Chronic consumption of a bergamot-based beverage does not affect glucose, lipid and inflammatory biomarkers of cardiometabolic risk in healthy subjects: a randomised controlled intervention study.

Background: Pure bergamot juice exerts lipid lowering effects in dyslipidemic subjects. It is unknown whether bergamot-based beverages exert similar effects in healthy subjects. Aim: To assess the effects, if any, of a bergamot-based beverage (BBB, bergamot juice ≤25%) on lipid, metabolic and inflammatory biomarkers. Methods: Forty-five healthy subjects were randomised 1 : 1 to BBB intake (400 mL day-1) (55.5%) or control (44.5%) for 12 weeks. Anthropometric (waist circumference, body mass index (BMI)) and clinical (blood pressure) parameters, blood samples (glucose, glycated haemoglobin, insulinemia, lipid profile, liver and renal function, inflammatory biomarkers) and 24-h urine for the analysis of (poly)phenol metabolites were collected at the baseline and at 12 weeks. Intakes of energy, nutrients and food groups were assessed by a 7-day dietary record. Results: Both groups exhibited a time-related significant decrease in total cholesterol (p = 0.02), fasting plasma glucose (p = 0.016), insulin (p = 0.034), BMI (p < 0.001) and waist circumference (p = 0.04), but with no significant between-arm difference. The urinary profile of metabolites from the BBB-derived (poly)phenols well discriminated the two study groups, documenting good compliance in the intervention arm. Notably, urinary bergamot 3-hydroxy-3-methylglutaryl (HMG) -containing flavanones or derived HMG-containing metabolites were not detectable. BBB was well tolerated and no adverse events were recorded. Conclusion: This first randomized controlled trial of BBB consumption in healthy subjects showed no effects of BBB on the cardiometabolic risk profile. BBB consumption is a safe nutritional adjunct in the context of a well balanced diet.

Using Targeted Metabolomics to Unravel Phenolic Metabolites of Plant Origin in Animal Milk.

Milk holds a high nutritional value and is associated with diverse health benefits. The understanding of its composition of (poly)phenolic metabolites is limited, which necessitates a comprehensive evaluation of the subject. This study aimed at analyzing the (poly)phenolic profile of commercial milk samples from cows and goats and investigating their sterilization treatments, fat content, and lactose content. Fingerprinting of phenolic metabolites was achieved by using ultra-high-performance liquid chromatography coupled with triple-quadrupole mass spectrometry (UHPLC-QqQ-MS/MS). Two hundred and three potential microbial and phase II metabolites of the main dietary (poly)phenols were targeted. Twenty-five metabolites were identified, revealing a diverse array of phenolic metabolites in milk, including isoflavones and their microbial catabolites equol and O-desmethylangolensin, phenyl-γ-valerolactones (flavan-3-ol microbial catabolites), enterolignans, urolithins (ellagitannin microbial catabolites), benzene diols, and hippuric acid derivates. Goat's milk contained higher concentrations of these metabolites than cow's milk, while the sterilization process and milk composition (fat and lactose content) had minimal impact on the metabolite profiles. Thus, the consumption of goat's milk might serve as a potential means to supplement bioactive phenolic metabolites, especially in individuals with limited production capacity. However, further research is needed to elucidate the potential health effects of milk-derived phenolics.

Correction: Nutrikinetics and urinary excretion of phenolic compounds after a 16-week supplementation with a flavanone-rich ingredient.

Correction for 'Nutrikinetics and urinary excretion of phenolic compounds after a 16-week supplementation with a flavanone-rich ingredient' by Jananee Muralidharan et al., Food Funct., 2023, 14, 10506-10519, https://doi.org/10.1039/D3FO02820H.

Factors driving the inter-individual variability in the metabolism and bioavailability of (poly)phenolic metabolites: A systematic review of human studies.

This systematic review provides an overview of the available evidence on the inter-individual variability (IIV) in the absorption, distribution, metabolism, and excretion (ADME) of phenolic metabolites and its determinants. Human studies were included investigating the metabolism and bioavailability of (poly)phenols and reporting IIV. One hundred fifty-three studies met the inclusion criteria. Inter-individual differences were mainly related to gut microbiota composition and activity but also to genetic polymorphisms, age, sex, ethnicity, BMI, (patho)physiological status, and physical activity, depending on the (poly)phenol sub-class considered. Most of the IIV has been poorly characterised. Two major types of IIV were observed. One resulted in metabolite gradients that can be further classified into high and low excretors, as seen for all flavonoids, phenolic acids, prenylflavonoids, alkylresorcinols, and hydroxytyrosol. The other type of IIV is based on clusters of individuals defined by qualitative differences (producers vs. non-producers), as for ellagitannins (urolithins), isoflavones (equol and O-DMA), resveratrol (lunularin), and preliminarily for avenanthramides (dihydro-avenanthramides), or by quali-quantitative metabotypes characterized by different proportions of specific metabolites, as for flavan-3-ols, flavanones, and even isoflavones. Future works are needed to shed light on current open issues limiting our understanding of this phenomenon that likely conditions the health effects of dietary (poly)phenols.

Exploring and disentangling the production of potentially bioactive phenolic catabolites from dietary (poly)phenols, phenylalanine, tyrosine and catecholamines.

Following ingestion of fruits, vegetables and derived products, (poly)phenols that are not absorbed in the upper gastrointestinal tract pass to the colon, where they undergo microbiota-mediated ring fission resulting in the production of a diversity of low molecular weight phenolic catabolites, which appear in the circulatory system and are excreted in urine along with their phase II metabolites. There is increasing interest in these catabolites because of their potential bioactivity and their use as biomarkers of (poly)phenol intake. Investigating the fate of dietary (poly)phenolics in the colon has become confounded as a result of the recent realisation that many of the phenolics appearing in biofluids can also be derived from the aromatic amino acids, l-phenylalanine and l-tyrosine, and to a lesser extent catecholamines, in reactions that can be catalysed by both colonic microbiota and endogenous mammalian enzymes. The available evidence, albeit currently rather limited, indicates that substantial amounts of phenolic catabolites originate from phenylalanine and tyrosine, while somewhat smaller quantities are produced from dietary (poly)phenols. This review outlines information on this topic and assesses procedures that can be used to help distinguish between phenolics originating from dietary (poly)phenols, the two aromatic amino acids and catecholamines.

A Systematic Review and Comprehensive Evaluation of Human Intervention Studies to Unravel the Bioavailability of Hydroxycinnamic Acids.

Significance: Hydroxycinnamic acids (HCAs) are the main phenolic acids in the western diet. Harmonizing the available information on the absorption, distribution, metabolism, and excretion (ADME) of HCAs is fundamental to unraveling the compounds responsible for their health effects. This work systematically assessed pharmacokinetics, including urinary recovery, and bioavailability of HCAs and their metabolites, based on literature reports. Recent Advances: Forty-seven intervention studies with coffee, berries, herbs, cereals, tomato, orange, grape products, and pure compounds, as well as other sources yielding HCA metabolites, were included. Up to 105 HCA metabolites were collected, mainly acyl-quinic and C6-C3 cinnamic acids. C6-C3 cinnamic acids, such as caffeic and ferulic acid, reached the highest blood concentrations (maximum plasma concentration [Cmax] = 423 nM), with time to reach Cmax (Tmax) values ranging from 2.7 to 4.2 h. These compounds were excreted in urine in higher amounts than their phenylpropanoic acid derivatives (4% and 1% of intake, respectively), but both in a lower percentage than hydroxybenzene catabolites (11%). Data accounted for 16 and 18 main urinary and blood HCA metabolites, which were moderately bioavailable in humans (collectively 25%). Critical Issues: A relevant variability emerged. It was not possible to unequivocally assess the bioavailability of HCAs from each ingested source, and data from some plant based-foods were absent or inconsistent. Future Directions: A comprehensive study investigating the ADME of HCAs derived from their most important dietary sources is urgently required. Eight key metabolites were identified and reached interesting plasma Cmax concentrations and urinary recoveries, opening up new perspectives to evaluate their bioactivity at physiological concentrations. Antioxid. Redox Signal. 40, 510-541.

Nutrikinetics and urinary excretion of phenolic compounds after a 16-week supplementation with a flavanone-rich ingredient.

Background: Polyphenols are a broad group of compounds with a complex metabolic fate. Flavanones and their metabolites provide cardiovascular protection and assistance in long-term body composition management. Objective: This study evaluates the nutrikinetics and the bioavailability of phenolic compounds after both acute and chronic supplementation with a flavanone-rich product, namely Sinetrol® Xpur, in healthy overweight and obese volunteers. Design: An open-label study including 20 volunteers was conducted for 16 weeks. Participants received Sinetrol® Xpur, either a low dose (900 mg per day) or a high dose (1800 mg per day), in capsules during breakfast and lunch. They were advised to follow an individualized isocaloric diet and avoid a list of polyphenol-rich foods 48 hours before and during the pharmacokinetic measurements. Results: Over 20 phase II and colonic metabolites were measured in the plasma. Two peaks were observed at 1 h and 7h-10 h after the first capsule ingestion. No significant differences in the AUC were observed in circulating metabolites between both doses. In urine excretion, 53 metabolites were monitored, including human phase II and colonic metabolites, at weeks 1 and 16. Cumulative urine excretion was higher after the high dose than after the low dose in both acute and chronic studies. Total urinary metabolites were significantly lower in week 16 compared to week 1. Conclusion: Although the urinary excreted metabolites reduced significantly over 16 weeks, the circulating metabolites did not decrease significantly. This study suggests that chronic intake might not offer the same bioavailability as in the acute study, and this effect does not seem to be dose-dependent. The clinical trial registry number is NCT03823196.

Unravelling phenolic metabotypes in the frame of the COMBAT study, a randomized, controlled trial with cranberry supplementation.

Cranberry (poly)phenols may have potential health benefits. Circulating (poly)phenol metabolites can act as mediators of these effects, but they are subjected to an extensive inter-individual variability. This study aimed to quantify both plasma and urine (poly)phenol metabolites following a 12-week intake of a cranberry powder in healthy older adults, and to investigate inter-individual differences by considering the existence of urinary metabotypes related to dietary (poly)phenols. Up to 13 and 67 metabolites were quantified in plasma and urine respectively. Cranberry consumption led to changes in plasma metabolites, mainly hydroxycinnamates and hippuric acid. Individual variability in urinary metabolites was assessed using different data sets and a combination of statistical models. Three phenolic metabotypes were identified, colonic metabolism being the main driver for subject clustering. Metabotypes were characterized by quali-quantitative differences in the excretion of some metabolites such as phenyl-γ-valerolactones, hydroxycinnamic acids, and phenylpropanoic acids. Metabotypes were further confirmed when applying a model only focused on flavan-3-ol colonic metabolites. 5-(3',4'-dihydroxyphenyl)-γ-valerolactone derivatives were the most relevant metabolites for metabotyping. Metabotype allocation was well preserved after 12-week intervention. This metabotyping approach for cranberry metabolites represents an innovative step to handle the complexity of (poly)phenol metabolism in free-living conditions, deciphering the existence of metabotypes derived from the simultaneous consumption of different classes of (poly)phenols. These results will help contribute to studying the health effects of cranberries and other (poly)phenol-rich foods, mainly considering gut microbiota-driven individual differences.

Excretion by subjects on a low (poly)phenol diet of phenolic gut microbiota catabolites sequestered in tissues or associated with catecholamines and surplus amino acids.

Phenolic catabolites excreted by fasting subjects with a functioning colon and ileostomists on a low (poly)phenol diet have been investigated. Urine was collected over a 12 h fasting period after adherence to a low (poly)phenol diet for 36 h. UHPLC-HR-MS quantified 77 phenolics. Some were present in the urine of both groups in similar trace amounts and others were excreted in higher amounts by participants with a colon indicating the involvement of the microbiota. Most were present in sub- or low-µmol amounts, but hippuric acid dominated accounting on average for 60% of the total for both volunteer categories indicating significant production from sources other than non-nutrient dietary (poly)phenols. The potential origins of the phenolics associated with the low (poly)phenol diet, include endogenous catecholamines, surplus tyrosine and phenylalanine, and washout of catabolites derived from pre-study intakes of non-nutrient dietary (poly)phenols.

Italian Grape Ale Beers Obtained with Malvasia di Candia Aromatica Grape Variety: Evolution of Phenolic Compounds during Fermentation.

Italian grape ale (IGA) beers have been categorized by the Beer Judge Certification Program as a sub-category of fruit beers in which grape, or grape must, is added during the brewing process to provide additional characteristics to the final beer. In the present work, IGA beers have been produced with must and pomace of the Malvasia di Candia Aromatica (MaCA) grape variety, which were added before fermentation at two different percentages (10% and 20%). The (poly)phenolic profile of IGA beers have been characterized with HPLC-MS/MS and compared to a golden ale control beer (produced in the same conditions without the addition of grape-derived ingredients). A series of sub-samples have been collected to monitor the (poly)phenol profile at time 0 and during the different phases of the fermentation process (1, 3, 5, 7 30, 65 days). Results demonstrated how the addition of pomace allowed to significantly enrich (p < 0.05) final beers in total (poly)phenols detected by MS, while must addition did not influence that amount if compared to the control sample. However, a PCA cluster analysis identified strong similarities among IGA beers and differentiated them to control beer samples. This study underlined how the addition of must and pomace from the MaCA grape variety improved the (poly)phenolic profile of beer from both a qualitative and quantitative point of view.

Revisiting the bioavailability of flavan-3-ols in humans: A systematic review and comprehensive data analysis.

This systematic review summarizes findings from human studies investigating the different routes of absorption, metabolism, distribution and excretion (ADME) of dietary flavan-3-ols and their circulating metabolites in healthy subjects. Literature searches were performed in PubMed, Scopus and the Web of Science. Human intervention studies using single and/or multiple intake of flavan-3-ols from food, extracts, and pure compounds were included. Forty-nine human intervention studies met inclusion criteria. Up to 180 metabolites were quantified from blood and urine samples following intake of flavan-3-ols, mainly as phase 2 conjugates of microbial catabolites (n = 97), with phenyl-γ-valerolactones being the most representative ones (n = 34). Phase 2 conjugates of monomers and phenyl-γ-valerolactones, the main compounds in both plasma and urine, reached two peak plasma concentrations (Cmax) of 260 and 88 nmol/L at 1.8 and 5.3 h (Tmax) after flavan-3-ol intake. They contributed to the bioavailability of flavan-3-ols for over 20%. Mean bioavailability for flavan-3-ols was moderate (31 ± 23%, n bioavailability values = 20), and it seems to be scarcely affected by the amount of ingested compounds. While intra- and inter-source differences in flavan-3-ol bioavailability emerged, mean flavan-3-ol bioavailability was 82% (n = 1) and 63% (n = 2) after (-)-epicatechin and nut (hazelnuts, almonds) intake, respectively, followed by 25% after consumption of tea (n = 7), cocoa (n = 5), apples (n = 3) and grape (n = 2). This highlights the need to better clarify the metabolic yield with which monomer flavan-3-ols and proanthocyanidins are metabolized in humans. This work clarified in a comprehensive way for the first time the ADME of a (poly)phenol family, highlighting the pool of circulating compounds that might be determinants of the putative beneficial effects linked to flavan-3-ol intake. Lastly, methodological inputs for implementing well-designed human and experimental model studies were provided.

Human colonic catabolism of dietary flavan-3-ol bioactives.

Understanding the fate of ingested polyphenols is crucial in elucidating the molecular mechanisms underlying the beneficial effects of a fruit and vegetable-based diet. This review focuses on the colon microbiota-mediated transformation of the flavan-3-ols and the structurally related procyanidins found in dietary plant foods and beverages, plus the flavan-3-ol-derived theaflavins of black tea, and the post-absorption phase II metabolism of the gut microbiota catabolites. Despite significant advances in the last decade major analytical challenges remain. Strategies to address them are presented.

Exposure to (Poly)phenol Metabolites after a Fruit and Vegetable Supplement Intake: A Double-Blind, Cross-Over, Randomized Trial.

Dietary (poly)phenol intake derived from the daily consumption of five portions of fruits and vegetables could protect against the development of non-communicable diseases. However, the general population does not meet the recommended intake. Supplementation with (poly)phenol-rich ingredients, within a varied and balanced diet, could help in filling this nutritional gap. This study aimed to validate the proof-of-concept of a (poly)phenolic supplementation developed to enhance the daily consumption of potentially bioactive compounds. Oxxynea® is a (poly)phenol-rich ingredient developed to provide the quantity and the variety corresponding to five-a-day fruit and vegetable consumption. In this double-blind, randomized cross-over study, 10 participants were supplemented with 450 mg of a (poly)phenol-based supplement or a placebo. Pharmacokinetics and urinary excretion profiles were measured for 24 and 48 h, respectively, using UPHLC-MS/MS analysis. The pharmacokinetic profile displayed a triphasic absorption, indicating peaks of circulating metabolites at 1.75 ± 0.25 h, 4.50 ± 0.34 h, 9.50 ± 0.33 h and an average Tmax (time of maximal plasma concentration) of 6.90 ± 0.96 h. Similarly, the urinary profile showed maximum metabolite excretion at 3-6 h, 6-10 h and 14-24 h after supplement consumption. Compared to individual metabolites belonging to different (poly)phenolic subfamilies, the total circulating and excreted metabolites showed a reduced coefficient of variation (CV 38%). The overall bioavailability estimated was 27.4 ± 3.4%. Oxxynea® supplementation may provide a sustained exposure to several (poly)phenolic metabolites and catabolites and reduces the inter-individual variation that could arise from supplementing only one class of (poly)phenol.

Characterization of the (Poly)Phenolic Fraction of Fig Peel: Comparison among Twelve Cultivars Harvested in Tuscany.

(1) Background: The fig tree (Ficus carica L.) is widely cultivated in the Mediterranean area and it produces fruits largely consumed in the Mediterranean diet. Previous studies have shown that this fruit represents a rich source of (poly)phenols, which are mainly located in the peel rather than the pulp. In our study, fig peel derived from twelve different cultivars located in Tuscany was assessed for its (poly)phenol profile. (2) Methods: The (poly)phenol characterization was performed through ultra-high performance liquid chromatography coupled to multiple-stage mass spectrometry. (3) Results: Twenty-eight (poly)phenolic compounds were quantified in the investigated fig peel. It was possible to observe an interesting variability in the (poly)phenol content among the twelve cultivars of fig peel. Rutin and 5-caffeoylquinic acid were the main compounds in the greenish fig peel, while cyanidin-3-O-rutinoside was the main component in the dark-violet fig peel. (4) Conclusions: fig peel could be used as a (poly)phenol-rich ingredient in several food products to increase the bioactive compound content of foods. Moreover, dark-violet peel could be considered potentially suitable as a natural food colorant.

A wheat aleurone-rich diet improves oxidative stress but does not influence glucose metabolism in overweight/obese individuals: Results from a randomized controlled trial.

BACKGROUND AND AIMS: Aleurone is the innermost layer of wheat bran, rich in fiber, minerals, vitamins, phenolic compounds, and betaine. The metabolic effects of aleurone rich foods are still unknown. Our aim was to investigate the effects of consuming a Wheat Aleurone rich diet vs. a Refined Wheat diet for 8 weeks on fasting and postprandial glycemic and lipid metabolism, inflammation, and oxidative stress in overweight/obese individuals. METHODS AND RESULTS: According to a randomized cross-over study design, 23 overweight/obese individuals, age 56 ± 9 years (M±SD), were assigned to two isoenergetic diet - Wheat Aleurone and Refined Wheat diets - for 8 weeks. The diets were similar for macronutrient composition but different for the aleurone content (40-50 g/day in the Wheat Aleurone diet). After each diet, fasting and postprandial plasma metabolic profile, ferulic acid metabolites and 8-isoprostane concentrations in 24-h urine samples were evaluated. Compared with the Refined Wheat Diet, the Wheat Aleurone Diet increased fasting plasma concentrations of betaine by 15% (p = 0.042) and decreased the excretion of 8-isoprostane by 33% (p = 0.035). Conversely, it did not affect the fasting and postprandial glucose, insulin and triglyceride responses, homocysteine, and C-Reactive Protein concentrations, nor excretion of phenolic metabolites. CONCLUSION: An 8-week Wheat Aleurone Diet improves the oxidative stress and increases plasma betaine levels in overweight/obese individuals with an increased cardiometabolic risk. However, further studies with longer duration and larger sample size are needed to evaluate the benefits of aleurone-rich foods on glucose and lipid metabolism in individuals with more severe metabolic abnormalities. CLINICAL TRIAL REGISTRY NUMBER: NCT02150356, (https://clinicaltrials.gov).

In Vitro Faecal Fermentation of Monomeric and Oligomeric Flavan-3-ols: Catabolic Pathways and Stoichiometry.

SCOPE: The study evaluates the influence of flavan-3-ol structure on the production of phenolic catabolites, principally phenyl-γ-valerolactones (PVLs), and phenylvaleric acids (PVAs). METHODS AND RESULTS: A set of 12 monomeric flavan-3-ols and proanthocyanidins (degree of polymerization (DP) of 2-5), are fermented in vitro for 24 h using human faecal microbiota, and catabolism is analyzed by UHPLC-ESI-MS/MS. Up to 32 catabolites strictly related to microbial catabolism of parent compounds are detected. (+)-Catechin and (-)-epicatechin have the highest molar mass recoveries, expressed as a percentage with respect to the incubated concentration (75 µmol L-1 ) of the parent compound, for total PVLs and PVAs, both at 5 h (about 20%) and 24 h (about 40%) of faecal incubation. Only A-type dimer and B-type procyanidins underwent the ring fission step, and no differences are found in total PVL and PVA production (≃1.5% and 6.0% at 5 and 24 h faecal incubation, respectively) despite the different DPs. CONCLUSION: The flavan-3-ol structure strongly affects the colonic catabolism of the native compounds, influencing the profile of PVLs and PVAs produced in vitro. This study opens new perspectives to further elucidate the colonic fate of oligomeric flavan-3-ols and their availability in producing bioactive catabolites.

Metabotypes of flavan-3-ol colonic metabolites after cranberry intake: elucidation and statistical approaches.

PURPOSE: Extensive inter-individual variability exists in the production of flavan-3-ol metabolites. Preliminary metabolic phenotypes (metabotypes) have been defined, but there is no consensus on the existence of metabotypes associated with the catabolism of catechins and proanthocyanidins. This study aims at elucidating the presence of different metabotypes in the urinary excretion of main flavan-3-ol colonic metabolites after consumption of cranberry products and at assessing the impact of the statistical technique used for metabotyping. METHODS: Data on urinary concentrations of phenyl-γ-valerolactones and 3-(hydroxyphenyl)propanoic acid derivatives from two human interventions has been used. Different multivariate statistics, principal component analysis (PCA), cluster analysis, and partial least square-discriminant analysis (PLS-DA), have been considered. RESULTS: Data pre-treatment plays a major role on resulting PCA models. Cluster analysis based on k-means and a final consensus algorithm lead to quantitative-based models, while the expectation-maximization algorithm and clustering according to principal component scores yield metabotypes characterized by quali-quantitative differences in the excretion of colonic metabolites. PLS-DA, together with univariate analyses, has served to validate the urinary metabotypes in the production of flavan-3-ol metabolites and to confirm the robustness of the methodological approach. CONCLUSIONS: This work proposes a methodological workflow for metabotype definition and highlights the importance of data pre-treatment and clustering methods on the final outcomes for a given dataset. It represents an additional step toward the understanding of the inter-individual variability in flavan-3-ol metabolism. TRIAL REGISTRATION: The acute study was registered at clinicaltrials.gov as NCT02517775, August 7, 2015; the chronic study was registered at clinicaltrials.gov as NCT02764749, May 6, 2016.

Effect of different patterns of consumption of coffee and a cocoa-based product containing coffee on the nutrikinetics and urinary excretion of phenolic compounds.

BACKGROUND: Coffee consumption is associated with a reduced risk of several chronic diseases in a dose-dependent manner. Chronic intake results in the transient appearance of bioactive phenolic metabolites in the circulatory system. However, there is a lack of information on the impact of different patterns of coffee consumption on plasma and urinary profiles of phenolic metabolites. OBJECTIVES: Plasma and urinary phenolic metabolites were investigated following regular consumption of different daily dosages of coffee or cocoa-based products containing coffee (CBPCC) under a real-life setting. METHODS: A repeated-dose, randomized, crossover human intervention was conducted with 21 healthy volunteers. For 1 mo, participants consumed 1) 1 cup of coffee (1C), 2) 3 cups of coffee (3C), or 3) 1 cup of coffee + 2 CBPCC twice daily (PC). Plasma and urine samples were collected over a 24-h period after each treatment. The nutrikinetics and urinary excretion of native, human phase II, and colonic metabolites were assessed. RESULTS: A total of 51 (poly)phenolic metabolites were quantified, with 41 metabolites being strictly related to coffee consumption. Significant differences were observed among treatments for most of the metabolites. The metabolites present in the highest amounts were the hydroxycinnamate, phenylpropanoic acid, benzaldehyde, and benzene classes, along with (-)-epicatechin and phenyl-γ-valerolactone derivatives after PC treatment. Daily average concentrations did not exceed 200 nmol/L and were <100 nmol/L for most of the metabolites. The excretion of coffee phenolics ranged from 40% to 70% of intake, indicating that coffee hydroxycinnamates are notably more bioavailable than previously thought. Interindividual variability was also investigated. CONCLUSIONS: The absorption, metabolism, nutrikinetic profile, and bioavailability of coffee phenolics were established for different patterns of coffee consumption under real-life conditions. This work provides the basis for further nutritional epidemiology research and mode-of-action cell-based studies. This study was registered at clinicaltrials.gov as NCT03166540.

Plasma TMAO increase after healthy diets: results from 2 randomized controlled trials with dietary fish, polyphenols, and whole-grain cereals.

BACKGROUND: Plasma trimethylamine N-oxide (TMAO) has drawn much attention as a marker of several chronic diseases. Data on the relation between diet and TMAO are discordant and few human intervention studies have assessed causality for this association. OBJECTIVES: We aimed to evaluate the effects on plasma TMAO of diets based on foods rich in polyphenols (PP) and/or long-chain n-3 fatty acids (LCn3) or whole-grain cereals (WGCs), in individuals at high cardiometabolic risk. METHODS: An ancillary study was performed within 2 randomized controlled trials, aimed at evaluating the medium-term effects on cardiometabolic risk factors of diets naturally rich in PP and/or LCn3 (Etherpaths Project) or WGCs (HealthGrain Project). RESULTS: In the Etherpaths study (n = 78), the changes in TMAO (8-wk minus baseline) were statistically significant for the diets rich in LCn3 (+1.15 ± 11.58 µmol/L) (P = 0.007), whereas they were not for the diets rich in PP (-0.14 ± 9.66 µmol/L) (P = 0.905) or their interaction (P = 0.655) (2-factor ANOVA). In the HealthGrain Study (n = 48), the TMAO change (12-wk minus baseline) in the WGC group (+0.94 ± 3.58 µmol/L) was significantly different from that in the Refined Cereal group (-1.29 ± 3.09 µmol/L) (P = 0.037). Considering the pooled baseline data of the participants in the 2 studies, TMAO concentrations directly correlated with LCn3, EPA (20:5n-3), and protein intake, but not SFAs, fiber, MUFAs, and PP intake. Among food groups, TMAO directly correlated with the intake of fish, vegetables, and whole-grain products, but not meat, processed meat, and dairy products. CONCLUSIONS: Diets rich in LCn3 of marine origin or WGCs significantly increased plasma TMAO concentration. These changes mirrored the direct associations between TMAO concentrations and intakes of fish and WGCs, suggesting that TMAO reflects intakes of these healthy foods and, therefore, it is not a universally valid biomarker of cardiometabolic risk independent of the background diet.These trials were registered at clinicaltrials.gov as NCT01154478 and NCT00945854.