( -)-Epicatechin and cardiometabolic risk factors: a focus on potential mechanisms of action.

This review summarizes experimental evidence on the beneficial effects of ( -)-epicatechin (EC) attenuating major cardiometabolic risk factors, i.e., dyslipidemias, obesity (adipose tissue dysfunction), hyperglycemia (insulin resistance), and hypertension (endothelial dysfunction). Studies in humans are revised and complemented with experiments in animal models, and cultured cells, aiming to understand the molecular mechanisms involved in EC-mediated effects. Firstly, an assessment of EC metabolism gives relevance to both conjugated-EC metabolites product of host metabolism and microbiota-derived species. Integration and analysis of results stress the maintenance of redox homeostasis and mitigation of inflammation as relevant processes associated with cardiometabolic diseases. In these processes, EC appears having significant effects regulating NADPH oxidase (NOX)-dependent oxidant production, nitric oxide (NO) production, and energy homeostasis (mitochondrial biogenesis and function). The potential participation of cell membranes and membrane-bound receptors is also discussed in terms of direct molecular action of EC and EC metabolites reaching cells and tissues.

Functional implications of bound phenolic compounds and phenolics-food interaction: A review.

Sizeable scientific evidence indicates the health benefits related to phenolic compounds and dietary fiber. Various phenolic compounds-rich foods or ingredients are also rich in dietary fiber, and these two health components may interrelate via noncovalent (reversible) and covalent (mostly irreversible) interactions. Notwithstanding, these interactions are responsible for the carrier effect ascribed to fiber toward the digestive system and can modulate the bioaccessibility of phenolics, thus shaping health-promoting effects in vivo. On this basis, the present review focuses on the nature, occurrence, and implications of the interactions between phenolics and food components. Covalent and noncovalent interactions are presented, their occurrence discussed, and the effect of food processing introduced. Once reaching the large intestine, fiber-bound phenolics undergo an intense transformation by the microbial community therein, encompassing reactions such as deglycosylation, dehydroxylation, α- and ß-oxidation, dehydrogenation, demethylation, decarboxylation, C-ring fission, and cleavage to lower molecular weight phenolics. Comparatively less information is still available on the consequences on gut microbiota. So far, the very most of the information on the ability of bound phenolics to modulate gut microbiota relates to in vitro models and single strains in culture medium. Despite offering promising information, such models provide limited information about the effect on gut microbes, and future research is deemed in this field.

Lignans and Gut Microbiota: An Interplay Revealing Potential Health Implications.

Plant polyphenols are a broad group of bioactive compounds characterized by different chemical and structural properties, low bioavailability, and several in vitro biological activities. Among these compounds, lignans (a non-flavonoid polyphenolic class found in plant foods for human nutrition) have been recently studied as potential modulators of the gut-brain axis. In particular, gut bacterial metabolism is able to convert dietary lignans into therapeutically relevant polyphenols (i.e., enterolignans), such as enterolactone and enterodiol. Enterolignans are characterized by various biologic activities, including tissue-specific estrogen receptor activation, together with anti-inflammatory and apoptotic effects. However, variation in enterolignans production by the gut microbiota is strictly related to both bioaccessibility and bioavailability of lignans through the entire gastrointestinal tract. Therefore, in this review, we summarized the most important dietary source of lignans, exploring the interesting interplay between gut metabolites, gut microbiota, and the so-called gut-brain axis.

Metabolic and Microbial Modulation of the Large Intestine Ecosystem by Non-Absorbed Diet Phenolic Compounds: A Review.

Phenolic compounds represent a diverse group of phytochemicals whose intake is associated with a wide spectrum of health benefits. As consequence of their low bioavailability, most of them reach the large intestine where, mediated by the action of local microbiota, a series of related microbial metabolites are accumulated. In the present review, gut microbial transformations of non-absorbed phenolic compounds are summarized. Several studies have reached a general consensus that unbalanced diets are associated with undesirable changes in gut metabolism that could be detrimental to intestinal health. In terms of explaining the possible effects of non-absorbed phenolic compounds, we have also gathered information regarded their influence on the local metabolism. For this purpose, a number of issues are discussed. Firstly, we consider the possible implications of phenolic compounds in the metabolism of colonic products, such as short chain fatty acids (SCFA), sterols (cholesterol and bile acids), and microbial products of non-absorbed proteins. Due to their being recognized as affective antioxidant and anti-inflammatory agents, the ability of phenolic compounds to counteract or suppress pro-oxidant and/or pro-inflammatory responses, triggered by bowel diseases, is also presented. The modulation of gut microbiota through dietetic maneuvers including phenolic compounds is also commented on. Although the available data seems to assume positive effects in terms of gut health protection, it is still insufficient for solid conclusions to be extracted, basically due to the lack of human trials to confirm the results obtained by the in vitro and animal studies. We consider that more emphasis should be focused on the study of phenolic compounds, particularly in their microbial metabolites, and their power to influence different aspects of gut health.

Phenol Biological Metabolites as Food Intake Biomarkers, a Pending Signature for a Complete Understanding of the Beneficial Effects of the Mediterranean Diet.

The Mediterranean diet (MD) has become a dietary pattern of reference due to its preventive effects against chronic diseases, especially relevant in cardiovascular diseases (CVD). Establishing an objective tool to determine the degree of adherence to the MD is a pending task and deserves consideration. The central axis that distinguishes the MD from other dietary patterns is the choice and modality of food consumption. Identification of intake biomarkers of commonly consumed foods is a key strategy for estimating the degree of adherence to the MD and understanding the protective mechanisms that lead to a positive impact on health. Throughout this review we propose potential candidates to be validated as MD adherence biomarkers, with particular focus on the metabolites derived from the phenolic compounds that are associated with the consumption of typical Mediterranean plant foods. Certain phenolic metabolites are good indicators of the intake of specific foods, but others denote the intake of a wide-range of foods. For this, it is important to emphasise the need to increase the number of dietary interventions with specific foods in order to validate the biomarkers of MD adherence. Moreover, the identification and quantification of food phenolic intake biomarkers encouraging scientific research focuses on the study of the biological mechanisms in which polyphenols are involved.

Beta-Glucan and Phenolic Compounds: Their Concentration and Behavior during in Vitro Gastrointestinal Digestion and Colonic Fermentation of Different Barley-Based Food Products.

Among cereals, barley ( Hordeum vulgare L.) is notable for its high content of bioactives such as ß-glucan and phenolic compounds, but it is not used as widely in human nutrition as wheat. To compare the impact of food formulation and processing on barley bioactives, crackers, cookies, and fresh pasta were prepared combining wheat and barley flour. After quantification of ß-glucan and PCs in the barley flour and barley-based products, their behavior during in vitro gastrointestinal digestion and colonic fermentation was studied. The ß-glucan and PCs were not drastically affected by processing. The amount of bioaccessible compounds after gastrointestinal digestion was lower than the amount retained in the undigested fraction. After in vitro colonic fermentation, ß-glucan was mainly metabolized to acetic and propionic acids and PCs to phenylpropionic and phenylacetic acids. Based on the results of the study, the daily ingestion of barley-based foods may contribute to the intake of beneficial bioactive compounds.

Cardiovascular Benefits of Phenol-Enriched Virgin Olive Oils: New Insights from the Virgin Olive Oil and HDL Functionality (VOHF) Study.

SCOPE: The main findings of the "Virgin Olive Oil and HDL Functionality" (VOHF) study and other related studies on the effect of phenol-enriched virgin olive oil (VOO) supplementation on cardiovascular disease are integrated in the present work. METHODS AND RESULTS: VOHF assessed whether VOOs, enriched with their own phenolic compounds (FVOO) or with those from thyme (FVOOT), improve quantity and functionality of HDL. In this randomized, double-blind, crossover, and controlled trial, 33 hypercholesterolemic subjects received a control VOO (80 mg kg-1 ), FVOO (500 mg kg-1 ), and FVOOT (500 mg kg-1 ; 1:1) for 3 weeks. Both functional VOOs promoted cardioprotective changes, modulating HDL proteome, increasing fat-soluble antioxidants, improving HDL subclasses distribution, reducing the lipoprotein insulin resistance index, increasing endogenous antioxidant enzymes, protecting DNA from oxidation, ameliorating endothelial function, and increasing fecal microbial metabolic activity. Additional cardioprotective benefits were observed according to phenol source and content in the phenol-enriched VOOs. These insights support the beneficial effects of OO and PC from different sources. CONCLUSION: Novel therapeutic strategies should increase HDL-cholesterol levels and enhance HDL functionality. The tailoring of phenol-enriched VOOs is an interesting and useful strategy for enhancing the functional quality of HDL, and thus, it can be used as a complementary tool for the management of hypercholesterolemic individuals.

Exploring the Colonic Metabolism of Grape and Strawberry Anthocyanins and Their in Vitro Apoptotic Effects in HT-29 Colon Cancer Cells.

Beneficial properties attributed to the intake of fruit and red wine have been associated with the presence of significant amounts of anthocyanins. However, their low absorption and consequent accumulation in the gut have generated the suspicion that colonic metabolites of anthocyanins are probably involved in these protective effects. Grape pomace and strawberry extracts, rich in malvidin- and pelargonidin-glucoside, respectively, were fermented in vitro using human feces as microbial inoculum. After 8 h of anaerobic incubation, the anthocyanins were almost completely degraded, whereas their microbial metabolite concentrations were highest at 24 h. Syringic acid and tyrosol were the main metabolites of grape and strawberry extracts, respectively. On the basis of the metabolites detected, metabolic pathways of malvidin- and pelargonidin-glucosides were proposed. Anthocyanin-rich grape and strawberry extracts and their generated metabolites such as hydroxyphenylacetic acid showed apoptotic effects in HT-29 colon cancer cells and may suggest their possible contribution as anticarcinogenic agents.

Determinants of HDL Cholesterol Efflux Capacity after Virgin Olive Oil Ingestion: Interrelationships with Fluidity of HDL Monolayer.

SCOPE: Cholesterol efflux capacity of HDL (CEC) is inversely associated with cardiovascular risk. HDL composition, fluidity, oxidation, and size are related with CEC. We aimed to assess which HDL parameters were CEC determinants after virgin olive oil (VOO) ingestion. METHODS AND RESULTS: Post-hoc analyses from the VOHF study, a crossover intervention with three types of VOO. We assessed the relationship of 3-week changes in HDL-related variables after intervention periods with independence of the type of VOO. After univariate analyses, mixed linear models were fitted with variables related with CEC and fluidity. Fluidity and Apolipoprotein (Apo)A-I content in HDL was directly associated, and HDL oxidative status inversely, with CEC. A reduction in free cholesterol, an increase in triglycerides in HDL, and a decrease in small HDL particle number or an increase in HDL mean size, were associated to HDL fluidity. CONCLUSIONS: HDL fluidity, ApoA-I concentration, and oxidative status are major determinants for CEC after VOO. The impact on CEC of changes in free cholesterol and triglycerides in HDL, and those of small HDL or HDL mean size, could be mechanistically linked through HDL fluidity. Our work points out novel therapeutic targets to improve HDL functionality in humans through nutritional or pharmacological interventions.

Understanding of human metabolic pathways of different sub-classes of phenols from Arbutus unedo fruit after an acute intake.

Arbutus unedo is a small Mediterranean fruit, commonly named strawberry tree, which is a rich source of different sub-classes of phenolic compounds, the more representative being the gallic acid derivatives, including its mono and oligomeric forms esterified with quinic and shikimic acids. In addition, galloyl derivatives, particularly gallotannins, described in A. unedo, are part of a very selective phenolic group, present in a reduced number of plant-products. The aim of the present study is to provide a better understanding of human metabolic pathways of different sub-classes of phenols from the A. unedo fruit after an acute intake by healthy adults. Therefore, the A. unedo phenolic metabolites were studied in whole blood samples (0 to 24 h), urine (24 h) and feces (12 and 24 h). Special focus was placed on the application of dried blood spot (DBS) cards for the sample collection and for the analysis of phenolic metabolites in whole blood samples. The results of the blood analysis revealed two peaks for the maximum concentrations of the main phenolic metabolites. Furthermore, it is appropriate to highlight the application of DBS cards as an efficient and accurate way to collect blood samples in post-prandial bioavailability studies. The analysis of urine (24 h) gave a wide range of phenolic metabolites showing the extensive metabolism that A. unedo phenolic compounds underwent in the human body. The results of the study provide a relevant contribution to the understanding of the in vivo human bioavailability of phenolic compounds, especially galloyl derivatives, a singular phenolic sub-group present in the A. unedo fruit.

Stability and metabolism of Arbutus unedo bioactive compounds (phenolics and antioxidants) under in vitro digestion and colonic fermentation.

The natural antioxidants of Arbutus unedo highlight the importance of this fruit as natural source of bioactive compounds. In the present study, to evaluate the stability of phenolic compounds, ascorbic acid and fat-soluble antioxidants (α-tocopherol, ß-carotene and lutein), in vitro gastrointestinal digestion was applied to A. unedo fruit. After that, the non-absorbable fraction was anaerobically incubated with human faeces and the metabolic pathway for gallotannins, ellagitannins, flavan-3-ols and anthocyanins from A. unedo fruit was proposed. The results showed that the presence of pectin from the fruit hampered the solubilization of the phenolic compounds (with exception of gallic and ellagic acids) and fat-soluble vitamins during gastric digestion. Degradation of pectin-gel during the duodenal digestion favored the release of the phenolic compounds and fat-soluble antioxidants to the media. The catabolic activity of human microbiota led to the generation of a wide range of simple phenols, such as p-hydroxybenzoic acid and catechol, derived from the catabolism of gallotannins, ellagitannins, flavan-3-ols and anthocyanins.

Effect of daily intake of pomegranate juice on fecal microbiota and feces metabolites from healthy volunteers.

SCOPE: The purpose of the study was to evaluate the effect, regarding the metabolic and microbial profile of feces, of diet supplementation of healthy adults with pomegranate juice (PJ). METHODS AND RESULTS: Twelve healthy adults were recruited to the study, which consisted of the intake of 200 mL/day of PJ during 4 weeks. Feces were collected before and after the supplementation with PJ. Metabolites (phenolic catabolites, short-chain fatty acids, and fecal steroids) and microbial profile were analyzed at baseline and at 4 weeks. Fecal phenolic metabolites, 3-phenylpropionic acid, catechol, hydroxytyrosol, and urolithin A, showed a significant increase in their concentration after supplementation with PJ. Among fecal steroids, parallel to the significant increase of cholesterol concentration, a significant decrease of coprostanol was observed. Although no significant changes in the microbiota profile were observed, different relationships between initial microbiota and the metabolites produced were found. Catechol showed positive and negative correlation with Oscillospora and Paraprevotella genera, respectively, and 3-phenylpropionic acid was positively correlated with Odoribacter genus. CONCLUSION: Inclusion of PJ in the diet did not significantly alter the gut microbiota composition in healthy adults, but the individual bacterial composition could contribute to the generation of potential health-promoting phenolic metabolites.

Study of the catabolism of thyme phenols combining in vitro fermentation and human intervention.

The gut metabolism of four thyme phenolics (monoterpenes thymol and carvacrol, rosmarinic acid, and eriodictyol) was evaluated in vitro. After the in vitro transformations of the individual phenols had been studied, the presence of their microbial metabolites was investigated in human feces collected before and after a sustained intake (3 weeks) of 25 mL/day of a thyme phenol-enriched olive oil. Results of in vitro fermentation showed low degradation of thymol and carvacrol. By contrast, large catabolism was noted when rosmarinic acid and eriodictyol were fermented, yielding hydroxyphenylpropionic acid as the main metabolite. In accordance with these results, after the in vivo intervention with thyme phenol-enriched olive oil, an increase in the concentration of hydroxyphenylpropionic and phenylpropionic acids was observed in human feces, confirming the effective in vivo microbial degradation of rosmarinic acid and eriodictyol. Carvacrol was detected in fecal samples at trace levels, suggesting that monoterpenes are well absorbed in the upper part of the gastrointestinal tract.

Faecal microbial metabolism of olive oil phenolic compounds: in vitro and in vivo approaches.

SCOPE: In the present study, the individual colonic metabolism of the main components of the virgin olive oil phenolic fraction was evaluated by an in vitro model using human faecal microbiota. To assess differences in metabolism related to the molecular structure, four phenolic standards were selected, tyrosol, hydroxytyrosol, hydroxytyrosol acetate and oleuropein. After studying the in vitro colonic metabolism pathways of the individual phenols, the presence of their colonic metabolites was investigated in human faecal samples obtained before and after the sustained intake (3 weeks) of a daily dose of 25 mL of a phenol-enriched olive oil. METHODS AND RESULTS: The in vitro colon fermentation of the four individual phenolic compounds revealed (i) an increase in phenolic acids, (ii) the stability of hydroxytyrosol and tyrosol and (iii) the high degradation of hydroxytyrosol acetate and oleuropein. Additionally, a moderate intake of a phenol-rich olive oil raised the concentration in human faeces of free hydroxytyrosol and phenylacetic and phenylpropionic acids. CONCLUSION: The products of colonic catabolism of olive oil phenolic compounds could be good candidates for novel preventive strategies and open a promising line of research into the preventive action of olive oil phenols in colon and other bowel diseases.