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.
Flavanones, flavonoids abundant in Citrus, have been shown to interfere with quorum sensing (QS) and affect related physiological processes. We have investigated the QS-inhibitory effects of an ...orange extract enriched in O-glycosylated flavanones (mainly naringin, neohesperidin, and hesperidin). The QS-inhibitory capacity of this extract and its main flavanone components was first screened using the bacteriological monitoring system Chromobacterium violaceum. We next examined the ability of the orange extract and of some of the flavanones to (i) reduce the levels of the QS mediators produced by Y. enterocolitica using HPLC-MS/MS, (ii) inhibit biofilm formation, and (iii) inhibit swimming and swarming motility. Additionally, we evaluated changes in the expression of specific genes involved in the synthesis of the lactones (yenI, yenR) and in the flagellar regulon (flhDC, fleB, fliA) by RT-PCR. The results showed that the orange extract and its main flavanone components inhibited QS in C. violaceum, diminished the levels of lactones secreted by Y. enterocolitica to the media, and decreased QS-associated biofilm maturation without affecting bacterial growth. Among the tested compounds, naringin was found to inhibit swimming motility. Exposure to the orange extract and (or) to naringin was also found to be associated with induction of the transcription levels of yenR, flhDC, and fliA. This work shows the in vitro QS-inhibitory effects of an orange extract enriched in flavanones against a human enteropathogen at doses that can be achieved through the diet and suggests that consumption of these natural extracts may have a beneficial antipathogenic effect.
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.
.
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.
Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in adult women worldwide. Over 85% of BC cases are non-hereditary, caused by modifiable extrinsic ...factors related to lifestyle, including dietary habits, which play a crucial role in cancer prevention. Although many epidemiological and observational studies have inversely correlated the fruit and vegetable consumption with the BC incidence, the involvement of their phenolic content in this correlation remains contradictory. During decades, wrong approaches that did not consider the bioavailability, metabolism, and breast tissue distribution of dietary phenolics persist behind the large currently existing gap between preclinical and clinical research. In the present review, we provide comprehensive preclinical and clinical evidence according to physiologically relevant in vitro and in vivo studies. Some dietary phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin gallate (EGCG), lignans, and curcumin are gaining attention for their chemopreventive properties in preclinical research. However, the clinical evidence of dietary phenolics as BC chemopreventive compounds is still inconclusive. Therefore, the only way to validate promising preclinical results is to conduct clinical trials in BC patients. In this regard, future perspectives on dietary phenolics and BC research are also critically discussed.
5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial ...impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE
), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.
The consumption of pomegranate juices and extracts has long been linked to many health benefits beyond nutrition, described mainly by innumerable preclinical studies. However, the European Food ...Safety Authority (EFSA) concluded in 2010 that a cause and effect relationship could not be established between the consumption of pomegranate-derived products and all the health claims presented. There are no additional EFSA opinions on health claims specifically addressed to pomegranate in the last decade.
This review comprehensively compiles all human studies conducted on pomegranate. The aim is to discuss these studies critically to identify possible flaws and propose guidelines that might help establish a cause and effect relationship between pomegranate-derived product consumption and health.
To date, 86 human studies have evaluated the health benefits of pomegranate juices and extracts. The most promising, albeit scarce, evidence is related to blood pressure improvement. Less evidence deals with inflammation, cancer, cognitive function, physical activity, and gut microbiota modulation (prebiotic effects). After a decade since EFSA's opinion, human evidence remains inconsistent, making it difficult to support most claimed health effects. The lack of effects and(or) data discrepancy might be attributable to design limitations, including insufficient product characterization and interindividual variability that influence pomegranate polyphenols' bioefficacy. New coordinated strategies between policy makers, research/academic institutions, and industry are needed to move forward. Therefore, this review presents a roadmap to conduct well-designed trials and cover existing gaps, which could establish a cause-effect relation between pomegranate consumption and health benefits beyond nutrition.
•To date, no health claims dealing with pomegranate have been approved by the EFSA.•Eighty-six human trials have evaluated the health-related benefits of pomegranate.•The current evidence is related to blood pressure improvement.•Design limitation and interindividual variability account for data disparity.•The evidence remains weak to claim health benefits linked to pomegranate consumption.
The intake of hesperidin-rich sources, mostly found in orange juice, can decrease cardiometabolic risk, potentially linked to the gut microbial phase-II hesperetin derivatives. However, the low ...hesperidin solubility hampers its bioavailability and microbial metabolism, yielding a high inter-individual variability (high vs. low-producers) that prevents consistent health-related evidence. Contrarily, the human metabolism of (lemon) eriocitrin is hardly known. We hypothesize that the higher solubility of (lemon) eriocitrin vs. (orange) hesperidin might yield more bioavailable metabolites than hesperidin. A randomized-crossover human pharmacokinetic study (
= 16) compared the bioavailability and metabolism of flavanones from lemon and orange extracts and postprandial changes in oxidative, inflammatory, and metabolic markers after a high-fat-high-sugars meal. A total of 17 phase-II flavanone-derived metabolites were identified. No significant biomarker changes were observed. Plasma and urinary concentrations of all metabolites, including hesperetin metabolites, were higher after lemon extract intake. Total plasma metabolites showed significantly mean lower T
(6.0 ± 0.4 vs. 8.0 ± 0.5 h) and higher C
and AUC values after lemon extract intake. We provide new insights on hesperetin-eriodictyol interconversion and naringenin formation from hesperidin in humans. Our results suggest that regular consumption of a soluble and eco-friendly eriocitrin-rich lemon extract could provide a circulating concentration metabolites threshold to exert health benefits, even in the so-called low-producers.
Scope
Urolithins (Uro), gut microbial metabolites derived from ellagic acid (EA), reach significant concentrations in the human colon. Uro‐A exerts anti‐inflammatory activity in animal models of ...inflammatory bowel diseases (IBDs). It is hypothesized that Uro can modulate the biosynthesis of leukocyte‐derived inflammatory eicosanoids from the 5‐lipoxygenase (5‐LOX), cyclooxygenase‐2 (COX‐2), and 5‐LOX/COX‐2 pathways, relevant in the onset and progression of IBDs, including 5‐hydroxyeicosatetraenoic acids (5‐HETEs), leukotriene‐B4 (LTB4), prostaglandin E2 (PGE2), and hemiketals (HKE2 and HKD2).
Methods and results
Leukocytes, obtained from six healthy donors, are stimulated with lipopolysaccharide and calcium ionophore A23187. Uro, at concentrations found in the human colon (1–15 µm), decrease eicosanoid biosynthesis and COX‐2 levels in the activated leukocytes. In contrast, EA and conjugated Uro (glucuronides and sulfates) are inactive. Uro‐A and isourolithin‐A reduce the formation of the 5‐LOX/COX‐2 products HKE2 and HKD2 through the COX‐2 pathway (down‐regulation of COX‐2 and PGE2), whereas Uro‐C reduces 5‐HETE and LTB4 via inhibition of 5‐LOX.
Conclusions
The results show that physiologically relevant colonic Uro target eicosanoid biosynthetic pathways. The effect on HKs and LTB4 formation is unprecedented and expands the knowledge on anti‐inflammatory mechanisms of Uro against IBDs.
Relevant colonic urolithins (Uro), including Uro‐A, IsoUro‐A, and Uro‐C decrease the formation of leukotrienes, prostaglandins, and the newly discovered hemiketal eicosanoids via modulation of the 5‐lipoxygenase and the cyclooxygenase‐2 pathways in human leukocytes. Due to the importance of these molecules in the modulation of the inflammatory response, this may be a novel anti‐inflammatory mechanism of Uro against intestinal inflammation.
L. (EP) preparations are globally popular herbal supplements known for their medicinal benefits, including anti-inflammatory activities, partly related to their phenolic composition. However, ...regarding their use for the management of inflammation-related intestinal diseases, the knowledge about the fate of orally ingested constituents throughout the human gastrointestinal tract and the exposition of in vitro digested extracts in relevant inflammatory models are unknown. This study investigated for the first time the impact of in vitro gastrointestinal digestion (INFOGEST) on the phenolic composition and anti-inflammatory properties of EP extracts from flowers (EF), leaves (EL), and roots (ER) on IL-1β-treated human colon-derived CCD-18Co cells. Among the seven hydroxycinnamic acids identified using HPLC-UV-MS/MS, chicoric and caftaric acids showed the highest concentrations in EL, followed by EF and ER, and all extracts exerted significant reductions in IL-6, IL-8, and PGE
levels. After digestion, despite reducing the bioaccessibility of their phenolics, the anti-inflammatory effects were preserved for digested EL and, to a lesser extent, for EF, but not for digested ER. The lower phenolic content in digested EF and ER could explain these findings. Overall, this study emphasizes the potential of EP in alleviating intestinal inflammatory conditions and related disorders.
PDF
