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The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r2 = 0.74, p < 0.05), driven by caffeic acid 4-O-ß-d-glucuronide, quercetin-3-O-ß-d-glucuronide, ferulic acid 4-O-ß-d-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O-ß-d-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3′-hydroxyphenyl)-γ-valerolactone-4′-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r2 ≥ 0.89, p < 0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.

Toxicology studies have shown adverse effects of developmental exposure to industrial phenols. Evaluation in humans is challenged by potentially marked within-subject variability of phenol biomarkers in pregnant women, which is poorly characterized. We aimed to characterize within-day, between-day, and between-week variability of phenol urinary biomarker concentrations during pregnancy. In eight French pregnant women, we collected all urine voids over a 1-wk period (average, 60 samples per week per woman) at three occasions (15±2, 24±2, and 32±1 gestational weeks) in 2012-2013. Aliquots of each day and of the whole week were pooled within-subject. We assayed concentrations of 10 phenols in these pools, and, for two women, in all spot (unpooled) samples collected during a 1-wk period. We characterized variability using intraclass correlation coefficients (ICCs) with spot samples (within-day variability), daily pools (between-day variability), and weekly pools (between-week variability). For most biomarkers, the within-day variability was high (ICCs between 0.03 and 0.50). The between-day variability, based on samples pooled within each day, was much lower, with ICCs >0.60 except for bisphenol S (0.14, 95% confidence interval [CI]: 0.00, 0.39). The between-week variability differed between compounds, with triclosan and bisphenol S having the lowest ICCs (<0.3) and 2,5-dichlorophenol the highest (ICC >0.9). During pregnancy, phenol biomarkers showed a strong within-day variability, while the variability between days of a given week was more limited. One biospecimen is not enough to efficiently characterize exposure; collecting biospecimens during a single week may be enough to represent well the whole pregnancy exposure for some but not all phenols. https://doi.org/10.1289/EHP1994.

The goal of eating five servings of fruits and vegetables a day has not yet been achieved. The intake of polyphenols such as anthocyanins (ACN) could be improved by consuming smoothies and juices that are increasingly popular, especially in children; however, bioavailability data concerning food matrix effects are scarce. Thus, we conducted a randomised, cross-over, bioavailability study (n 10) to determine the bioavailability of ACN and their metabolites from an ACN-rich grape/blueberry juice (841 mg ACN/litre) and smoothie (983 mg ACN/litre) in vivo, and the uptake of a corresponding grape/blueberry extract in vitro. After the intake of beverage (0·33 litres), plasma and fractionated urine samples were collected and analysed by ultra-performance liquid chromatography coupled to MS. The most abundant ACN found in plasma and urine were malvidin and peonidin as native ACN and as glucuronidated metabolites as well as 3,4-dihydroxybenzoic acid (3,4-DHB); minor ACN (delphinidin, cyanidin and petunidin) were only detected as native glycosides. Plasma pharmacokinetics and recoveries of urinary metabolites of ACN were not different for juice or smoothie intake; however, the phenolic acid 3,4-DHB was significantly better bioavailable from juice in comparison to smoothie. In vitro data with absorptive intestinal cells indicated that despite their weak chemical stability, ACN and 3,4-DHB could be detected at the basal side in their native forms. Whether smoothies as well as juices should be recommended to increase the intake of potentially health-promoting ACN and other polyphenols requires the consideration of other ingredients such as their relatively high sugar content.

Although there has been increasing interest in the use of high protein diets, little is known about dietary protein related changes in the mammalian metabolome. We investigated the influence of protein intake on selected tryptophan and phenolic compounds, derived from both endogenous and colonic microbial metabolism. Furthermore, potential inter-species metabolic differences were studied. For this purpose, 29 healthy subjects were allocated to a high (n = 14) or low protein diet (n = 15) for 2 weeks. In addition, 20 wild-type FVB mice were randomized to a high protein or control diet for 21 days. Plasma and urine samples were analyzed with liquid chromatography-mass spectrometry for measurement of tryptophan and phenolic metabolites. In human subjects, we observed significant changes in plasma level and urinary excretion of indoxyl sulfate (P 0.004 and P 0.001), and in urinary excretion of indoxyl glucuronide (P 0.01), kynurenic acid (P 0.006) and quinolinic acid (P 0.02). In mice, significant differences were noted in plasma tryptophan (P 0.03), indole-3-acetic acid (P 0.02), p-cresyl glucuronide (P 0.03), phenyl sulfate (P 0.004) and phenylacetic acid (P 0.01). Thus, dietary protein intake affects plasma levels and generation of various mammalian metabolites, suggesting an influence on both endogenous and colonic microbial metabolism. Metabolite changes are dissimilar between human subjects and mice, pointing to inter-species metabolic differences with respect to protein intake.

The health-promoting effects of phenolic compounds depend on their bioaccessibility from the food matrix and their consequent bioavailability. We carried out a randomized crossover pilot clinical trial to evaluate the matrix effect (raw flesh and juice) of ‘Ataulfo’ mango on the bioavailability of its phenolic compounds. Twelve healthy male subjects consumed a dose of mango flesh or juice. Blood was collected for six hours after consumption, and urine for 24 h. Plasma and urine phenolics were analyzed by electrochemical detection coupled to high performance liquid chromatography (HPLC-ECD). Five compounds were identified and quantified in plasma. Six phenolic compounds, plus a microbial metabolite (pyrogallol) were quantified in urine, suggesting colonic metabolism. The maximum plasma concentration (Cmax) occurred 2–4 h after consumption; excretion rates were maximum at 8–24 h. Mango flesh contributed to greater protocatechuic acid absorption (49%), mango juice contributed to higher chlorogenic acid absorption (62%). Our data suggests that the bioavailability and antioxidant capacity of mango phenolics is preserved, and may be increased when the flesh is processed into juice.

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) that has been associated with various human disorders. Human exposure is ubiquitous. The primary route of exposure is ingestion, as BPA can leach from plastic food packaging and the epoxy resin lining of cans into food. Restrictions on the use of BPA in consumer products due to its health concerns have resulted in the development and introduction of new BPA alternatives. These compounds are likely to have health effects comparable to those of BPA. However, data on the type and amount of substitutes used in consumer products are difficult to obtain, and studies on their prevalence of use and impact on health in human populations are sparse. The aim of the present study was to evaluate the urinary concentrations of BPA and its analogues after the consumption of soda from cans compared to polyethylene terephthalate (PET) bottles and glass bottles. Additionally, we investigated blood pressure levels before and after soda consumption from cans, PET bottles, and glass bottles. We conducted a randomized crossover trial with 103 female participants between 30 and 65 years of age. The participants were assigned to drink soda (Coca-Cola light) from cans, PET bottles and glass bottles on two days of an intervention week. Urine samples were collected two to three hours after the intervention. Blood pressure levels were measured before and two to three hours after the intervention. Urinary bisphenol concentrations were measured via GC-AEI-MS/MS. The associations between the intervention and log10-transformed bisphenol concentrations and blood pressure levels were evaluated via a mixed models approach. For comparisons of the interventions, we used Tukey tests. We found significantly higher BPA concentrations in the urine samples of our study participants after soda consumption from cans than after soda consumption from PET bottles (+ 22.3%, 95% CI 3.37;44.64, P value 0.014). There was no difference compared to glass bottles. In addition to BPA, we detected BPF, BPS and BPE in some of the urine samples, but to a lesser extent, and independent of beverage packaging. Systolic and diastolic blood pressure increased across all interventions independent of whether soda was consumed from cans, PET bottles, or glass bottles. This study suggests that canned soda may increase the amount of BPA excreted in the urine of humans. The increase in blood pressure, independent of beverage packaging, may be due to the caffeine content of the consumed beverage. Given the potential of bisphenol exposure from canned food and beverage consumption, as well as the availability of alternatives in the epoxy resin lining of cans, complete removal of BPA from cans is an attractive option for mitigating human exposure to bisphenols. Universal Trial Number/ DRKS-ID: U1111-1244-7033/ DRKS00019922 (Registration Date 29/11/2019).

The leaves of the olive plant ( Olea europaea ) are rich in polyphenols, of which oleuropein and hydroxytyrosol (HT) are most characteristic. Such polyphenols have been demonstrated to favourably modify a variety of cardiovascular risk factors. The aim of the present intervention was to investigate the influence of olive leaf extract (OLE) on vascular function and inflammation in a postprandial setting and to link physiological outcomes with absorbed phenolics. A randomised, double-blind, placebo-controlled, cross-over, acute intervention trial was conducted with eighteen healthy volunteers (nine male, nine female), who consumed either OLE (51 mg oleuropein; 10 mg HT), or a matched control (separated by a 4-week wash out) on a single occasion. Vascular function was measured by digital volume pulse (DVP), while blood collected at baseline, 1, 3 and 6 h was cultured for 24 h in the presence of lipopolysaccharide in order to investigate effects on cytokine production. Urine was analysed for phenolic metabolites by HPLC. DVP-stiffness index and ex vivo IL-8 production were significantly reduced ( P < 0·05) after consumption of OLE compared to the control. These effects were accompanied by the excretion of several phenolic metabolites, namely HT and oleuropein derivatives, which peaked in urine after 8–24 h. The present study provides the first evidence that OLE positively modulates vascular function and IL-8 production in vivo , adding to growing evidence that olive phenolics could be beneficial for health.

Very low-carbohydrate diets are often used to promote weight loss, but their effects on bowel health and function are largely unknown. We compared the effects of a very low-carbohydrate, high-fat (LC) diet with a high-carbohydrate, high-fibre, low-fat (HC) diet on indices of bowel health and function. In a parallel study design, ninety-one overweight and obese participants (age 50·6 (sd 7·5) years; BMI 33·7 (sd 4·2) kg/m2) were randomly assigned to either an energy-restricted (about 6-7 MJ, 30 % deficit) planned isoenergetic LC or HC diet for 8 weeks. At baseline and week 8, 24 h urine and faecal collections were obtained and a bowel function questionnaire was completed. Compared with the HC group, there were significant reductions in the LC group for faecal output (21 (sd 145) v. - 61 (sd 147) g), defecation frequency, faecal excretion and concentrations of butyrate ( - 0·5 (sd 10·4) v. - 3·9 (sd 9·7) mmol/l) and total SCFA (1·4 (sd 40·5) v. - 15·8 (sd 43·6) mmol/l) and counts of bifidobacteria (P < 0·05 time x diet interaction, for all). Urinary phenols and p-cresol excretion decreased (P <= 0·003 for time) with no difference between diets (P >= 0·25). Faecal form, pH, ammonia concentration and numbers of coliforms and Escherichia coli did not change with either diet. No differences between the diets were evident for incidences of adverse gastrointestinal symptoms, which suggests that both diets were well tolerated. Under energy-restricted conditions, a short-term LC diet lowered stool weight and had detrimental effects on the concentration and excretion of faecal SCFA compared with an HC diet. This suggests that the long-term consumption of an LC diet may increase the risk of development of gastrointestinal disorders.

IntroductionPhthalates and bisphenols, chemicals commonly used in the production of plastic products, exhibit endocrine disrupting properties linked to obesity and systemic inflammation. Given the ubiquitous use of plastic chemicals, their adverse impact on human health is of great importance. In this protocol, we describe a randomised controlled trial aimed at testing whether minimising exposure to plastics and plastic-associated chemicals (PACs) in community-dwelling adults with cardiometabolic risk factors can reduce urinary excretion of PACs and improve cardiometabolic health.Methods and analysisThe study will recruit (n=60) community-dwelling adults (18–60 years) with cardiometabolic risk factors, characterised by a body mass index of ≥30 kg/m2 and waist circumference of ≥88 cm in women and ≥102 cm in men. Participants will be randomised to a control (n=30) or an intervention group (n=30) receiving a 4-week diet and lifestyle modification designed to reduce plastic exposure, which includes the replacement of all food, kitchen utensils and equipment, personal care and cleaning products. The primary outcome is a reduction in urinary excretion of bisphenols after the 4-week intervention compared with the control arm. The secondary outcomes are the reduction in urinary excretion of low and high molecular weight phthalates. Finally, tertiary outcomes investigate improvements to cardiometabolic biomarkers, body composition, waist circumference and blood pressure. Participants will self-collect urine, stool and nasal lavage samples a day before beginning the intervention and at the end of each week. Fasting blood samples and health assessments will be collected during clinic visits: at baseline, mid-point and a day after the intervention period. Urinary PAC excretion and cardiometabolic health outcomes will be compared between the intervention and control groups.Ethics and disseminationThe PERTH Trial has ethics approval from the University of Western Australia Human Research Ethics Committee; 2021-ET001118. Results will be submitted for publication in peer-reviewed journals and presented at conferences.Trial registration numberNCT06571994.

Diet is a primary source of exposure for high-molecular-weight phthalates and bisphenol A (BPA), but little is known about the efficacy of various interventions to reduce exposures. We conducted a randomized trial with 10 families to test the efficacy of a 5-day complete dietary replacement (Arm 1; n =21) versus written recommendations to reduce phthalate and BPA exposures (Arm 2; n =19). We measured phthalate and BPA concentrations in urine samples at baseline, intervention, and post-intervention periods. We used Wilcoxon paired signed-rank tests to assess change in concentrations across time and multi-level mixed effects regression models to assess differences between Arms 1 and 2. Urinary di(2-ethylhexyl) phthalate (DEHP) metabolite concentrations increased unexpectedly from a median of 283.7 nmol/g at baseline to 7027.5 nmol/g during the intervention ( P <0.0001) among Arm 1 participants, and no significant changes were observed for Arm 2 participants. We observed a statistically significant increase in total BPA concentration between baseline and intervention periods in Arm 1 but no significant changes in Arm 2. Arm 1 food ingredient testing for DEHP revealed concentrations of 21,400 ng/g in ground coriander and 673 ng/g in milk. Food contamination with DEHP led to unexpected increases in urinary phthalate concentrations in a trial intended to minimize exposure. In the absence of regulation to reduce phthalate and BPA concentrations in food production, it may be difficult to develop effective interventions that are feasible in the general population. An estimate of DEHP daily intake for children in the dietary replacement Arm was above the US Environmental Protection Agency oral reference dose and the European Food Safety Authority’s tolerable daily intake, suggesting that food contamination can be a major source of DEHP exposure.