Regular physical exercise provides many health benefits, protecting against the development of ch... more Regular physical exercise provides many health benefits, protecting against the development of chronic diseases, and improving quality of life. Some of the mechanisms by which exercise provides these effects are the promotion of an anti-inflammatory state, reinforcement of the neuromuscular function, and activation of the hypothalamic-pituitary-adrenal (HPA) axis. Recently, it has been proposed that physical exercise is able to modify gut microbiota, and thus this could be another factor by which exercise promotes well-being, since gut microbiota appears to be closely related to health and disease. The purpose of this paper is to review the recent findings on gut microbiota modification by exercise, proposing several mechanisms by which physical exercise might cause changes in gut microbiota.
There is no pharmaceutical or definitive surgical cure for inflammatory bowel diseases (IBDs). Th... more There is no pharmaceutical or definitive surgical cure for inflammatory bowel diseases (IBDs). The naturally occurring polyphenol resveratrol exerts anti-inflammatory properties. However, its rapid metabolism diminishes its effectiveness in the colon. The design of prodrugs to targeting active molecules to the colon provides an opportunity for therapy of IBDs. Herein we explore the efficacy of different resveratrol prodrugs and pro-prodrugs to ameliorate colon inflammation in the murine dextran sulfate sodium (DSS) model. Mice fed with a very low dose (equivalent to 10 mg for a 70 kg-person) of either resveratrol-3-O-(6 0 -O-butanoyl)-β-D-glucopyranoside (6) or resveratrol-3-O-(6 0 -O-octanoyl)-β-D-glucopyranoside (7) did not develop colitis symptoms and improved 6-fold the disease activity index (DAI) compared to resveratrol. Our results indicate that these pro-prodrugs exerted a dual effect: (1) they prevented the rapid metabolism of resveratrol and delivered higher quantities of resveratrol to the colon and (2) they reduced mucosal barrier imbalance and prevented diarrhea, which consequently facilitated the action of the delivered resveratrol in the colon mucosa.
... Mar Larrosa, Rafael Llorach, Juan Carlos Espín * and Francisco A. Tomás-Barberán. ... JA LARR... more ... Mar Larrosa, Rafael Llorach, Juan Carlos Espín * and Francisco A. Tomás-Barberán. ... JA LARRAURI, I. GOÑI, N. MARTIN-CARRON, P. RUPEREZ and F. SAURA-CALIXTO, Measurement of health-promoting properties in fruit dietary fibres: antioxidant capacity, fermentability and ...
The efficacy of resveratrol and some glucosyl, glucosylacyl, and glucuronide derivatives in inhib... more The efficacy of resveratrol and some glucosyl, glucosylacyl, and glucuronide derivatives in inhibiting the adhesion of Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes Scott A to Caco-2 and HT-29 colonic cells was investigated. The three bacteria strains were capable of adhering to both colonic epithelial cell lines, which responded by producing the pro-inflammatory interleukin 8 (IL-8). Adhesion inhibition of E. coli O157:H7 and S. Typhimurium to colonic cells was ≥60 and ≥40%, respectively, when resveratrol and most of the resveratrol derivatives were applied. Lower adhesion inhibition was observed for the bacteria with higher adherence potential, L. monocytogenes (≥20%). Resveratrol-3-O-(6′-Obutanoyl)-β-D-glucopyranoside (BUT) (50 and 100 μM) and resveratrol-3-O-(6′-O-octanoyl)-β-D-glucopyranoside (OCT) (50 μM) reduced IL-8 secretion by 100%. These results suggest that one mechanism for the beneficial attributes of resveratrol and especially the derivatives BUT and OCT could be the ability to reduce the adhesion and consequent pro-inflammatory cytokine production in intestinal epithelial cells in response to pathogen adhesion. The potential use of these compounds in the prevention of foodborne infections, intestinal homeostasis loss, and inflammatory bowel diseases could be another step in finding coadjuvants or alternatives to antibiotic treatments.
The health benefits attributed to pomegranate have been associated with its high content in polyp... more The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2-20 M. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based on in vitro testing, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number of in vivo studies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Both in vivo and mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reached in vivo.
Berries and red fruits are important dietary sources of polyphenols . In vitro and animal studies... more Berries and red fruits are important dietary sources of polyphenols . In vitro and animal studies have demonstrated the bioavailability and the anti-proliferative and anticarcinogenic properties of these fruits or of their phenolic components . Consumption of berries may contribute to the reduction of colon cancer by mechanisms not yet understood. Gene expression analysis using microarrays allows for a more comprehensive study of the possible molecular mechanisms by which food or food components may prevent certain cancers of the gastrointestinal tract . The aim of this research is to investigate the anti-proliferative effects of a polyphenol-rich berry juice on a human model of colon cancer cells and its association to transcriptional changes in relation to colon cancer.
Purpose Preclinical studies suggest a potential protective effect of oleuropein in osteoporosis, ... more Purpose Preclinical studies suggest a potential protective effect of oleuropein in osteoporosis, and one of the proposed mechanisms is the modulation of the oxidative stress. Oleuropein bioavailability and its effect on antioxidant status in pre-and postmenopausal women are unknown. The aim of the present study was to investigate the oral bioavailability of an olive leaf extract rich in oleuropein (40 %) and its effect on antioxidant status in postmenopausal women compared to premenopausal women. Methods Premenopausal (n = 8) and postmenopausal women (n = 8) received 250 mg of olive leaf extract, blood samples (t = 0, 1, 2, 3, 4, 6, 8, 12, 16 and 24 h) were taken, and 24-h urine divided into five fractions was collected. Olive-leaf-extract-derived metabolites were analyzed in plasma and urine by HPLC-ESI-QTOF and UPLC-ESI-QqQ, and pharmacokinetics parameters were determined. Ferric reducing antioxidant ability and malondialdehyde levels were measured in plasma. Results Plasma levels of hydroxytyrosol glucuronide, hydroxytyrosol sulfate, oleuropein aglycon glucuronide and oleuropein aglycon derivative 1 were higher in postmenopausal women. MDA levels were significantly decreased (32 %) in postmenopausal women and inversely correlated with hydroxytyrosol sulfate levels. Postmenopausal women excreted less sulfated metabolites in urine than premenopausal women. Conclusions Our results suggest that postmenopausal women could be a target population for the intake of olive phenolics in order to prevent age-related and oxidative stress-related processes such as osteoporosis. * Significant difference (P \ 0.05) between premenopausal and postmenopausal women # Marginal difference (0.1 [ P [ 0.05) Eur J Nutr
The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effec... more The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effects attributed to fruit and vegetable intake. Although their properties have been relatively well studied, the activity of their metabolites, produced after ingestion, has been poorly investigated. Thus, the aim of this work was to study the potential anti-inflammatory effect of 18 polyphenol metabolites, derived from colon microbiota. They were screened by measuring prostaglandin E 2 (PGE 2 ) production by CCD-18 colon fibroblast cells stimulated with IL-1b. Metabolites that inhibited more than 50% PGE 2 production were hydrocaffeic (HCAF), dihydroxyphenyl acetic (dOHPA), and hydroferulic acid (HFER), that subsequently were tested with the writhing and paw pressure test in rodents where all three compounds showed an anti-inflammatory effect. The effect of HCAF administered orally (50 mg/kg) was also tested in the dextran sodium sulfate (DSS)-induced colitis model. Weight loss and fecal water content were more pronounced in DSS rats than in DSS-HCAF treated rats. HCAF treatment diminished the expression of the cytokines IL-1b, IL-8, and TNF-a, reduced malonyldialdehyde (MDA) levels and oxidative DNA damage (measured as 8-oxo-29-deoxyguanosine levels) in distal colon mucosa. These results indicate that HCAF, dOHPA, and HFER have anti-inflammatory activity in vitro and in vivo.
Scope: trans-Resveratrol (RES) and/(or) its metabolites exert many effects in vivo. Our aim was t... more Scope: trans-Resveratrol (RES) and/(or) its metabolites exert many effects in vivo. Our aim was to study the metabolism and tissue distribution of RES using the pig, a mammal physiologically close to humans. Methods and results: Forty-seven tissues, organs and fluids were analyzed 6 h after intragastric RES administration (5.9 mg/kg body weight) using HPLC-MS/MS. Twelve RES and seven dihydroresveratrol (DH-RES) metabolites were detected. DH-RES was the main metabolite in cecum, colon and rectum, whereas RES-3-O-glucuronide was the most abundant one in fluids and organs. Approximately 74.5% of the total RES administered was recovered in the form of RES, DH-RES and derived metabolites (65.1% along the gastrointestinal tract, 7.7% in urine, 1.2% in bile and 0.5% in organs). We report here, for the first time, the occurrence of RES ribosyl-sulfate derivative, DH-RES diglucuronide, DH-RES sulfoglucuronide and DH-RES disulfate as well as the metabolic profile of RES and DH-RES in the aorta, lymph, lymph node, ovaries, uterus, cerebellum, pancreas, urinary bladder tissue, fat and muscle. Conclusion: This study contributes to the clarification of the metabolism and tissue distribution of RES and could help to further understand the mechanisms underlying its effects.
International Conference on Antimicrobial Research (ICAR2010), 2011
ABSTRACT Yersinia enterocolitica is a mammalian enteropathogen which may cause gastrointestinal s... more ABSTRACT Yersinia enterocolitica is a mammalian enteropathogen which may cause gastrointestinal syndromes. Yersinia spp. produces N-acyl homoserine lactone (AHL), Quorum Sensing (QS) signal molecules which are involved in the cell population density dependent regulation of virulence, secondary metabolite production, and biofilm maturation. Urolithins (Uro-A and Uro-B), metabolites produced after the consumption of ellagitannins, have anti-inflammatory action in colitis and modulate microbiota. Our objective was to evaluate the effect of Uro-A and B, as QS inhibitors in Y. enterocolitica and to determine whether or not they affect the expression of specific genes involved in virulence processes. It was found that Uro-A and B were effective inhibiting QS of Y. enterocolitica when applied at 5 and 3 μM, respectively. The data obtained by Real-time PCR showed that urolithins increased the transcription of QS regulated genes when low concentrations were used. Thus, urolithins have an antipathogenic effect against Y. enterocolitica and can be used as QS inhibitors increasing the expression of virulence related genes.
Previous studies have reported the anti-inflammatory properties of pomegranate extracts, suggesti... more Previous studies have reported the anti-inflammatory properties of pomegranate extracts, suggesting that ellagitannins (ET) and ellagic acid (EA) are the main anti-inflammatory compounds. However, both ET and EA are metabolised in vivo by the gut microbiota to yield urolithins (Uro) which can be found in the gut and in systemic bloodstream. The present study was carried out to evaluate the individual effect of EA and their microbiota-derived metabolites Uro on colon fibroblasts upon IL-1b treatment as an in vitro inflammation model. Uro-A and Uro-B (10 mM) inhibited PGE 2 production (85 and 40 %, respectively) after IL-1b stimulation, whereas EA did not show any effect. Uro-A, but not Uro-B, down-regulated cyclo-oxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) mRNA expression and protein levels. Both Uro inhibited NF-kB translocation to nucleus. Slight but significant effects were found in the activation of mitogen-activated protein kinase (MAPK) pathways. Uro-A lowered c-Jun N-terminal kinase phosphorylation state, and both Uro inhibited p38 activation. No metabolites derived from Uro or EA were found in the cell media upon incubation of EA or Uro with the cells, and only traces of the compounds were found inside the cells. The present results suggest that Uro, mainly Uro-A, are the main compounds that are responsible for the pomegranate anti-inflammatory properties. The mechanism of action implicated seems to be via the inhibition of activation of NF-kB and MAPK, down-regulation of COX-2 and mPGES-1 expressions, and consequently,via the reduction of PGE 2 production. Taking into account that Uro did not enter the cells, a competitive binding for IL-1b membrane receptor cannot be discarded.
Background: Rosemary (Rosmarinus officinalis L.) extracts (REs) exhibit hepatoprotective, anti-ob... more Background: Rosemary (Rosmarinus officinalis L.) extracts (REs) exhibit hepatoprotective, anti-obesity and anti-inflammatory properties and are widely used in the food industry. REs are rich in carnosic acid (CA) and carnosol which may be responsible for some of the biological activities of REs. The aim of this study was to investigate whether inhibition of lipase activity in the gut may be a mechanism by which a RE enriched in CA (40%) modulates body weight and lipids levels in a rat model of metabolic disorders and obesity.
Background: Carnosic acid (CA) and rosemary extracts (RE) show body-weight, energy metabolism and... more Background: Carnosic acid (CA) and rosemary extracts (RE) show body-weight, energy metabolism and inflammation regulatory properties in animal models but the mechanisms are not yet understood. Gut microbiota plays an important role in the host metabolism and inflammatory status and is modulated by the diet. The aim of this research was to investigate whether a RE enriched in CA affected caecum microbiota composition and activity in a rat model of genetic obesity.
Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human tri... more Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited. Furthermore, the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood. Therefore, the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells (PBMCs) associated to the oneyear daily intake of a RES enriched (8 mg) grape extract (GE-RES) in hypertensive male patients with type 2 diabetes mellitus (T2DM). We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs (miRs) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES. We also examined the changes in several serobiochemical variables, inflammatory and fibrinolytic markers. Our results showed that supplementation with GE or GE-RES did not affect body weight, blood pressure, glucose, HbA1c or lipids, beyond the values regulated by gold standard medication in these patients. We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels. The expression of the proinflammatory cytokines CCL3, IL-1ˇ and TNF-˛ was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in PBMCs from patients taking the GE-RES extract. Also, a group of miRs involved in the regulation of the inflammatory response: miR-21, miR-181b, miR-663, miR-30c2, miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months. Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients.
The cardioprotective role of resveratrol as part of the human diet is not yet clear. Our aim was ... more The cardioprotective role of resveratrol as part of the human diet is not yet clear. Our aim was to investigate the effect of a grape supplement containing 8 mg resveratrol in oxidized LDL (LDLox), apolipoprotein-B (ApoB), and serum lipids on statin-treated patients in primary cardiovascular disease prevention (PCP). Methods and results: A triple-blind, randomized, placebo-controlled trial was conducted. Seventy-five patients (three parallel arms) consumed one capsule (350 mg) daily for 6 months containing resveratrol-enriched grape extract (GE-RES, Stilvid R ), grape extract (GE, similar polyphenolic content but no resveratrol), or placebo (maltodextrin). After 6 months, no changes were observed in the placebo group and only LDL cholesterol (LDLc) decreased by 2.9% (p = 0.013) in the GE group. In contrast, LDLc (−4.5%, p = 0.04), ApoB (−9.8%, p = 0.014), LDLox (−20%, p = 0.001), and LDLox/ApoB (−12.5%, p = 0.000) decreased in the Stilvid R group, whereas the ratio non-HDLc (total atherogenic cholesterol load)/ApoB increased (8.5%, p = 0.046). No changes were observed in hepatic, thyroid, and renal function. No adverse effects were observed in any of the patients. Conclusion: This GE-RES reduced atherogenic markers and might exert additional cardioprotection beyond the gold-standard medication in patients from PCP. The presence of resveratrol in the GE was necessary to achieve these effects.
Scope: Numerous in vitro and in vivo studies indicate that ellagitannins exhibit antiinflammatory... more Scope: Numerous in vitro and in vivo studies indicate that ellagitannins exhibit antiinflammatory, 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 M concentrations. We investigated whether urolithin glucuronides and their aglycones exhibit vascular protective effects. Methods and results: Human aortic endothelial cells were exposed to tumor necrosis factor alpha and to Uro-A glucuronide, Uro-B glucuronide or their corresponding aglycones at low M 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 M) inhibited monocyte adhesion and endothelial cell migration in a significant manner. These effects were associated with a moderate but significant downregulation 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). Conclusion: Our results suggest that these metabolites might be involved, at least in part, in the beneficial effects against cardiovascular diseases attributed to the consumption of ellagitannincontaining foods.
Carnosic acid (CA) and rosemary extracts (REs) have antiobesity effects but the mechanisms are no... more Carnosic acid (CA) and rosemary extracts (REs) have antiobesity effects but the mechanisms are not understood. We investigated some of the potential mechanisms contributing to the metabolic effects of an RE enriched in CA. Methods and results: An RE (∼40% CA) was administered to lean (Le, fa/+) and obese (Ob, fa/fa) female Zucker rats for 64 days. Several adipocytokines, brain-derived neurotrophic factor, phosphorylated AMP-activated protein kinase, and hepatic gene expression changes were investigated. The RE significantly decreased circulating tumor necrosis factor alpha (RE/CT = 0.36, p < 0.0003), IL-1 (0.48, p < 0.032), and leptin (0.48, p < 0.002), and upregulated adiponectin (1.47, p < 0.045) in the Le rats. The RE also induced phase I and phase II gene expression and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Notably, the RE decreased adipose phosphorylated AMP-activated protein kinase and did not affect hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the Ob rats. Conclusion: Our results show that an RE rich in CA exerts anti-inflammatory effects and affects hepatic metabolism in normal Le rats. We report significant differences in the expression and regulation of key metabolic sensors between Le and Ob rats that may contribute to explain the different ability of the two genotypes to respond to the RE.
Regular physical exercise provides many health benefits, protecting against the development of ch... more Regular physical exercise provides many health benefits, protecting against the development of chronic diseases, and improving quality of life. Some of the mechanisms by which exercise provides these effects are the promotion of an anti-inflammatory state, reinforcement of the neuromuscular function, and activation of the hypothalamic-pituitary-adrenal (HPA) axis. Recently, it has been proposed that physical exercise is able to modify gut microbiota, and thus this could be another factor by which exercise promotes well-being, since gut microbiota appears to be closely related to health and disease. The purpose of this paper is to review the recent findings on gut microbiota modification by exercise, proposing several mechanisms by which physical exercise might cause changes in gut microbiota.
There is no pharmaceutical or definitive surgical cure for inflammatory bowel diseases (IBDs). Th... more There is no pharmaceutical or definitive surgical cure for inflammatory bowel diseases (IBDs). The naturally occurring polyphenol resveratrol exerts anti-inflammatory properties. However, its rapid metabolism diminishes its effectiveness in the colon. The design of prodrugs to targeting active molecules to the colon provides an opportunity for therapy of IBDs. Herein we explore the efficacy of different resveratrol prodrugs and pro-prodrugs to ameliorate colon inflammation in the murine dextran sulfate sodium (DSS) model. Mice fed with a very low dose (equivalent to 10 mg for a 70 kg-person) of either resveratrol-3-O-(6 0 -O-butanoyl)-β-D-glucopyranoside (6) or resveratrol-3-O-(6 0 -O-octanoyl)-β-D-glucopyranoside (7) did not develop colitis symptoms and improved 6-fold the disease activity index (DAI) compared to resveratrol. Our results indicate that these pro-prodrugs exerted a dual effect: (1) they prevented the rapid metabolism of resveratrol and delivered higher quantities of resveratrol to the colon and (2) they reduced mucosal barrier imbalance and prevented diarrhea, which consequently facilitated the action of the delivered resveratrol in the colon mucosa.
... Mar Larrosa, Rafael Llorach, Juan Carlos Espín * and Francisco A. Tomás-Barberán. ... JA LARR... more ... Mar Larrosa, Rafael Llorach, Juan Carlos Espín * and Francisco A. Tomás-Barberán. ... JA LARRAURI, I. GOÑI, N. MARTIN-CARRON, P. RUPEREZ and F. SAURA-CALIXTO, Measurement of health-promoting properties in fruit dietary fibres: antioxidant capacity, fermentability and ...
The efficacy of resveratrol and some glucosyl, glucosylacyl, and glucuronide derivatives in inhib... more The efficacy of resveratrol and some glucosyl, glucosylacyl, and glucuronide derivatives in inhibiting the adhesion of Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes Scott A to Caco-2 and HT-29 colonic cells was investigated. The three bacteria strains were capable of adhering to both colonic epithelial cell lines, which responded by producing the pro-inflammatory interleukin 8 (IL-8). Adhesion inhibition of E. coli O157:H7 and S. Typhimurium to colonic cells was ≥60 and ≥40%, respectively, when resveratrol and most of the resveratrol derivatives were applied. Lower adhesion inhibition was observed for the bacteria with higher adherence potential, L. monocytogenes (≥20%). Resveratrol-3-O-(6′-Obutanoyl)-β-D-glucopyranoside (BUT) (50 and 100 μM) and resveratrol-3-O-(6′-O-octanoyl)-β-D-glucopyranoside (OCT) (50 μM) reduced IL-8 secretion by 100%. These results suggest that one mechanism for the beneficial attributes of resveratrol and especially the derivatives BUT and OCT could be the ability to reduce the adhesion and consequent pro-inflammatory cytokine production in intestinal epithelial cells in response to pathogen adhesion. The potential use of these compounds in the prevention of foodborne infections, intestinal homeostasis loss, and inflammatory bowel diseases could be another step in finding coadjuvants or alternatives to antibiotic treatments.
The health benefits attributed to pomegranate have been associated with its high content in polyp... more The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2-20 M. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based on in vitro testing, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number of in vivo studies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Both in vivo and mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reached in vivo.
Berries and red fruits are important dietary sources of polyphenols . In vitro and animal studies... more Berries and red fruits are important dietary sources of polyphenols . In vitro and animal studies have demonstrated the bioavailability and the anti-proliferative and anticarcinogenic properties of these fruits or of their phenolic components . Consumption of berries may contribute to the reduction of colon cancer by mechanisms not yet understood. Gene expression analysis using microarrays allows for a more comprehensive study of the possible molecular mechanisms by which food or food components may prevent certain cancers of the gastrointestinal tract . The aim of this research is to investigate the anti-proliferative effects of a polyphenol-rich berry juice on a human model of colon cancer cells and its association to transcriptional changes in relation to colon cancer.
Purpose Preclinical studies suggest a potential protective effect of oleuropein in osteoporosis, ... more Purpose Preclinical studies suggest a potential protective effect of oleuropein in osteoporosis, and one of the proposed mechanisms is the modulation of the oxidative stress. Oleuropein bioavailability and its effect on antioxidant status in pre-and postmenopausal women are unknown. The aim of the present study was to investigate the oral bioavailability of an olive leaf extract rich in oleuropein (40 %) and its effect on antioxidant status in postmenopausal women compared to premenopausal women. Methods Premenopausal (n = 8) and postmenopausal women (n = 8) received 250 mg of olive leaf extract, blood samples (t = 0, 1, 2, 3, 4, 6, 8, 12, 16 and 24 h) were taken, and 24-h urine divided into five fractions was collected. Olive-leaf-extract-derived metabolites were analyzed in plasma and urine by HPLC-ESI-QTOF and UPLC-ESI-QqQ, and pharmacokinetics parameters were determined. Ferric reducing antioxidant ability and malondialdehyde levels were measured in plasma. Results Plasma levels of hydroxytyrosol glucuronide, hydroxytyrosol sulfate, oleuropein aglycon glucuronide and oleuropein aglycon derivative 1 were higher in postmenopausal women. MDA levels were significantly decreased (32 %) in postmenopausal women and inversely correlated with hydroxytyrosol sulfate levels. Postmenopausal women excreted less sulfated metabolites in urine than premenopausal women. Conclusions Our results suggest that postmenopausal women could be a target population for the intake of olive phenolics in order to prevent age-related and oxidative stress-related processes such as osteoporosis. * Significant difference (P \ 0.05) between premenopausal and postmenopausal women # Marginal difference (0.1 [ P [ 0.05) Eur J Nutr
The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effec... more The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effects attributed to fruit and vegetable intake. Although their properties have been relatively well studied, the activity of their metabolites, produced after ingestion, has been poorly investigated. Thus, the aim of this work was to study the potential anti-inflammatory effect of 18 polyphenol metabolites, derived from colon microbiota. They were screened by measuring prostaglandin E 2 (PGE 2 ) production by CCD-18 colon fibroblast cells stimulated with IL-1b. Metabolites that inhibited more than 50% PGE 2 production were hydrocaffeic (HCAF), dihydroxyphenyl acetic (dOHPA), and hydroferulic acid (HFER), that subsequently were tested with the writhing and paw pressure test in rodents where all three compounds showed an anti-inflammatory effect. The effect of HCAF administered orally (50 mg/kg) was also tested in the dextran sodium sulfate (DSS)-induced colitis model. Weight loss and fecal water content were more pronounced in DSS rats than in DSS-HCAF treated rats. HCAF treatment diminished the expression of the cytokines IL-1b, IL-8, and TNF-a, reduced malonyldialdehyde (MDA) levels and oxidative DNA damage (measured as 8-oxo-29-deoxyguanosine levels) in distal colon mucosa. These results indicate that HCAF, dOHPA, and HFER have anti-inflammatory activity in vitro and in vivo.
Scope: trans-Resveratrol (RES) and/(or) its metabolites exert many effects in vivo. Our aim was t... more Scope: trans-Resveratrol (RES) and/(or) its metabolites exert many effects in vivo. Our aim was to study the metabolism and tissue distribution of RES using the pig, a mammal physiologically close to humans. Methods and results: Forty-seven tissues, organs and fluids were analyzed 6 h after intragastric RES administration (5.9 mg/kg body weight) using HPLC-MS/MS. Twelve RES and seven dihydroresveratrol (DH-RES) metabolites were detected. DH-RES was the main metabolite in cecum, colon and rectum, whereas RES-3-O-glucuronide was the most abundant one in fluids and organs. Approximately 74.5% of the total RES administered was recovered in the form of RES, DH-RES and derived metabolites (65.1% along the gastrointestinal tract, 7.7% in urine, 1.2% in bile and 0.5% in organs). We report here, for the first time, the occurrence of RES ribosyl-sulfate derivative, DH-RES diglucuronide, DH-RES sulfoglucuronide and DH-RES disulfate as well as the metabolic profile of RES and DH-RES in the aorta, lymph, lymph node, ovaries, uterus, cerebellum, pancreas, urinary bladder tissue, fat and muscle. Conclusion: This study contributes to the clarification of the metabolism and tissue distribution of RES and could help to further understand the mechanisms underlying its effects.
International Conference on Antimicrobial Research (ICAR2010), 2011
ABSTRACT Yersinia enterocolitica is a mammalian enteropathogen which may cause gastrointestinal s... more ABSTRACT Yersinia enterocolitica is a mammalian enteropathogen which may cause gastrointestinal syndromes. Yersinia spp. produces N-acyl homoserine lactone (AHL), Quorum Sensing (QS) signal molecules which are involved in the cell population density dependent regulation of virulence, secondary metabolite production, and biofilm maturation. Urolithins (Uro-A and Uro-B), metabolites produced after the consumption of ellagitannins, have anti-inflammatory action in colitis and modulate microbiota. Our objective was to evaluate the effect of Uro-A and B, as QS inhibitors in Y. enterocolitica and to determine whether or not they affect the expression of specific genes involved in virulence processes. It was found that Uro-A and B were effective inhibiting QS of Y. enterocolitica when applied at 5 and 3 μM, respectively. The data obtained by Real-time PCR showed that urolithins increased the transcription of QS regulated genes when low concentrations were used. Thus, urolithins have an antipathogenic effect against Y. enterocolitica and can be used as QS inhibitors increasing the expression of virulence related genes.
Previous studies have reported the anti-inflammatory properties of pomegranate extracts, suggesti... more Previous studies have reported the anti-inflammatory properties of pomegranate extracts, suggesting that ellagitannins (ET) and ellagic acid (EA) are the main anti-inflammatory compounds. However, both ET and EA are metabolised in vivo by the gut microbiota to yield urolithins (Uro) which can be found in the gut and in systemic bloodstream. The present study was carried out to evaluate the individual effect of EA and their microbiota-derived metabolites Uro on colon fibroblasts upon IL-1b treatment as an in vitro inflammation model. Uro-A and Uro-B (10 mM) inhibited PGE 2 production (85 and 40 %, respectively) after IL-1b stimulation, whereas EA did not show any effect. Uro-A, but not Uro-B, down-regulated cyclo-oxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) mRNA expression and protein levels. Both Uro inhibited NF-kB translocation to nucleus. Slight but significant effects were found in the activation of mitogen-activated protein kinase (MAPK) pathways. Uro-A lowered c-Jun N-terminal kinase phosphorylation state, and both Uro inhibited p38 activation. No metabolites derived from Uro or EA were found in the cell media upon incubation of EA or Uro with the cells, and only traces of the compounds were found inside the cells. The present results suggest that Uro, mainly Uro-A, are the main compounds that are responsible for the pomegranate anti-inflammatory properties. The mechanism of action implicated seems to be via the inhibition of activation of NF-kB and MAPK, down-regulation of COX-2 and mPGES-1 expressions, and consequently,via the reduction of PGE 2 production. Taking into account that Uro did not enter the cells, a competitive binding for IL-1b membrane receptor cannot be discarded.
Background: Rosemary (Rosmarinus officinalis L.) extracts (REs) exhibit hepatoprotective, anti-ob... more Background: Rosemary (Rosmarinus officinalis L.) extracts (REs) exhibit hepatoprotective, anti-obesity and anti-inflammatory properties and are widely used in the food industry. REs are rich in carnosic acid (CA) and carnosol which may be responsible for some of the biological activities of REs. The aim of this study was to investigate whether inhibition of lipase activity in the gut may be a mechanism by which a RE enriched in CA (40%) modulates body weight and lipids levels in a rat model of metabolic disorders and obesity.
Background: Carnosic acid (CA) and rosemary extracts (RE) show body-weight, energy metabolism and... more Background: Carnosic acid (CA) and rosemary extracts (RE) show body-weight, energy metabolism and inflammation regulatory properties in animal models but the mechanisms are not yet understood. Gut microbiota plays an important role in the host metabolism and inflammatory status and is modulated by the diet. The aim of this research was to investigate whether a RE enriched in CA affected caecum microbiota composition and activity in a rat model of genetic obesity.
Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human tri... more Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited. Furthermore, the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood. Therefore, the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells (PBMCs) associated to the oneyear daily intake of a RES enriched (8 mg) grape extract (GE-RES) in hypertensive male patients with type 2 diabetes mellitus (T2DM). We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs (miRs) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES. We also examined the changes in several serobiochemical variables, inflammatory and fibrinolytic markers. Our results showed that supplementation with GE or GE-RES did not affect body weight, blood pressure, glucose, HbA1c or lipids, beyond the values regulated by gold standard medication in these patients. We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels. The expression of the proinflammatory cytokines CCL3, IL-1ˇ and TNF-˛ was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in PBMCs from patients taking the GE-RES extract. Also, a group of miRs involved in the regulation of the inflammatory response: miR-21, miR-181b, miR-663, miR-30c2, miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months. Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients.
The cardioprotective role of resveratrol as part of the human diet is not yet clear. Our aim was ... more The cardioprotective role of resveratrol as part of the human diet is not yet clear. Our aim was to investigate the effect of a grape supplement containing 8 mg resveratrol in oxidized LDL (LDLox), apolipoprotein-B (ApoB), and serum lipids on statin-treated patients in primary cardiovascular disease prevention (PCP). Methods and results: A triple-blind, randomized, placebo-controlled trial was conducted. Seventy-five patients (three parallel arms) consumed one capsule (350 mg) daily for 6 months containing resveratrol-enriched grape extract (GE-RES, Stilvid R ), grape extract (GE, similar polyphenolic content but no resveratrol), or placebo (maltodextrin). After 6 months, no changes were observed in the placebo group and only LDL cholesterol (LDLc) decreased by 2.9% (p = 0.013) in the GE group. In contrast, LDLc (−4.5%, p = 0.04), ApoB (−9.8%, p = 0.014), LDLox (−20%, p = 0.001), and LDLox/ApoB (−12.5%, p = 0.000) decreased in the Stilvid R group, whereas the ratio non-HDLc (total atherogenic cholesterol load)/ApoB increased (8.5%, p = 0.046). No changes were observed in hepatic, thyroid, and renal function. No adverse effects were observed in any of the patients. Conclusion: This GE-RES reduced atherogenic markers and might exert additional cardioprotection beyond the gold-standard medication in patients from PCP. The presence of resveratrol in the GE was necessary to achieve these effects.
Scope: Numerous in vitro and in vivo studies indicate that ellagitannins exhibit antiinflammatory... more Scope: Numerous in vitro and in vivo studies indicate that ellagitannins exhibit antiinflammatory, 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 M concentrations. We investigated whether urolithin glucuronides and their aglycones exhibit vascular protective effects. Methods and results: Human aortic endothelial cells were exposed to tumor necrosis factor alpha and to Uro-A glucuronide, Uro-B glucuronide or their corresponding aglycones at low M 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 M) inhibited monocyte adhesion and endothelial cell migration in a significant manner. These effects were associated with a moderate but significant downregulation 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). Conclusion: Our results suggest that these metabolites might be involved, at least in part, in the beneficial effects against cardiovascular diseases attributed to the consumption of ellagitannincontaining foods.
Carnosic acid (CA) and rosemary extracts (REs) have antiobesity effects but the mechanisms are no... more Carnosic acid (CA) and rosemary extracts (REs) have antiobesity effects but the mechanisms are not understood. We investigated some of the potential mechanisms contributing to the metabolic effects of an RE enriched in CA. Methods and results: An RE (∼40% CA) was administered to lean (Le, fa/+) and obese (Ob, fa/fa) female Zucker rats for 64 days. Several adipocytokines, brain-derived neurotrophic factor, phosphorylated AMP-activated protein kinase, and hepatic gene expression changes were investigated. The RE significantly decreased circulating tumor necrosis factor alpha (RE/CT = 0.36, p < 0.0003), IL-1 (0.48, p < 0.032), and leptin (0.48, p < 0.002), and upregulated adiponectin (1.47, p < 0.045) in the Le rats. The RE also induced phase I and phase II gene expression and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Notably, the RE decreased adipose phosphorylated AMP-activated protein kinase and did not affect hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the Ob rats. Conclusion: Our results show that an RE rich in CA exerts anti-inflammatory effects and affects hepatic metabolism in normal Le rats. We report significant differences in the expression and regulation of key metabolic sensors between Le and Ob rats that may contribute to explain the different ability of the two genotypes to respond to the RE.
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Papers by Mar Larrosa