Disentangling the genetic underpinnings of neuropsychiatric symptoms in Alzheimer's disease in the Alzheimer's Disease Sequencing Project: Study design and methodology.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms. METHODS: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP). RESULTS: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole-genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD. DISCUSSION: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations. Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site.

We Are What, When, And How We Eat: The Evolutionary Impact of Dietary Shifts on Physical and Cognitive Development, Health, and Disease.

"We are what, when, and how we eat": the evolution of human dietary habits mirrors the evolution of humans themselves. Key developments in human history, such as the advent of stone tool technology, the shift to a meat-based diet, control of fire, advancements in cooking and fermentation techniques, and the domestication of plants and animals, have significantly influenced human anatomical, physiological, social, cognitive, and behavioral changes. Advancements in scientific methods, such as the analysis of microfossils like starch granules, plant-derived phytoliths, and coprolites, have yielded unprecedented insights into past diets. Nonetheless, the isolation of ancient food matrices remains analytically challenging. Future technological breakthroughs and a more comprehensive integration of paleogenomics, paleoproteomics, paleoglycomics, and paleometabolomics will enable a more nuanced understanding of early human ancestors' diets, which holds the potential to guide contemporary dietary recommendations and tackle modern health challenges, with far-reaching implications for human well-being, and ecological impact on the planet.

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.

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.

Colon-available mango (poly)phenols exhibit mitigating effects on the intestinal barrier function in human intestinal cell monolayers under inflammatory conditions.

This study investigated the impact of in vivo available colon-mango (poly)phenols on stress-induced impairment of intestinal barrier function. Caco-2/HT29-MTX cells were incubated with six extracts of ileal fluid collected pre- and 4-8 h post-mango consumption before being subjected to inflammatory stress. (Poly)phenols in ileal fluids were analysed by UHPLC-HR-MS. Epithelial barrier function was monitored by measurement of trans-epithelial electrical resistance (TEER) and the production of selected inflammatory markers (interleukin-8 (IL-8) and nitric oxide (NO)) and the major mucin of the mucosal layer (MUC2). Post-mango intake ileal fluids contained principally benzoic acids, hydroxybenzenes and galloyl derivatives. There was a high interindividual variability in the levels of these compounds, which was reflected by the degree of variability in the protective effects of individual ileal extracts on inflammatory changes in the treated cell cultures. The 24 h treatment with non-cytotoxic doses of extracts of 4-8 h post-mango intake ileal fluid significantly reduced the TEER decrease in monolayers treated with the inflammatory cytomix. This effect was not associated with changes in IL-8 expression and secretion or claudine-7 expression. The mango derived-ileal fluid extract (IFE) also mitigated cytomix-dependent nitrite secretion, as a proxy of NO production, and the MUC2 reduction observed upon the inflammatory challenge. These insights shed light on the potential protective effect of mango (poly)phenols on the intestinal barrier exposed to inflammatory conditions.

Generalizability of Tau and Amyloid Plasma Biomarkers in Alzheimer's Disease Cohorts of Diverse Genetic Ancestries.

Introduction: Plasma phosphorylated threonine-181 of Tau and amyloid beta are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, generalizability of existing biomarker data is not assured. Methods: In 2,086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvians) we measured plasma pTau-181 and Aß42/Aß40. Differences in biomarkers between cohorts and clinical diagnosis groups and the potential discriminative performance of the two biomarkers were assessed. Results: pTau-181 and Aß42/Aß40 were consistent across cohorts. Higher levels of pTau181 were associated with AD while Aß42/Aß40 had minimal differences. Correspondingly, pTau-181 had greater predictive value than Aß42/Aß40, however, the area under the curve differed between cohorts. Discussion: pTau-181 as a plasma biomarker for clinical AD is generalizable across genetic ancestries, but predictive value may differ. Combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses.

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.

The interaction between Mediterranean diet and intestinal microbiome: relevance for preventive strategies against frailty in older individuals.

Age-related changes in intestinal microbiome composition and function are increasingly recognized as pivotal in the pathophysiology of aging and are associated with the aging phenotype. Diet is a major determinant of gut-microbiota composition throughout the entire lifespan, and several of the benefits of a healthy diet in aging could be mediated by the microbiome. Mediterranean diet (MD) is a traditional dietary pattern regarded as the healthy diet paradigm, and a large number of studies have demonstrated its benefits in promoting healthy aging. MD has also a positive modulatory effect on intestinal microbiome, favoring bacterial taxa involved in the synthesis of several bioactive compounds, such as short-chain fatty acids (SCFAs), that counteract inflammation, anabolic resistance, and tissue degeneration. Intervention studies conducted in older populations have suggested that the individual response of older subjects to MD, in terms of reduction of frailty scores and amelioration of cognitive function, is significantly mediated by the gut-microbiota composition and functionality. In this context, the pathophysiology of intestinal microbiome in aging should be considered when designing MD-based interventions tailored to the needs of geriatric patients.

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.

Comparison of vitamin C and flavanones between freshly squeezed orange juices and commercial 100% orange juices from four European countries.

Knowing the true levels of nutrients and dietary bioactives in fruit juices at the point of consumption is key to properly understand their potential health benefits. The objective was to characterise the vitamin C and flavanone content in commercial orange juices consumed in Europe, compared with fresh-squeezed juices. Commercial juices were a rich source of vitamin C (>30% of the Nutrient Reference Value). Vitamin C in fresh-squeezed juices, at the end of their shelf-life, remained 33% higher than the levels found in the commercial juices. Flavanones had similar values from both commercial and fresh juices, except for fresh samples stored for 48 h, where fresh juices had higher values (22.36 mg/100 mL). Thus, orange juices preserve their bioactive compounds during storage, with very little influence of the brand, country, industrial process or storage conditions. Main bioactive compounds in commercial juices are present at nutritionally significant levels to the freshly-squeezed ones.

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.

Dietary (Poly)phenols and Cognitive Decline: A Systematic Review and Meta-Analysis of Observational Studies.

SCOPE: This study aims to systematically review observational studies investigating the relation between dietary (poly)phenol consumption and various cognitive outcomes. METHODS AND RESULTS: Embase and PubMed databases are searched from inception to April 2023 for observational studies investigating the relation between dietary (poly)phenol intake and cognitive outcomes. For quantitative analyses, random effects models, subgroup analyses, and dose-response analyses are performed. A total of 37 studies are included in the systematic review. Among (poly)phenols, a higher intake of flavonoids is associated with better cognitive function and lower odds of cognitive decline (although with some exceptions). A quantitative meta-analysis shows an overall inverse association with cognitive impairment and reduced association with the incidence of dementia or related disorders for total flavonoids (relative risk (RR) = 0.83, 95% confidence interval (CI): 0.76, 0.89), anthocyanins (RR = 0.73, 95% CI: 0.60, 0.89), flavones (RR = 0.77, 95% CI: 0.63, 0.94), flavan-3-ols (RR = 0.86, 95% CI: 0.82, 0.91), and flavonols (RR = 0.88, 95% CI: 0.80, 0.96). Data on other (poly)phenolic compounds (i.e., phenolic acids) are promising but too preliminary. CONCLUSION: Habitual inclusion of flavonoids in the diet may play a preventive role against cognitive disorders.

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.

Neuropsychiatric features in a multi-ethnic population with Alzheimer disease and mild cognitive impairment.

BACKGROUND: Alzheimer disease (AD) is more prevalent in African American (AA) and Hispanic White (HIW) compared to Non-Hispanic White (NHW) individuals. Similarly, neuropsychiatric symptoms (NPS) vary by population in AD. This is likely the result of both sociocultural and genetic ancestral differences. However, the impact of these NPS on AD in different groups is not well understood. METHODS: Self-declared AA, HIW, and NHW individuals were ascertained as part of ongoing AD genetics studies. Participants who scored higher than 0.5 on the Clinical Dementia Rating (CDR) Scale (CDR) were included. Group similarities and differences on Neuropsychiatric Inventory Questionnaire (NPI-Q) outcomes (NPI-Q total score, NPI-Q items) were evaluated using univariate ANOVAs and post hoc comparisons after controlling for sex and CDR stage. RESULTS: Our sample consisted of 498 participants (26% AA; 30% HIW; 44% NHW). Overall, NPI-Q total scores differed significantly between our groups, with HIW having the highest NPI-Q total scores, and by AD stage as measured by CDR. We found no significant difference in NPI-Q total score by sex. There were six NPI-Q items with comparable prevalence in all groups and six items that significantly differed between the groups (Anxiety, Apathy, Depression, Disinhibition, Elation, and Irritability). Further, within the HIW group, differences were found between Puerto Rican and Cuban American Hispanics across several NPI-Q items. Finally, Six NPI-Q items were more prevalent in the later stages of AD including Agitation, Appetite, Hallucinations, Irritability, Motor Disturbance, and Nighttime Behavior. CONCLUSIONS: We identified differences in NPS among HIW, AA, and NHW individuals. Most striking was the high burden of NPS in HIW, particularly for mood and anxiety symptoms. We suggest that NPS differences may represent the impact of sociocultural influences on symptom presentation as well as potential genetic factors rooted in ancestral background. Given the complex relationship between AD and NPS it is crucial to discern the presence of NPS to ensure appropriate interventions.

Health effects of 100% fruit and vegetable juices: evidence from human subject intervention studies.

The health effects of 100% fruit and vegetable juices (FVJ) represent a controversial topic. FVJ contain notable amounts of free sugars, but also vitamins, minerals, and secondary compounds with proven biological activities like (poly)phenols and carotenoids. The review aimed to shed light on the potential impact of 100% FVJ on human subject health, comprehensively assessing the role each type of juice may have in specific health outcomes for a particular target population, as reported in dietary interventions. The effects of a wide range of FVJ (orange, grapefruit, mandarin, lemon, apple, white, red, and Concord grapes, pomegranate, cranberry, chokeberry, blueberry, other minor berries, sweet and tart cherry, plum, tomato, carrot, beetroot, and watermelon, among others) were evaluated on a series of outcomes (anthropometric parameters, body composition, blood pressure and vascular function, lipid profile, glucose homeostasis, biomarkers of inflammation and oxidative stress, cognitive function, exercise performance, gut microbiota composition and bacterial infections), providing a thorough picture of the contribution of each FVJ to a health outcome. Some juices demonstrated their ability to exert potential preventive effects on some outcomes while others on other health outcomes, emphasising how the differential composition in bioactive compounds defines juice effects. Research gaps and future prospects were discussed. Although 100% FVJ appear to have beneficial effects on some cardiometabolic health outcomes, cognition and exercise performance, or neutral effects on anthropometric parameters and body composition, further efforts are needed to better understand the impact of 100% FVJ on human subject health.

Performance of Urinary Phenyl-γ-Valerolactones as Biomarkers of Dietary Flavan-3-ol Exposure.

BACKGROUND: Phenyl-γ-valerolactones (PVLs) have been identified as biomarkers of dietary flavan-3-ol exposure, although their utility requires further characterization. OBJECTIVES: We investigated the performance of a range of PVLs as biomarkers indicative of flavan-3-ol intake. METHODS: We report the results of 2 companion studies: a 5-way randomized crossover trial (RCT) and an observational cross-sectional study. In the RCT (World Health Organization, Universal Trial Number: U1111-1236-7988), 16 healthy participants consumed flavan-3-ol-rich interventions (of apple, cocoa, black tea, green tea, or water [control]) for 1 d each. First morning void samples and 24-h urine samples were collected with diet standardized throughout. For each participant, 1 intervention period was extended (to 2 d) to monitor PVL kinetics after repeat exposure. In the cross-sectional study, 86 healthy participants collected 24-h urine samples, and concurrent weighed food diaries from which flavan-3-ol consumption was estimated using Phenol-Explorer. A panel of 10 urinary PVLs was quantified using liquid chromatography tandem mass spectrometry. RESULTS: In both studies, 2 urinary PVLs [5-(3'-hydroxyphenyl)-γ-valerolactone-4'-sulfate and putatively identified 5-(4'-hydroxyphenyl)-γ-valerolactone-3'-glucuronide] were the principal compounds excreted (>75%). In the RCT, the sum of these PVLs was significantly higher than the water (control) after each intervention; individually, there was a shift from sulfation toward glucuronidation as the total excretion of PVLs increased across the different interventions. In the extended RCT intervention period, no accumulation of these PVLs was observed after consecutive days of treatment, and after withdrawal of treatment on the third day, there was a return toward negligible PVL excretion. All results were consistent, whether compounds were measured in 24-h urine or first morning void samples. In the observational study, the sum of the principal PVLs correlated dose dependently (Rs = 0.37; P = 0.0004) with dietary flavan-3-ol intake, with similar associations for each individually. CONCLUSIONS: Urinary 5-(3'-hydroxyphenyl)-γ-valerolactone-4'-sulfate and putatively identified 5-(4'-hydroxyphenyl)-γ-valerolactone-3'-glucuronide are recommended biomarkers for dietary flavan-3-ol exposure.

Are (poly)phenols contained in 100% fruit juices mediating their effects on cardiometabolic risk factors? A meta-regression analysis.

Background: The consumption of 100% fruit juices has not been associated with substantial detrimental outcomes in population studies and may even contribute to improving the cardiometabolic profile if included in a healthy balanced diet. The main contributors to such potential beneficial effects include vitamins, minerals, and likely the (poly)phenol content. This study aimed to investigate whether the (poly)phenols contained in 100% fruit juices may mediate their effects on cardiometabolic risk factors based on published randomized controlled trials (RCT). Methods: A systematic search in PubMed/MEDLINE and Embase, updated till the end of October 2022, was carried out to identify RCT providing quantitative data on (poly)phenol content in 100% fruit juices and used as an intervention to improve cardiometabolic parameters such as blood lipids, glucose, and blood pressure. Meta-regression analysis was performed to calculate the effect of the intervention [expressed as standardized mean difference and 95% confidence intervals (CI)] using the (poly)phenol content as moderator. Results: A total of 39 articles on RCT investigating the effects of 100% fruit juices on cardiometabolic risk factors reporting data on total (poly)phenol and anthocyanin content were included in the analysis. Total (poly)phenol content was substantially unrelated to any outcome investigated. In contrast, each 100 mg per day increase in anthocyanins was related to 1.53 mg/dL decrease in total cholesterol (95% CI, -2.83, -0.22, p = 0.022) and 1.94 mg/dL decrease in LDL cholesterol (95% CI, -3.46, -0.42, p = 0.012). No other potential mediating effects of anthocyanins on blood triglycerides, glucose, systolic and diastolic pressure were found, while a lowering effect on HDL cholesterol after excluding one outlier study was observed. Discussion: In conclusion, the present study showed that anthocyanins may mediate the potential beneficial effects of some 100% fruit juices on some blood lipids. Increasing the content of anthocyanins through specific fruit varieties or plant breeding could enhance the health benefits of 100% fruit juices.

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.