patients were genotyped for NOD2 and ATG16L1 polymorphisms. A series of 200 CD patients (140 in remission, 60 with active disease) was included in the study. Bisphenol A was significantly higher in patients with active disease versus remission and in colonic versus ileal disease. GPER was significantly increased in active patients and correlated with BPA levels. BPA was significantly increased in patients with bacterial‐DNA and correlated with serum endotoxin levels, (r = 0.417; P = .003). Serum butyrate and tryptophan levels were significantly lower in patients with bacterial‐DNA and an inverse relationship was present between them and BPA levels (r = −0.491; P = .001) (r = −0.611; P = .001). Serum BPA levels correlated with IL‐23 (r = 0.807; P = .001) and IL‐17A (r = 0.743; P = .001). The multivariate analysis revealed an independent significant contribution of BPA and bacterial‐DNA to serum levels of IL‐23 and IL‐17A. In conclusion, bisphenol A significantly affects systemic inflammatory response in CD patients with gut barrier disruption and dysbiotic microbiota secretory products in blood. These results provide evidence of an endocrine disruptor playing an actual pathogenic role on CD.
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