ScopeNumerous in vitro and in vivo studies indicate that ellagitannins exhibit anti‐inflammatory, anti‐atherosclerotic and anti‐angiogenic activity which support their potential preventive effect ...against cardiovascular diseases. Ellagitannins exhibit low bioavailability and are transformed in the gut to ellagic acid and its microbiota metabolites urolithin A (Uro‐A) and urolithin B (Uro‐B). Urolithins are found in plasma mostly as glucuronides at low μM concentrations. We investigated whether urolithin glucuronides and their aglycones exhibit vascular protective effects.
Methods and resultsHuman aortic endothelial cells were exposed to tumor necrosis factor alpha and to Uro‐A glucuronide, Uro‐B glucuronide or their corresponding aglycones at low μM concentrations to determine their effects on monocytes adhesion and endothelial cell migration. The levels of related adhesion cytokines and growth molecular markers were also measured. Uro‐A glucuronide (∼5–15 μM) inhibited monocyte adhesion and endothelial cell migration in a significant manner. These effects were associated with a moderate but significant down‐regulation of the levels of chemokine (C–C motif) ligand 2 (CCL2) and plasminogen activator inhibitor‐1 (PAI‐1). Uro‐A inhibited endothelial cell migration and was able to decrease the expression of CCL2 and interleukin‐8 (IL‐8).
ConclusionOur results suggest that these metabolites might be involved, at least in part, in the beneficial effects against cardiovascular diseases attributed to the consumption of ellagitannin‐containing foods.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The breast cancer resistance protein (BCRP/ABCG2) is a drug efflux transporter that can affect the pharmacological and toxicological properties of many molecules. Urolithins, metabolites produced by ...the gut microbiota from ellagic acid (EA) and ellagitannins, have been acknowledged with in vivo anti-inflammatory and cancer chemopreventive properties. This study evaluated whether urolithins (Uro-A, -B, -C, and -D) and their main phase II metabolites Uro-A sulfate, Uro-A glucuronide, and Uro-B glucuronide as well as their precursor EA were substrates for ABCG2/BCRP. Parental and Bcrp1-transduced MDCKII cells were used for active transport assays. Uro-A and, to a lesser extent, Uro-A sulfate showed a significant increase in apically directed translocation in Bcrp1-transduced cells. Bcrp1 did not show affinity for the rest of the tested compounds. Data were confirmed for murine, human, bovine, and ovine BCRP-transduced subclones as well as with the use of the selective BCRP inhibitor Ko143. The transport inhibition by Uro-A was analyzed by flow cytometry compared to Ko143 using the antineoplastic agent mitoxantrone as a model substrate. Results showed that Uro-A was able to inhibit mitoxantrone transport in a dose-dependent manner. This study reports for the first time that Uro-A and its sulfate conjugate are ABCG2/BCRP substrates. The results suggest that physiologically relevant concentrations of these gut microbiota-derived metabolites could modulate ABCG2/BCRP-mediated transport processes and mechanisms of cancer drug resistance. Further in vivo investigations are warranted.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Summary Background & aims Urolithins are microbial metabolites produced after consumption of ellagitannin-containing foods such as pomegranates and walnuts. Parallel to isoflavone-metabolizing ...phenotypes, ellagitannin-metabolizing phenotypes (urolithin metabotypes A, B and 0; UM-A, UM-B and UM-0, respectively) can vary among individuals depending on their body mass index (BMI), but correlations between urolithin metabotypes (UMs) and cardiometabolic risk (CMR) factors are unexplored. We investigated the association between UMs and CMR factors in individuals with different BMI and health status. Methods UM was identified using UPLC-ESI-qToF-MS in individuals consuming pomegranate or nuts. The associations between basal CMR factors and the urine urolithin metabolomic signature were explored in 20 healthy normoweight individuals consuming walnuts (30 g/d), 49 healthy overweight-obese individuals ingesting pomegranate extract (450 mg/d) and 25 metabolic syndrome (MetS) patients consuming nuts (15 g-walnuts, 7.5 g-hazelnuts and 7.5 g-almonds/d). Results Correlations between CMR factors and urolithins were found in overweight-obese individuals. Urolithin-A (mostly present in UM-A) was positively correlated with apolipoprotein A-I ( P ≤ 0.05) and intermediate-HDL-cholesterol ( P ≤ 0.05) while urolithin-B and isourolithin-A (characteristic from UM-B) were positively correlated with total-cholesterol, LDL-cholesterol ( P ≤ 0.001), apolipoprotein B ( P ≤ 0.01), VLDL-cholesterol, IDL-cholesterol, oxidized-LDL and apolipoprotein B:apolipoprotein A-I ratio ( P ≤ 0.05). In MetS patients, urolithin-A only correlated inversely with glucose ( P ≤ 0.05). Statin-treated MetS patients with UM-A showed a lipid profile similar to that of healthy normoweight individuals while a poor response to lipid-lowering therapy was observed in MB patients. Conclusions UMs are potential CMR biomarkers. Overweight-obese individuals with UM-B are at increased risk of cardiometabolic disease, whereas urolithin-A production could protect against CMR factors. Further research is warranted to explore these associations in larger cohorts and whether the effect of lipid-lowering drugs or ellagitannin-consumption on CMR biomarkers depends on individuals’ UM. Clinical Trial Registry numbers and websites NCT01916239 ( https://clinicaltrials.gov/ct2/show/NCT01916239 ) and ISRCTN36468613 ( http://www.isrctn.com/ISRCTN36468613 ).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Several randomized controlled trials (RCTs) and meta-analyses support the benefits of flavanols on cardiometabolic health, but the factors affecting variability in the responses to these compounds ...have not been properly assessed. The objectives of this meta-analysis were to systematically collect the RCTs-based-evidence of the effects of flavanol-containing tea, cocoa and apple products on selected biomarkers of cardiometabolic risk and to explore the influence of various factors on the variability in the responses to the consumption of these products. A total of 120 RCTs were selected. Despite a high heterogeneity, the intake of the flavanol-containing products was associated using a random model with changes (reported as standardized difference in means (SDM)) in body mass index (−0.15, p < 0.001), waist circumference (−0.29, p < 0.001), total-cholesterol (−0.21, p < 0.001), LDL-cholesterol (−0.23, p < 0.001), and triacylglycerides (−0.11, p = 0.027), and with an increase of HDL-cholesterol (0.15, p = 0.005). Through subgroup analyses, we showed the influence of baseline-BMI, sex, source/form of administration, medication and country of investigation on some of the outcome measures and suggest that flavanols may be more effective in specific subgroups such as those with a BMI ≥ 25.0 kg/m2, non-medicated individuals or by specifically using tea products. This meta-analysis provides the first robust evidence of the effects induced by the consumption of flavanol-containing tea, cocoa and apple products on weight and lipid biomarkers and shows the influence of various factors that can affect their bioefficacy in humans. Of note, some of these effects are quantitatively comparable to those produced by drugs, life-style changes or other natural products. Further, RCTs in well-characterized populations are required to fully comprehend the factors affecting inter-individual responses to flavanol and thereby improve flavanols efficacy in the prevention of cardiometabolic disorders.
Chemotherapy increases the overall survival in colorectal cancer (CRC) patients. 5-Fluorouracil (5-FU) remains as a drug of first choice in CRC therapy over the last four decades. However, only ...10-15% of patients with advanced CRC respond positively to 5-FU monotherapy. Therefore, new strategies to enhance the 5-FU effectiveness, overcome the tumor cell resistance and decrease the unspecific toxicity are critically needed. Urolithin A (Uro-A) is the main metabolite produced by the human gut microbiota from the dietary polyphenol ellagic acid. Uro-A targets the colonic mucosa of CRC patients, and preclinical studies have shown the anti-inflammatory and cancer chemopreventive activities of this metabolite. We evaluated here whether Uro-A, at concentrations achievable in the human colorectum, could sensitize colon cancer cells to 5-FU and 5′DFUR (a pro-drug intermediate of 5-FU). We found that both 5-FU and 5′DFUR arrested the cell cycle at the S phase by regulating cyclins A and B1 in the human colon cancer cells Caco-2, SW-480 and HT-29, and also triggered apoptosis through the activation of caspases 8 and 9. Co-treatments with Uro-A decreased IC
50
values for both 5-FU and 5′DFUR and additionally arrested the cell cycle at the G
2
/M phase together with a slight increase in caspases 8 and 9 activation. Overall, we show that Uro-A potentiated the effects of both 5-FU and 5′DFUR on colon cancer cells. This suggests the need for lower 5-FU doses to achieve similar effects, which could reduce possible adverse effects. Further
in vivo
investigations are warranted to explore the possible role of Uro-A as a chemotherapy adjuvant.
The ellagic acid-derived gut microbiota metabolite, urolithin A, at concentrations achievable in the human colorectum, enhances the anticancer effects of 5-FU-chemotherapy on three different colon cancer cells.
PURPOSE: Urolithins, gut microbiota metabolites derived from ellagic acid and ellagitannins, reach micromolar concentrations in the colon lumen where can have anti-inflammatory and anticancer ...effects. The antiproliferative activity of urolithins (Uro-A, Uro-B, Uro-C and Uro-D) and their most relevant in vivo glucuronides were evaluated in three human colon cancer cell lines (Caco-2, SW480 and HT-29). METHODS: Cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and Trypan blue exclusion assays. Cell cycle was evaluated by flow cytometry and urolithins metabolism by HPLC–MS/MS. RESULTS: Urolithins inhibited cell proliferation and cell cycle progression in a time- and dose-dependent manner and arrested the cells at S and G2/M phases, depending on the urolithin. Uro-A exerted the highest antiproliferative activity, followed by Uro-C, Uro-D and Uro-B. Unlike Caco-2 and SW480 cells, HT-29 cells partially overcame the effects after 48 h, which was related to the complete glucuronidation of urolithins. Uro-A or Uro-B glucuronides did not affect cell cycle and showed lower antiproliferative activity than their aglycone counterparts. Uro-A or Uro-B plus inhibitors of drug efflux ABC transporters partially prevented the glucuronidation of urolithins in HT-29 cells which became more sensitive. CONCLUSIONS: Uro-A, Uro-B, Uro-C and Uro-D exerted different antiproliferative effects depending on the colon cancer cell line. We also report here, for the first time, the role of ABC transporters and Phase-II metabolism in HT-29 cells as a mechanism of cancer resistance against urolithins due to their conversion to glucuronide conjugates that exerted lower antiproliferative activity.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols poorly absorbed but extensively metabolized by the human gut microbiota to produce different urolithins (Uros). Depending on the ...individuals' microbial signatures, ETs metabolism can yield the Uro metabotypes A, B, or 0, potentially impacting human health after consuming ETs. Human evidence points to improved brain health after consuming ET-rich foods, mainly pomegranate juices and extracts containing punicalagin, punicalin, and different EA-derivatives. Although ETs and (or) EA are necessary to exert the effects, the precise mechanism, actual metabolites, or final drivers responsible for the observed effects have not been unraveled. The cause-and-effect evidence on Uro-A administration and the improvement of animal brain health is consistent but not addressed in humans. The Uro-A's in vivo anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities suggest it as a possible final driver in neuroprotection. However, the precise Uro metabolic forms reaching the brain are unknown. In addition to the possible participation of direct effectors in brain tissues, the current evidence points out that improving blood flow, gut microbiota ecology, and gut barrier by ET-rich foods and (or) Uro-A could contribute to the neuroprotective effects. We show here the current human evidence on ETs and brain health, the possible link between the gut microbiota metabolism of ETs and their effects, including the preservation of the gut barrier integrity, and the possible role of Uros. Finally, we propose a roadmap to address what is missing on ETs, Uros, and neuroprotection.
•Human evidence points to improved brain health after consuming ET-rich foods.•Neuroprotection could arise through direct and indirect mediators.•Gut microbiota and gut barrier improvement could contribute to the effects.•Current evidence suggests that urolithin A is directly involved in neuroprotection.•The ultimate driver(s) of the effects have not been unequivocally identified.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Urolithin A produced in vivo was positively associated to Gordonibacter levels.•Faecal cultures confirmed the relationship between Gordonibacter and urolithin A.•The metabolic phenotypes observed in ...vivo were reproduced in vitro faecal culture.•DMSO modified the in vitro growth of bacterial groups and also the phenotype.•Individuals' Gordonibacter abundance can affect ellagitanin health benefits.
The contribution of Gordonibacter to the different abilities, both qualitative and quantitative, of individuals to transform dietary ellagic acid into anti-inflammatory urolithins was investigated. A specific and suitable q-PCR system was developed for the detection and quantification of Gordonibacter. Ellagic acid metabolism in the gut and faecal microbiota of healthy individuals, who consumed walnuts (n = 20) or a pomegranate extract (n = 49), were studied. Urolithin-A was positively correlated to Gordonibacter in faeces, whereas excretion of isourolithin-A and/or urolithin-B was inversely correlated to both. The relationship between Gordonibacter and urolithin-A found in vivo was also confirmed in vitro. This suggests that the beneficial effects attributed to the consumption of foods containing ellagic acid could be mediated by the individuals' Gordonibacter levels. The development of prebiotics, probiotics or synbiotic aimed at increasing Gordonibacter and related species could improve the individual's ability to produce the anti-inflammatory, cardioprotective and anticancer metabolite urolithin-A.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Novel gene expression profiles and cellular functions modulated in Caco‐2 cells in response to the dietary polyphenol, ellagic acid (EA), and its colonic metabolites, urolithin‐A ...(3,8‐dihydroxy‐6H‐dibenzob,d pyran‐6‐one) and urolithin‐B (3‐hydroxy‐6H‐dibenzob,d pyran‐6‐one) have been identified. Exposure of cells to EA and urolithins arrested cell growth at the S‐ and G2/M‐phases. Transcriptional profiling using microarray and functional analysis revealed changes in the expression levels of MAPK signalling genes such as, growth factor receptors (FGFR2, EGFR), oncogenes (K‐Ras, c‐Myc), and tumour suppressors (DUSP6, Fos) and of genes involved in cell cycle (CCNB1, CCNB1IP1). Results suggest that EA and urolithin‐A and ‐B, at concentrations achievable in the lumen from the diet, might contribute to colon cancer prevention by modulating the expression of multiple genes in epithelial cells lining the colon. Some of these genes are involved in key cellular processes associated with cancer development and are currently being investigated as potential chemopreventive targets.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
Evidence exists regarding the beneficial effects of diets rich in plant-based foods regarding the prevention of cardiometabolic diseases. These plant-based foods are an exclusive and abundant ...source of a variety of biologically active phytochemicals, including polyphenols, carotenoids, glucosinolates and phytosterols, with known health-promoting effects through a wide range of biological activities, such as improvements in endothelial function, platelet function, blood pressure, blood lipid profile and insulin sensitivity. We know that an individual’s physical/genetic makeup may influence their response to a dietary intervention, and thereby may influence the benefit/risk associated with consumption of a particular dietary constituent. This inter-individual variation in responsiveness has also been described for dietary plant bioactives but has not been explored in depth. To address this issue, the European scientific experts involved in the COST Action POSITIVe systematically analyzed data from published studies to assess the inter-individual variation in selected clinical biomarkers associated with cardiometabolic risk, in response to the consumption of plant-based bioactives (poly)phenols and phytosterols. The present review summarizes the main findings resulting from the meta-analyses already completed.
Results
Meta-analyses of randomized controlled trials conducted within POSITIVe suggest that age, sex, ethnicity, pathophysiological status and medication may be responsible for the heterogeneity in the biological responsiveness to (poly)phenol and phytosterol consumption and could lead to inconclusive results in some clinical trials aiming to demonstrate the health effects of specific dietary bioactive compounds. However, the contribution of these factors is not yet demonstrated consistently across all polyphenolic groups and cardiometabolic outcomes, partly due to the heterogeneity in trial designs, low granularity of data reporting, variety of food vectors and target populations, suggesting the need to implement more stringent reporting practices in the future studies. Studies investigating the effects of genetic background or gut microbiome on variability were limited and should be considered in future studies.
Conclusion
Understanding why some bioactive plant compounds work effectively in some individuals but not, or less, in others is crucial for a full consideration of these compounds in future strategies of personalized nutrition for a better prevention of cardiometabolic disease. However, there is also still a need for the development of a substantial evidence-base to develop health strategies, food products or lifestyle solutions that embrace this variability.
Key messages
A balanced diet, rich in plant-based foods is known for the prevention of obesity, diabetes, and cardiovascular disease risk.
(Poly)phenols and phytosterols displayed a range of biological effects of relevance to contribute to the cardiometabolic health benefits of plant foods
However, inter-individual variability in response to plant food bioactive consumption exists, and there is a need to understand the causes of this variation.
Analysis of published RCTs examining impact of consumption of (poly)phenols and phytosterols on cardiometabolic risk factors demonstrated that a number of factors including age, sex, adiposity and health status could contribute to the effect demonstrated within these studies.
Genome and microbiome studies will help identify what may be causing this variation.
More studies, specifically designed to investigate individual variation are needed to fully understand the factors responsible for and the impact of this variation
Once fully understood, such variation should be used in directing personalised nutrition advice.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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