Association of microbiota polyphenols with cardiovascular health in the context of a Mediterranean diet.

BACKGROUND AND AIMS: The Mediterranean diet (MedDiet) is rich in polyphenols, phytochemicals that are beneficial for cardiovascular health. Phenolic compounds have poor bioavailability but they are extensively metabolized by the gut microbiota. Therefore, we aimed to assess the association of microbial phenolic metabolites (MPM) with adherence to the MedDiet, and their relationship with ideal cardiovascular health (ICVH) and cardiovascular risk factors. METHODS AND RESULTS: This cross-sectional substudy within the PREDIMED trial included 200 participants from the Barcelona-Clinic recruitment center. Five MPM were identified and quantified using a novel method based on liquid chromatography coupled to mass spectrometry: protocatechuic acid (PCA), enterodiol glucuronide (EDG), enterolactone glucuronide (ELG), vanillic acid glucuronide (VAG) and urolithin B glucuronide (UBG). Multivariable-adjusted regressions were used to evaluate the associations between MPM and MedDiet adherence, ICVH score, biochemical parameters, and blood pressure. Additionally, an MPM score was calculated as the weighted sum of MedDiet adherence and ICVH and found to be directly associated. Among individual polyphenols, UBG was inversely associated with LDL-cholesterol. CONCLUSIONS: A score of urinary MPM was associated with higher adherence to the MedDiet and ICVH, and individual MPM were related to better cardiovascular health. These findings suggest that the MedDiet may affect gut microbiota, whose metabolites are linked with cardiovascular health.

Retinoids stored locally in the lung are required to attenuate the severity of acute lung injury in male mice.

Retinoids are potent transcriptional regulators that act in regulating cell proliferation, differentiation, and other cellular processes. We carried out studies in male mice to establish the importance of local cellular retinoid stores within the lung alveolus for maintaining its health in the face of an acute inflammatory challenge induced by intranasal instillation of lipopolysaccharide. We also undertook single cell RNA sequencing and bioinformatic analyses to identify roles for different alveolar cell populations involved in mediating these retinoid-dependent responses. Here we show that local retinoid stores and uncompromised metabolism and signaling within the lung are required to lessen the severity of an acute inflammatory challenge. Unexpectedly, our data also establish that alveolar cells other than lipofibroblasts, specifically microvascular endothelial and alveolar epithelial cells, are able to take up lipoprotein-transported retinoid and to accumulate cellular retinoid stores that are directly used to respond to an acute inflammatory challenge.

Microbial Phenolic Metabolites in Urine Are Inversely Linked to Certain Features of Metabolic Syndrome in Spanish Adolescents.

(1) Background: To explore the association between microbial phenolic metabolites (MPM) and metabolic syndrome (MetS) and its clinical features in adolescents aged 12.02 ± 0.41 years. (2) Methods: a cross-sectional study was conducted in 560 participants at baseline in the SI! Program for Secondary Schools trial. The following MPM, coumaric acids (m-, o-, p-coumaric acids), dihydroxyphenylpropionic acid, dihydroresveratrol, enterolignans, gallic acid, hydroxybenzoic acids, hydroxyphenylacetic acid, hydroxytyrosol, protocatechuic acid, syringic acid, urolithins (A, B), and vanillic acid, were analyzed by HPLC-LTQ-Orbitrap-HRMS. MetS and its clinical features were defined in accordance with the International Diabetes Federation. (3) Results: Out of all MPM, urolithin A was inversely associated with the diastolic blood pressure z-score. Urolithin B was inversely associated with the MetS score and waist circumference z-score. Additionally, higher levels of gallic acid were associated with lower odds of presenting MetS (OR = 0.85, 95% CI: 0.77; 0.93) and abdominal obesity (OR = 0.93, 95% CI: 0.89; 0.98). Higher urolithin B levels were inversely associated with abdominal obesity (OR = 0.94, 95% CI: 0.89; 0.98) and high blood glucose (OR = 0.92, 95% CI:0.88; 0.96); (4) Conclusions: gallic acid, urolithin A and B were associated with lower odds of presenting MetS or some of its clinical features in adolescents. This is the first study that evaluates several MPM with MetS in adolescents, highlighting the importance of MPM on cardiometabolic health at early life stages.

Circulating carotenoids are associated with favorable lipid and fatty acid profiles in an older population at high cardiovascular risk.

Carotenoid intake has been reported to be associated with improved cardiovascular health, but there is little information on actual plasma concentrations of these compounds as biomarkers of cardiometabolic risk. The objective was to investigate the association between circulating plasma carotenoids and different cardiometabolic risk factors and the plasma fatty acid profile. This is a cross-sectional evaluation of baseline data conducted in a subcohort (106 women and 124 men) of an ongoing multi-factorial lifestyle trial for primary cardiovascular prevention. Plasma concentrations of carotenoids were quantified by liquid chromatography coupled to mass spectrometry. The associations between carotenoid concentrations and cardiometabolic risk factors were assessed using regression models adapted for interval-censored variables. Carotenoid concentrations were cross-sectionally inversely associated with serum triglyceride concentrations [-2.79 mg/dl (95% CI: -4.25, -1.34) and -5.15 mg/dl (95% CI: -7.38, -2.93), p-values = 0.0002 and <0.00001 in women and men, respectively], lower levels of plasma saturated fatty acids [-0.09% (95% CI: -0.14, -0.03) and -0.15 % (95% CI: -0.23, -0.08), p-values = 0.001 and 0.0001 in women and men, respectively], and higher levels of plasma polyunsaturated fatty acids [(0.12 % (95% CI: -0.01, 0.25) and 0.39 % (95% CI: 0.19, 0.59), p-values = 0.065 and 0.0001 in women and men, respectively] in the whole population. Plasma carotenoid concentrations were also associated with higher plasma HDL-cholesterol in women [0.47 mg/dl (95% CI: 0.23, 0.72), p-value: 0.0002], and lower fasting plasma glucose in men [-1.35 mg/dl (95% CI: -2.12, -0.59), p-value: 0.001].

One-Year Changes in Urinary Microbial Phenolic Metabolites and the Risk of Type 2 Diabetes-A Case-Control Study.

The intake of polyphenols has been associated with a risk reduction of type 2 diabetes. Nevertheless, to the best of our knowledge, the molecules that might be metabolically active after ingestion are only starting to be investigated regarding this metabolic disease. To investigate the association between one-year changes in urinary microbial phenolic metabolites (MPM) and the incidence of type 2 diabetes, we performed a case-control study using data and samples of the PREDIMED trial including 46 incident type 2 diabetes cases of 172 randomly selected participants. Eight urinary MPMs were quantified in urine by liquid chromatography coupled to mass spectrometry and used to assess their associations with type 2 diabetes risk by multivariable logistic regression models. Compared to participants in the lowest tertile of one-year changes in hydroxybenzoic acid glucuronide, those in the highest tertile had a significantly lowered probability of developing type 2 diabetes (OR [95% CI], 0.39 [0.23−0.64]; p < 0.001 for trend). However, when additionally adjusting for fasting plasma glucose, the statistical significance was lost. Changes in the dietary pattern can increase the concentrations of this compound, derived from many (poly)phenol-rich foods, and might be changing the gut microbial population as well, promoting the production of the metabolite.

Identification and Quantification of Urinary Microbial Phenolic Metabolites by HPLC-ESI-LTQ-Orbitrap-HRMS and Their Relationship with Dietary Polyphenols in Adolescents.

This study aimed to develop and validate a liquid chromatography/electrospray ionization-linear ion trap quadrupole-Orbitrap-high-resolution mass spectrometry (HPLC/ESI-LTQ-Orbitrap-HRMS) method to identify and quantify urinary microbial phenolic metabolites (MPM), as well as to explore the relationship between MPM and dietary (poly)phenols in Spanish adolescents. A total of 601 spot urine samples of adolescents aged 12.02 ± 0.41 years were analyzed. The quantitative method was validated for linearity, limit of detection, limit of quantification, recovery, intra- and inter-day accuracy and precision, as well as postpreparative stability according to the criteria established by the Association of Official Agricultural Chemists International. A total of 17 aglycones and 37 phase II MPM were identified and quantified in 601 spot urine samples. Phenolic acids were the most abundant urinary MPM, whereas stilbenes, hydroxytyrosol, and enterodiol were the least abundant. Urinary hydroxycoumarin acids (urolithins) were positively correlated with flavonoid and total (poly)phenol intake. An HPLC-ESI-LTQ-Orbitrap-HRMS method was developed and fully validated to quantify MPM. The new method was performed accurately and is suitable for MPM quantification in large epidemiological studies. Urinary lignans and urolithins are proposed as potential biomarkers of grain and nut intake in an adolescent population.

Effect of Crushing Peanuts on Fatty Acid and Phenolic Bioaccessibility: A Long-Term Study.

BACKGROUND: Peanuts are consumed worldwide and have been linked to multiple health benefits. Processing may affect the bioavailability of peanut bioactive compounds. Therefore, we aim to evaluate the effects of crushing peanuts on the bioavailability of fatty acids and phenolic compounds in healthy adults. METHODS: 44 participants from the ARISTOTLE study consumed 25 g/day of whole peanuts (WP) or 32 g/day of peanut butter (PB) for 6 months. Fatty acids and phenolic compounds in peanut products and biological samples were assessed by gas chromatography coupled to flame ionization detection and liquid chromatography coupled to high resolution mass spectrometry, respectively. RESULTS: Plasma concentrations of very long chain saturated fatty acids (VLCSFAs) increased significantly after 6 months of WP or PB intake (p < 0.001 in both cases). Participants in the WP group excreted twice as many VLCSFAs in feces as those in the PB group (p = 0.012). The most abundant polyphenols found in WP and PB were p-coumaric and isoferulic acids. Urinary excretion of isoferulic acid increased after the intake of WP and PB (p = 0.032 and p = 0.048, respectively), with no significant difference observed between interventions. CONCLUSION: The crushing step in peanut butter production seems to enhance the bioavailability of bioactive compounds.

Fruit and Vegetable Consumption is Inversely Associated with Plasma Saturated Fatty Acids at Baseline in Predimed Plus Trial.

SCOPE: Plasma fatty acids (FAs) are associated with the development of cardiovascular diseases and metabolic syndrome. The aim of our study is to assess the relationship between fruit and vegetable (F&V) consumption and plasma FAs and their subtypes. METHODS AND RESULTS: Plasma FAs are assessed in a cross-sectional analysis of a subsample of 240 subjects from the PREDIMED-Plus study. Participants are categorized into four groups of fruit, vegetable, and fat intake according to the food frequency questionnaire. Plasma FA analysis is performed using gas chromatography. Associations between FAs and F&V consumption are adjusted for age, sex, physical activity, body mass index (BMI), total energy intake, and alcohol consumption. Plasma saturated FAs are lower in groups with high F&V consumption (-1.20 mg cL-1 [95% CI: [-2.22, -0.18], p-value = 0.021), especially when fat intake is high (-1.74 mg cL-1 [95% CI: [-3.41, -0.06], p-value = 0.042). Total FAs and n-6 polyunsaturated FAs tend to be lower in high consumers of F&V only in the high-fat intake groups. CONCLUSIONS: F&V consumption is associated with lower plasma saturated FAs when fat intake is high. These findings suggest that F&V consumption may have different associations with plasma FAs depending on their subtype and on the extent of fat intake.

Moderate Consumption of Beer (with and without Ethanol) and Menopausal Symptoms: Results from a Parallel Clinical Trial in Postmenopausal Women.

The menopausal transition can be a challenging period for women's health and a trigger of uncomfortable symptoms. Beer is the main food source of isoxanthohumol, a precursor of 8-prenylnaringenin, the strongest phytoestrogen identified to date. As phytoestrogens are reported to reduce perimenopausal symptoms, we evaluated if a daily moderate consumption of beer with (AB) and without alcohol (NAB) could improve menopausal symptoms and modify cardiovascular risk factors. A total of 37 postmenopausal women were enrolled in a parallel controlled intervention trial and assigned to three study groups: 16 were administered AB (330 mL/day), 7 NAB (660 mL/day), and 14 were in the control group. After a 6-month follow-up of the 34 participants who finished the trial, both interventions (AB and NAB) significantly reduced the severity of the menopause-related symptoms (p-value AB vs. Control: 0.009; p-value NAB vs. Control: 0.033). Moreover, AB had a beneficial net effect on psychological menopausal discomforts compared to the control group. As the sex hormone profile did not differ significantly between the study groups, the effects of both types of beers (AB and NAB) are attributed to the non-alcoholic fraction of beer. Furthermore, moderate NAB consumption improved the lipid profile and decreased blood pressure in postmenopausal women.

High Fruit and Vegetable Consumption and Moderate Fat Intake Are Associated with Higher Carotenoid Concentration in Human Plasma.

Carotenoids are pigments contained mainly in fruit and vegetables (F&V) that have beneficial effects on cardiometabolic health. Due to their lipophilic nature, co-ingestion of fat appears to increase their bioavailability via facilitating transfer to the aqueous micellar phase during digestion. However, the extent to which high fat intake may contribute to increased carotenoid plasma concentrations is still unclear. The objective was to examine the degree to which the consumption of different amounts of both carotenoid-rich foods and fats is associated with plasma carotenoid concentrations within a Mediterranean lifestyle context (subsample from the PREDIMED-Plus study baseline) where consumption of F&V and fat is high. The study population was categorized into four groups according to their self-reported consumption of F&V and fat. Carotenoids were extracted from plasma samples and analyzed by HPLC-UV-VIS-QqQ-MS/MS. Carotenoid systemic concentrations were greater in high consumers of F&V than in low consumers of these foods (+3.04 µmol/L (95% CI: 0.90, 5.17), p-value = 0.005), but circulating concentrations seemed to decrease when total fat intake was very high (-2.69 µmol/L (-5.54; 0.16), p-value = 0.064). High consumption of F&V is associated with greater systemic levels of total carotenoids, in particular when fat intake is low-to-moderate rather than very high.

A Targeted Approach by High Resolution Mass Spectrometry to Reveal New Compounds in Raisins.

Raisins are dried grapes mostly obtained from cultivars of Vitis vinifera L. and are extensively consumed worldwide. They are rich in bioactive compounds such as polyphenols, which are associated with a broad range of health benefits. The aim of the present study was to compare the phenolic profiles of three different raisin varieties (Thompson seedless, Muscat, and sultanas). Total polyphenols (TPs) were evaluated by the Folin-Ciocalteu (F-C) assay and significant differences were observed among all raisin varieties. Furthermore, liquid chromatography coupled with electrospray ionization hybrid linear ion trap quadrupole-Orbitrap-mass spectrometry (LC/ESI-LTQ-Orbitrap-MS) was employed for the comprehensive identification of phenolic constituents. A total of 45 compounds were identified, including hydroxybenzoic and hydroxycinnamic acids, flavanoids, flavonoids, flavonols, flavones, and stilbenoids. The three varieties of raisins showed a similar phenolic profile, although the highest number of phenolic compounds was identified in Muscat raisins owing to the proanthocyanidins extracted from their seeds, while stilbenoids were not detected in the Thompson variety.

Is Eating Raisins Healthy?

Raisins are dried grapes consumed worldwide that contain beneficial components for human health. They are rich in fiber and phytochemicals such as phenolic compounds. Despite a 60% sugar content, several studies have reported health-promoting properties for raisins and this review compiles the intervention studies, as well as the cell line and animal model studies carried out to date. It has been demonstrated that raisins possess a low-to-moderate glycemic index, which makes them a healthy snack. They seem to contribute to a better diet quality and may reduce appetite. Their antioxidant capacity has been correlated to the phenolic content and this may be involved in the improvement of cardiovascular health. In addition, raisins maintain a good oral health due to their antibacterial activity, low adherence to teeth and an optimum oral pH. Raisin consumption also seems to be favorable for colon function, although more studies should be done to conclude this benefit. Moreover, gut microbiota could be affected by the prebiotic content of raisins. Cell line and animal model studies show other potential benefits in specific diseases, such as cancer and Alzheimer's disease. However, deeper research is required and future intervention studies with humans are needed. Overall, incorporating an 80-90 g portion of raisins (half a cup) into the daily diet may be favorable for human health.

Microbial Phenolic Metabolites: Which Molecules Actually Have an Effect on Human Health?

The role of gut microbiota in human health has been investigated extensively in recent years. The association of dysbiosis, detrimental changes in the colonic population, with several health conditions has led to the development of pro-, pre- and symbiotic foods. If not absorbed in the small intestine or secreted in bile, polyphenols and other food components can reach the large intestine where they are susceptible to modification by the microbial population, resulting in molecules with potentially beneficial health effects. This review provides an overview of studies that have detected and/or quantified microbial phenolic metabolites using high-performance liquid chromatography as the separation technique, followed by detection through mass spectrometry. Both in vitro experimental studies and human clinical trials are covered. Although many of the microbial phenolic metabolites (MPM) reported in in vitro studies were identified in human samples, further research is needed to associate them with clinical health outcomes.

Increase of 4-Hydroxybenzoic, a Bioactive Phenolic Compound, after an Organic Intervention Diet.

Consumption of organic products is increasing yearly due to perceived health-promoting qualities. Several studies have shown higher amounts of phytochemicals such as polyphenols and carotenoids in foods produced by this type of agriculture than in conventional foods, but whether this increase has an impact on humans still needs to be assessed. A randomized, controlled and crossover study was carried out in nineteen healthy subjects aged 18-40 years, who all followed an organic and conventional healthy diet, both for a 4-week period. Analysis of biological samples revealed a significant increase on the excretion of 4-hydroxybenzoic acid (4-HBA), a phenolic metabolite with biological activity, after the organic intervention. However, no changes were observed in the other variables analyzed.

A review of factors that affect carotenoid concentrations in human plasma: differences between Mediterranean and Northern diets.

Carotenoids are naturally occurring pigments of autotroph organisms that have been related to many health benefits and this is not only because some of them are precursors of vitamin A. Individual or whole carotenoid consumption has been associated with a lower risk of developing cancer, cardiovascular and metabolic diseases among others. However, the blood levels of carotenoids vary largely from person to person due to different factors. Diet is the most important one because of the dietary patterns that different populations follow, the time of the year of consumption or the personal preferences. Nevertheless, the intrinsic host factors such as the absorption, distribution, metabolism and excretion genetic polymorphisms, the volume of distribution and the person's microbiota and others such as carotenoid interactions are also inducing this so called inter-individual variability. Besides, culinary methods and processing produce changes in the foods that directly affect carotenoid content and hence their blood profile. Different types of studies have been performed to understand the between-subject variation of the carotenoid profile in human plasma. This research is focused on this matter as levels of carotenoids in human plasma could be useful for the prediction of some diseases. The Mediterranean diet is probably the most carotenoid rich diet stemming from its high proportion of fruits and vegetables. Its differences with other diets and the effect on the carotenoid blood profile of the consumers are currently a very interesting topic of study.

Health Effects of Resveratrol: Results from Human Intervention Trials.

The effect of resveratrol (RV) intake has been reviewed in several studies performed in humans with different health status. The purpose of this review is to summarize the results of clinical trials of the last decade, in which RV was determined in biological samples such as human plasma, urine, and feces. The topics covered include RV bioavailability, pharmacokinetics, effects on cardiovascular diseases, cognitive diseases, cancer, type 2 diabetes (T2D), oxidative stress, and inflammation states. The overview of the recent research reveals a clear tendency to identify RV in plasma, showing that its supplementation is safe. Furthermore, RV bioavailability depends on several factors such as dose, associated food matrix, or time of ingestion. Notably, enterohepatic recirculation of RV has been observed, and RV is largely excreted in the urine within the first four hours after consumption. Much of the research on RV in the last 10 years has focused on its effects on pathologies related to oxidative stress, inflammatory biomarkers, T2D, cardiovascular diseases, and neurological diseases.