Excretion Of Hippuric Acid Research Articles

Bioavailability of mango (poly)phenols: An evaluation of the impact of the colon, and phenylalanine and tyrosine on the production of phenolic catabolites

A mango pulp purée was ingested by ileostomists, whose colon had been removed surgically, and subjects with a full gastrointestinal (GI) tract, after which ileal fluid, urine and feces were collected over a 24 h period and analysed by UHPLC-HR-MS. The main (poly)phenols in the purée were gallotannins (356 μmol) and two hydroxy-methoxy-cinnamoyl glucose esters (43 μmol) together with the aromatic amino acids phenylalanine (22 μmol) and tyrosine (209 μmol). Analysis of ileal fluid revealed almost all the ingested gallotannins appeared to have broken down in the upper GI tract with the released benzoic acids being rapidly absorbed into the circulatory system prior to urinary excretion mainly as phase-2 metabolites. Likewise, the glucose moiety of the cinnamic acid conjugates was cleaved and the released cinnamic acids absorbed efficiently from the proximal GI tract and subjected to phase II metabolism prior to excretion. Among the main phenolics excreted after mango intake were phenylacetic and benzoic acids and hydroxybenzene catabolites which were present in lower, but none-the-less, substantial amounts, in the urine of ileostomists. This indicates that a portion of these phenolics, including the hydroxybenzene derivatives, originate from substrates absorbed in the upper GI tract and are principally products of endogenous metabolism rather than being derived from colonic microbiota-mediated catabolism. 1,2,3-Trihydroxybenzene (aka pyrogallol) was the dominant urinary catabolite in both groups. Hippuric acid excretion exceeded (poly)phenol intake indicating a significant contribution from phenylalanine and tyrosine. The aromatic amino acids, while present in the ingested pulp, can also originate from several sources including breakdown of dietary proteins in the GI tract, and endogenous breakdown of surplus mammalian proteins independent of the GI tract. The trial was registered at clinical trials.gov as NCT06182540.

Wilhelm Keller MD (1818-1877) and the emergence of xenobiochemistry.

Although there had been many previous inklings, the field of xenobiotic metabolism (as we know it today) began with an experiment reported in the 1841 literature proclaiming that the ingestion of benzoic acid led to the subsequent excretion of hippuric acid in human urine. A metabolic transformation undertaken by a living organism. One worker involved in the early stages of this discovery was Wilhelm Keller, although very little information about him is readily available. Hopefully, this article will go some way to counter this dearth and also highlight Keller's pioneering contribution in the development of the fields of drug metabolism and xenobiochemistry.

Moderate consumption of freeze-dried blueberry powder increased net bone calcium retention compared with no treatment in healthy postmenopausal women: a randomized crossover trial

BackgroundPreclinical studies suggest that blueberry consumption is associated with improved bone health. ObjectivesWe conducted a blueberry dose-response study in ovariectomized (OVX)-rats that informed a study in postmenopausal women using the urinary appearance of calcium (Ca) tracers from prelabeled bone to reflect changes in bone balance. We hypothesized that blueberry consumption would reduce bone loss in a dose-dependent manner compared with no treatment. MethodsOVX rats were fed 4 doses of blueberry powder (2.5%, 5%, 10%, and 15%) in randomized order to determine bone 45Ca retention. Fourteen healthy, nonosteoporotic women ≥4 y past menopause were dosed with 50 nCi of 41Ca, a long-lived radioisotope, and equilibrated for 5 mo to allow 41Ca deposition in bone. Following a 6-wk baseline period, participants were assigned to a random sequence of 3 6-wk interventions, a low (17.5 g/d), medium (35 g/d), or high (70 g/d) dose of freeze-dried blueberry powder equivalent to 0.75, 1.5, or 3 cups of fresh blueberries incorporated into food and beverage products. Urinary 41Ca:Ca ratio was measured by accelerator mass spectrometry. Serum bone resorption biomarkers and urinary polyphenols were measured at the end of each control and intervention period. Data were analyzed using a linear mixed model and repeated measures analysis of variance. ResultsIn both OVX rats and postmenopausal women, blueberry interventions benefited net bone calcium balance at lower but not at higher doses. In women, net bone calcium retention increased by 6% with the low (95% CI: 2.50, 8.60; P < 0.01) and 4% with the medium (95% CI: 0.96, 7.90; P < 0.05) dose compared with no treatment. Urinary excretion of hippuric acid increased dose-dependently with blueberry consumption. No significant relationships were found between bone resorption biomarkers, 25-hydroxyvitamin D, and interventions. ConclusionsModerate consumption (<1 cup/d) of blueberries may be an effective strategy to attenuate bone loss in healthy postmenopausal women.This trial was registered at clinicaltrials.gov as NCT02630797.

Disentangling the Complexity of Nutrition, Frailty and Gut Microbial Pathways during Aging: A Focus on Hippuric Acid.

Hippuric acid (HA) is a metabolite resulting from the hepatic glycine conjugation of benzoic acid (BA) or from the gut bacterial metabolism of phenylalanine. BA is generally produced by gut microbial metabolic pathways after the ingestion of foods of vegetal origin rich in polyphenolic compounds, namely, chlorogenic acids or epicatechins. It can also be present in foods, either naturally or artificially added as a preservative. The plasma and urine HA levels have been used in nutritional research for estimating the habitual fruit and vegetable intake, especially in children and in patients with metabolic diseases. HA has also been proposed as a biomarker of aging, since its levels in the plasma and urine can be influenced by the presence of several age-related conditions, including frailty, sarcopenia and cognitive impairment. Subjects with physical frailty generally exhibit reduced plasma and urine levels of HA, despite the fact that HA excretion tends to increase with aging. Conversely, subjects with chronic kidney disease exhibit reduced HA clearance, with HA retention that may exert toxic effects on the circulation, brain and kidneys. With regard to older patients with frailty and multimorbidity, interpreting the HA levels in the plasma and urine may result particularly challenging because HA is at the crossroads between diet, gut microbiota, liver and kidney function. Although these considerations may not make HA the ideal biomarker of aging trajectories, the study of its metabolism and clearance in older subjects may provide valuable information for disentangling the complex interaction between diet, gut microbiota, frailty and multimorbidity.

Dietary supplementation with red cabbage extract rich in anthocyanins increases urinary hippuric acid excretion and consequently decreases nitrous oxide emissions in beef bulls

Two consecutive experiments were conducted to investigate the effects of dietary supplementation with red cabbage extract (RCE) rich in anthocyanins on the nitrogen (N) metabolism in beef bulls and the nitrous oxide (N2O) emissions from the soil applied with the urine of beef bulls. In Experiment 1, 8 Simmental beef bulls (body weight 387.9 ± 40.7 kg) were used as experimental animals. Two levels of RCE, i.e. 0 and 114 g dry matter per day, were supplemented to a basal ration as experimental treatments. The animals and the treatments were allocated in a 2 × 2 crossover design. In Experiment 2, the static incubation technique was used to determine the N2O-N emissions from the soil applied with the urine samples collected from Experiment 1. The results of Experiment 1 indicated that RCE supplementation did not affect the N excretion, N retention, and N retention rate in beef bulls (P > 0.10). However, RCE supplementation increased the ratio of hippuric acid-N/urinary N (P < 0.05) and tended to increase the ratio of creatinine-N/urinary N (P = 0.081) without changing the excretion of other urinary nitrogenous components (P > 0.10). Plasma metabolome analysis indicated that RCE supplementation upregulated 12 metabolites while downregulated 18 metabolites (P < 0.05). The results of Experiment 2 indicated that RCE supplementation reduced the estimated urine N2O-N emissions by 33.1% through decreasing the ratio of N2O-N/urine-N (P < 0.05). In conclusion, RCE supplementation did not affect the N retention and N excretion of beef bulls, whereas it attenuated the urine N2O-N emissions of beef bulls through increasing urinary hippuric acid excretions.

Effects of daily consumption of wild blueberry on cognition and urinary metabolites in school-aged children: a pilot study

PurposeAcute intervention with wild blueberry (WBB) has previously revealed positive cognitive and mood effects in typically developing children; however, it is unclear whether effects persist after daily supplementation. In addition, no data have been published exploring the metabolite profiles of children following berry consumption, to our knowledge. A study of this kind could provide insight into a mechanism of action for the cognitive and mood improvements observed previously in children. The aim of this pilot study was to assess cognitive performance and urinary metabolite concentrations in healthy 7–10-year-old children across a 4 week daily WBB drink intervention.MethodsThis pilot study examined the effects of daily WBB consumption for 4 weeks (766 mg total polyphenols; 253 mg anthocyanins; equivalent to 240 g fresh blueberries per day) on cognition and mood in 15 healthy 7–10-year-old children. Polyphenol metabolites were measured in 24 h urine before and after the 4 week intervention.ResultsChronic WBB-related benefits were seen on cognitively demanding trials on the modified attention network task, a task measuring executive functioning. Specifically, the WBB group maintained significantly higher accuracy on incongruent trials (96%; SE 0.03) compared with placebo participants (85%; SE 0.03; p = 0.038) after the 4 week intervention, suggesting WBB was of most benefit on the more difficult aspects of the task. No significant WBB-related effects were observed on the auditory verbal learning task or the child’s version of the positive and negative affect schedule. Urinary metabolite analyses indicated significant increases in different metabolites in WBB and placebo groups after 4 week consumption.ConclusionThe research demonstrates 24 h WBB bioavailability in a child cohort for the first time with increases in urinary hippuric acid excretion during 2 week daily WBB consumption. This study highlights the importance of conducting a larger study in children investigating the mechanism of action behind cognitive effects using bioavailability data.

The relationship between urinary polyphenol metabolites and dietary polyphenol intakes in young adults

Spot urinary polyphenols have potential as a biomarker of polyphenol-rich food intakes. The aim of this study is to explore the relationship between spot urinary polyphenols and polyphenol intakes from polyphenol-rich food sources. Young adults (18-24 years old) were recruited into a sub-study of an online intervention aimed at improving diet quality. Participants' intake of polyphenols and polyphenol-rich foods was assessed at baseline and 3 months using repeated 24-h recalls. A spot urine sample was collected at each session, with samples analysed for polyphenol metabolites using LC-MS. To assess the strength of the relationship between urinary polyphenols and dietary polyphenols, Spearman correlations were used. Linear mixed models further evaluated the relationship between polyphenol intakes and urinary excretion. Total urinary polyphenols and hippuric acid (HA) demonstrated moderate correlation with total polyphenol intakes (rs = 0·29-0·47). HA and caffeic acid were moderately correlated with polyphenols from tea/coffee (rs = 0·26-0·46). Using linear mixed models, increases in intakes of total polyphenols or polyphenols from tea/coffee or oil resulted in a greater excretion of HA, whereas a negative relationship was observed between soya polyphenols and HA, suggesting that participants with higher intakes of soya polyphenols had a lower excretion of HA. Findings suggest that total urinary polyphenols may be a promising biomarker of total polyphenol intakes foods and drinks and that HA may be a biomarker of total polyphenol intakes and polyphenols from tea/coffee. Caffeic acid warrants further investigation as a potential biomarker of polyphenols from tea/coffee.

Effects of harvest date and grass species on silage cell wall components and lactation performance of dairy cows

This study evaluated the effect of harvest date and forage species on the concentration of hydroxycinnamic acids in silage and its relationship to dairy cow performance. Tall fescue and timothy were harvested at a regular date on June 27 and July 8, respectively, or at a late date on July 8 and 25, respectively, in the first regrowth. Forage was treated with a salt-based additive and ensiled in hard-pressed round bales. Forty-seven lactating dairy cows were used in a block design. Cows received 1 of 4 treatments: (1) tall fescue harvested at regular date (RTF), (2) timothy harvested at regular date (RTI), (3) tall fescue harvested at late date (LTF), and (4) timothy harvested at late date (LTI). Diets were formulated to have the same forage-to-concentrate ratio (46:54 on a dry matter basis). Harvesting at late date increased fiber components, but only for timothy, where LTI contained greater neutral detergent fiber, acid detergent fiber, and acid detergent lignin concentrations than the other silages. Concentrations of hydroxycinnamic acids were affected by forage species, where concentrations of esterified ferulic acid and p-coumaric acid were greater for tall fescue silages than for timothy silages. Cows fed the RTI diet showed the greatest intakes of dry matter, organic matter, and crude protein. Feeding diets containing timothy silages increased milk yield and energy-corrected milk yield compared with tall fescue diets when averaged over harvest dates. Cows fed the RTI diet had greater milk protein yield than cows fed the RTF and LTF diets, and milk lactose yield was greater for cows fed diets containing timothy silage compared with tall fescue silage when averaged over harvest dates. Cows fed the LTF diet showed greater urinary N excretion compared with the LTI diet, but RTI showed the lowest urinary N and urea N excretions when calculated as percent of N intake. Cows fed diets containing timothy silage excreted more uric acid than cows fed tall fescue diets. Allantoin excretion was greater for cows eating the RTI and LTI diets compared with cows eating the RTF diet. Cows fed the RTI diet had a greater estimated microbial N flow and a greater excretion of hippuric acid than the RTF and LTF groups. In conclusion, besides the effect of harvest date on increasing the fiber components of timothy, concentrations of hydroxycinnamic acids were mainly affected by forage species; consequently, milk production was only affected by forage species. This indicates that hydroxycinnamic acids, such as ferulic acid, which cross-links to glucuronoarabinoxylans, was a major factor regulating milk production of cows fed tall fescue- and timothy silage-based diets, where lower hydroxycinnamic acid concentrations were responsible for greater milk yield.

Moderate Consumption of Freeze-dried Blueberry Powder Increased Net Bone Calcium Retention in Healthy Postmenopausal Women: A Randomized Crossover Trial

Abstract Objectives Preclinical studies suggest that blueberry consumption is associated with improved bone health. This study quantified changes in urinary excretion of the long-lived calcium radioisotope 41Ca to assess the dose-response effect of blueberries on bone loss in postmenopausal women. We hypothesized that blueberry consumption would reduce bone loss in a dose-dependent manner. Methods Healthy women at least 4 years past menopause were dosed with 50 nCi of 41Ca and completed a 5-mo equilibration period for 41Ca deposition in bone followed by a 6-wk control period. Subsequently, participants were assigned to a random sequence of 3 intervention periods, each corresponding to a low (17.5 g/d), medium (35 g/d), or high (70 g/d) dose of freeze-dried blueberry powder equivalent to 0.75, 1.5, or 3 cups of fresh blueberries. The blueberry powder was incorporated into granola bars, spread, and drinks consumed daily for 6 wk, followed by a 6-wk washout period. Urinary 41Ca: Ca ratio was measured by accelerator mass spectrometry in 24-h urine collected weekly during intervention and every 3 wk during washout. Serum 25-hydroxyvitamin D and calcium concentrations were assessed prior to each intervention. Serum bone resorption biomarkers and urinary polyphenols were measured at the end of each control and intervention period. Data were analyzed using a linear mixed model and repeated measures ANOVA. Results Fourteen healthy, non-osteoporotic (mean bone mineral density t-score: −1.33) women completed the study. Net bone calcium retention increased by 6% in the low (P &amp;lt; 0.01) and 4% in the medium (P &amp;lt; 0.05) dose intervention compared with the control and washout periods. The high dose had no significant effect on net bone calcium retention (P = 0.19). Urinary excretion of hippuric acid increased dose-dependently with blueberry consumption. No significant relationships were found between bone resorption biomarkers, 25-hydroxyvitamin D, or calcium and any of the interventions. Conclusions A hormetic response was observed to blueberry intake, whereby daily consumption of foods containing 17.5–35 g, but not 70 g, of freeze-dried blueberry powder increased net bone calcium retention. Moderate consumption of blueberries may be an effective strategy to attenuate bone loss in healthy postmenopausal women. Funding Sources NIH/NCCIH, Project Development Team within the ICTSI NIH/NCRR.

The Effects of Fasting on Toluene Metabolite (Hippuric Acid) Excretion in Urine (A Case Study of Shoe-Makers in Tambak Oso Wilangun Village-Surabaya)

Background: An increase in toluene metabolite (hippuric acid) excretion in urine can be stimulated by such factors as fasting, smoking and coffee consumption. This research aimed at studying the effects of fasting on urinary toluene excretion of shoemakers in Tambak Oso Wilangun-Surabaya. Method: This controlled case-study was conducted to 20 workers with purposive sampling method from the population. The independent variables of the study include toluene concentration, fasting or not fasting condition, smoking, and coffee consumption. The dependent variable was urinary hippuric acid concentration. Pearson Correlation test was conducted to identify the correlation between toluene concentration and hippuric acid concentration. Paired-t-test was used to compare hippuric acid concentration in fasting and non-fasting condition. The correlations between coffee consumption and smoking and hippuric acid concentration were analyzed by using chi-square test (I±=0,05). Risk assessment was used to identify the health risk from occupational toluene exposure. Result: The research showed that most of the respondents (65) were at risk to health problems related to toluene exposure (RQ>1). The statistical tests showed no significant correlation between toluene concentration and hippuric acid concentration; there was a significant difference between hippuric acid concentration before and after fasting (p=0,016; p<I±); there was a significant correlation between hippuric acid concentration (non fasting) with smoking habit (p=0,022), coffee consuming habit (p=0,025); and between hippuric acid concentration (in fasting condition) with coffee consuming (p=0,039). Conclusion: Fasting, coffee consuming and smoking habit can increase urinary hippuric acid excretion. It is recommended for future researcher to control both coffee consumption and smoking when investigating the effects of fasting to urinary hippuric acid excretion to avoid biased results. Respondents are suggested to improve ventilation system in their workshops and use chemical cartridge respirator, apron and gloves while working. © 2019, Indian Journal of Forensic Medicine and Toxicology. All rights reserved.

Habitual Flavonoid Intake from Fruit and Vegetables during Adolescence and Serum Lipid Levels in Early Adulthood: A Prospective Analysis.

Flavonoids have been implicated in the prevention of cardiovascular diseases (CVD). In a prospective approach, we investigated whether habitual flavonoid intake from fruit, vegetables and juices (FlavFVJ) during adolescence is associated with adult levels of serum lipids, one of the main CVD risk factors. This analysis included healthy participants from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study, who had provided a fasting blood sample in adulthood (aged 18–39 years), data on FlavFVJ intake during adolescence (females: 9–15 years, males: 10–16 years)—estimated either from multiple 3-day weighed dietary records (n = 257), or from validated biomarker hippuric acid (uHA) excretion from multiple 24-h urine samples (n = 233)—together with information on relevant covariates. In multivariable linear regression analyses, a higher FlavFVJ intake during adolescence was independently associated with higher serum high-density lipoprotein cholesterol (HDL-C) levels among males (Ptrend = 0.038); however, the inclusion of adult waist circumference attenuated this association (Ptrend = 0.053). FlavFVJ was not associated with triglycerides (TG), total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C; all Ptrend ≥ 0.1), nor was uHA excretion with any serum lipid outcome among males (all Ptrend ≥ 0.5). Neither FlavFVJ intake nor uHA excretion was associated with serum lipids among women (all Ptrend ≥ 0.1). However, a higher flavonoid intake from fruit and vegetables was independently related to lower LDL-C levels (Ptrend = 0.021), while a higher intake from juices was associated with higher LDL-C levels (Ptrend = 0.016) among females. In conclusion, a higher flavonoid intake from fruit, vegetables and/or juices during adolescence may be linked to cholesterol levels in early adulthood in a sex- and food source-specific manner.

Concomitant ingestion of lactic acid bacteria and black tea synergistically enhances flavonoid bioavailability and attenuates d-galactose-induced oxidative stress in mice via modulating glutathione antioxidant system

Black tea (BT) has been positively linked to improved redox status, while its efficacy is limited due to the low bioavailability of BT flavonoids. In addition to the direct antioxidant activity, flavonoids regulate redox balance via inducing endogenous antioxidants, particularly glutathione (GSH) and GSH-dependent antioxidant enzymes. This work first examined the effect of lactic acid bacteria (LAB) and BT alone or in combination on flavonoid bioavailability and metabolism; next, the effect of LAB-fermented BT diet in attenuating oxidative stress in mice and the underlying mechanisms were studied. Phenolic profiles of plasma, urine and feces from healthy mice consuming plain yogurt, BT milk (BTM) or BT yogurt (BTY) were acquired using LC–MS/MS. Plasma antioxidant capacity, lipid peroxidation level, content of nonprotein thiols and expression of GSH-related antioxidant enzymes and Nrf2 were examined in d-galactose-treated mice. Total flavonoid content in plasma following a single dose of BTY attained 0.657 μmol/l, increased by 50% compared with the BTM group. Increased excretion of phenolic metabolite and hippuric acid in urine and feces indicated enhanced metabolism of flavonoids in BTY-fed mice. In the second study, 8-week concomitant LAB-BT treatment of oxidatively stressed mice effectively restored plasma antioxidant capacity and GSH levels, and mitigated lipid peroxidation, which were associated with significant induction of GSH-dependent antioxidant enzymes and nuclear accumulation of Nrf2. Our results demonstrated the effect of LAB fermentation in enhancing BT flavonoid bioavailability in vivo. The synergistic antioxidant efficacy of LAB-BT diet implied its therapeutic potential in enhancing antioxidant defenses and protecting organisms from oxidative damage.

Visual functions of workers exposed to organic solvents in petrochemical industries.

Aim:The purpose of this study was to evaluate the visual functions of workers exposed to organic solvents in petrochemical industries.Materials and Methods:Thirty workers from the petroleum refinery and 30 age-matched controls (mean age) were recruited. Visual functions and occupational exposure levels were assessed among both the groups. Visual acuity, contrast sensitivity, color vision, and visual fields were evaluated at the workplace. The biological samples, namely blood and urine, were collected at the workplace and transported to the laboratory for analysis. The urinary excretion of hippuric and methylhippuric acid as well as creatinine was measured by high performance liquid chromatography.Results:The mean age of the workers and controls were 39.7 ± 7.6 years and 38.6 ± 8.1, years respectively. The mean years of experience of the workers were 15.6 ± 6.8 years. Visual acuity was >0.01 LogMAR among both the control and case groups. The contrast sensitivity was reduced at 12cpd among workers. Comparison between groups was done using independent sample t-test. The mean difference in color confusion index was 0.11 ± 0.05 (P = 0.037*). The mean difference in visual fields was −0.31 ± 0.36 dB (P = 0.933). The mean difference in urinary hippuric acid level (urinary metabolite of toluene) between the groups was 0.19 ± 0.96 g/g creatinine (P = 0.049FNx01). The mean difference in the excretion of methylhippuric acid (urinary metabolite of xylene) was 0.06 ± 0.04g/g creatinine (P = 0.154). We also found that exposure was a significant risk factor for color vision defect with an odds ratio of 4.43 (95% CI: 1.36–14.4); P = 0.013.Conclusion:The study results showed that contrast sensitivity and color vision were affected among workers in petrochemical industry.

Relative validation of 24-h urinary hippuric acid excretion as a biomarker for dietary flavonoid intake from fruit and vegetables in healthy adolescents.

A biomarker for dietary flavonoid intake from fruit and vegetables (FlavFV) is needed to elucidate the relevance of flavonoids from these sources for the prevention of chronic diseases. Urinary hippuric acid (HA)-a major metabolite of flavonoids-is promising in this respect as it was shown to satisfyingly indicate fruit and vegetable consumption in different age groups. Therefore, we validated urinary HA as a biomarker for intake of FlavFV. Analyses included data from 287 healthy adolescents of the DONALD Study (aged 9-16years) for whom a minimum of two pairs of HA measurements from 24-h urine samples (test method) and FlavFV intake estimated from 3-day weighed dietary records (reference method) existed. Agreement between both methods was assessed by Spearman correlation and cross-classification analyses. Possible confounders of the association were identified by linear regression models. Analyses were performed using a split-sample approach allowing for consecutive exploration (n=192) and confirmation (n=95) of results. Agreement between urinary HA excretion and FlavFV intake was moderate according to correlation analysis in the exploratory sample (r unadjusted=0.47, P<0.0001). Yet, 79% of the subjects were classified into same/adjacent quartiles, and only 5% were misclassified into opposite quartiles. These findings were corroborated by analyses in the confirmatory sample (r unadjusted=0.64; 88% in same/adjacent vs. 4% in opposite quartiles). Body surface area (BSA) was the only relevant covariate in the exploratory sample, and its adjustment improved cross-classification estimates in both subsamples. BSA-adjusted 24-h urinary HA excretion represents a suitable biomarker of habitual FlavFV intake in healthy adolescents.

Relevance of fruits, vegetables and flavonoids from fruits and vegetables during early life, mid-childhood and adolescence for levels of insulin-like growth factor (IGF-1) and its binding proteins IGFBP-2 and IGFBP-3 in young adulthood.

The growth hormone (GH) insulin-like growth factor (IGF) axis has been linked to insulin metabolism and cancer risk. Experimental evidence indicates that the GH-IGF axis itself can be influenced by dietary flavonoids. As fruit and vegetable (FV) intake is a major source of flavonoid consumption, FV's beneficial health effects may be explained via flavonoids' influence on the GH-IGF axis, but observational evidence is currently rare. We used data from Dortmund Nutritional and Anthropometric Longitudinally Designed Study participants to analyse prospective associations between FV, fruit intake and flavonoid intake from FV (FlavFV) with IGF-1 and its binding proteins IGFBP-2 and IGFBP-3. Subjects needed to provide a fasting blood sample in adulthood (18-39 years) and at least two 3-d weighed dietary records in early life (0·5-2 years, n 191), mid-childhood (3-7 years, n 265) or adolescence (girls: 9-15 years, boys: 10-16 years, n 261). Additional analyses were conducted among those providing at least three 24-h urine samples in adolescence (n 236) to address the predictor urinary hippuric acid (HA), a biomarker of polyphenol intake. Higher fruit intake in mid-childhood and adolescence was related to higher IGFBP-2 in adulthood (P=0·03 and P=0·045). Comparable trends (P=0·045-0·09) were discernable for FV intake (but not FlavFV) in all three time windows. Similarly, higher adolescent HA excretion tended to be related (P=0·06) to higher adult IGFBP-2 levels. Regarding IGFBP-3, a marginal (P=0·08) positive association was observed with FlavFV in mid-childhood only. None of the investigated dietary factors was related to IGF-1. In conclusion, higher fruit and FV intakes during growth may be relevant for adult IGFBP-2, but probably not for IGFBP-3 or IGF-1.

Probiotics Blunt the Anti-Hypertensive Effect of Blueberry Feeding in Hypertensive Rats without Altering Hippuric Acid Production.

Previously we showed that feeding polyphenol-rich wild blueberries to hypertensive rats lowered systolic blood pressure. Since probiotic bacteria produce bioactive metabolites from berry polyphenols that enhance the health benefits of berry consumption, we hypothesized that adding probiotics to a blueberry-enriched diet would augment the anti-hypertensive effects of blueberry consumption. Groups (n = 8) of male spontaneously hypertensive rats were fed one of four AIN ‘93G-based diets for 8 weeks: Control (CON); 3% freeze-dried wild blueberry (BB); 1% probiotic bacteria (PRO); or 3% BB + 1% PRO (BB+PRO). Blood pressure was measured at weeks 0, 2, 4, 6, and 8 by the tail-cuff method, and urine was collected at weeks 4 and 8 to determine markers of oxidative stress (F2-isoprostanes), nitric oxide synthesis (nitrites), and polyphenol metabolism (hippuric acid). Data were analyzed using mixed models ANOVA with repeated measures. Diet had a significant main effect on diastolic blood pressure (p = 0.046), with significantly lower measurements in the BB- vs. CON-fed rats (p = 0.035). Systolic blood pressure showed a similar but less pronounced response to diet (p = 0.220), again with the largest difference between the BB and CON groups. Absolute increase in blood pressure between weeks 0 and 8 tended to be smaller in the BB and PRO vs. CON and BB+PRO groups (systolic increase, p = 0.074; diastolic increase, p = 0.185). Diet had a significant main effect on hippuric acid excretion (p<0.0001), with 2- and ~1.5-fold higher levels at weeks 4 and 8, respectively, in the BB and BB+PRO vs. PRO and CON groups. Diet did not have a significant main effect on F2-isoprostane (p = 0.159) or nitrite excretion (p = 0.670). Our findings show that adding probiotics to a blueberry-enriched diet does not enhance and actually may impair the anti-hypertensive effect of blueberry consumption. However, probiotic bacteria are not interfering with blueberry polyphenol metabolism into hippuric acid.

Probiotics Do Not Enhance Anti‐hypertensive Effect of Blueberry Diets in Hypertensive Rats

Previously we showed that feeding polyphenol‐rich wild blueberries (BB) to hypertensive rats lowered systolic blood pressure (BP). Since probiotic bacteria produce secondary metabolites from berry polyphenols which augment the health benefits of berry consumption, we hypothesized that adding probiotics to a BB‐enriched diet would augment the anti‐hypertensive effects of BB. Male spontaneously hypertensive rats were fed different AIN93G‐based diets for 8 weeks (n=8 rats each diet): Control; 3% freeze‐dried wild BB; 1% probiotic bacteria (PRO); or 3% BB + 1% PRO. BP was measured biweekly by the tail‐cuff method, and urine was collected twice to determine markers of oxidative stress [F2‐isoprostanes], nitric oxide synthesis [nitrites] and polyphenol metabolism [hippuric acid]. Systolic BP at week 8, but not sooner, was lower in the BB and PRO groups (163+5.9 mmHg and 168+6.2 mmHg, respectively) compared to the control diet (188+7.6 mmHg; p=0.04). Diet had main effects on diastolic BP at week 8 as well (p&lt;0.05). In contrast, the combined BB + PRO diet produced no significant effects on BP. Hippuric acid excretion, a marker of polyphenol metabolism, was 91% higher after 4 weeks and 74% higher after 8 weeks in BB‐fed rats compared to CON (p=0.0006). PRO by itself had no effect on urinary hippuric acid, and BB+PRO diet did not reduce the magnitude of the BB effect. Excretion of isoprostanes (p=0.989) and nitrite (p=0.373) did not differ across diet groups. Thus adding probiotics to a blueberry‐enriched diet does not enhance and actually may impair the antihypertensive effect of BB consumption. However, probiotic bacteria are not interfering with metabolism of BB polyphenols into hippuric acid.

A 1H NMR‐Based Approach to Investigate Metabolomic Differences in the Plasma and Urine of Young Women after Cranberry Juice or Apple Juice

The present study aimed to investigate overall metabolic changes caused by cranberry juice or apple juice consumption using a global 1H NMR‐based metabolomics approach. Eighteen female college students, between 21‐29 years old, were given either cranberry juice or apple juice for three days using a cross‐over design. Plasma and urine samples were collected before and after juice consumption. Metabolome in urine and plasma were analyzed using 1H NMR‐based metabolomics followed by multivariate analyses. No metabolic difference was observed in human plasma before and after juice consumption for either cranberry or apple juices. However, metabolome in plasma and urine after cranberry juice consumption were different from those after apple juice consumption. Cranberry juice consumption caused a greater increase in urinary excretion of hippuric acid and a higher level of citric acid in the plasma. On the other hand, cranberry juice decreased the plasma level of lactate, D‐glucose, and two unidentified metabolites compared to apple juice consumption. The metabolomic changes caused by cranberry juice consumption may help to explain its reported health benefits.This research is supported in part by Ocean Spray Cranberries, Inc.

A 1H NMR-based approach to investigate metabolomic differences in the plasma and urine of young women after cranberry juice or apple juice consumption

The overall metabolic changes caused by cranberry juice or apple juice consumption using a global 1H NMR-based metabolomics approach were investigated. Eighteen female college students were given either cranberry or apple juice for three days using a cross-over design. Plasma and urine samples were collected and analyzed using 1H NMR-based metabolomics followed by multivariate analyses. No metabolic difference was observed in plasma before and after juice consumption. However, metabolome in plasma and urine after cranberry juice consumption were different from those after apple juice consumption. Cranberry juice consumption caused a greater increase in urinary excretion of hippuric acid and a higher level of citric acid in the plasma. Furthermore, cranberry juice decreased the plasma level of lactate, D-glucose, and two unidentified metabolites compared to apple juice consumption. The metabolomic changes caused by cranberry juice consumption may help to explain its reported health benefits.

Hippuric acid in 24 h urine collections as a biomarker of fruits and vegetables intake in kidney stone formers

This work aimed to underline the prospects of hippuric acid, a product of the metabolism of polyphenols, as a new biomarker of fruits and vegetables intake associated with lithogenic risk. Biochemical parameters of lithogenic risk and hippuric acid were measured in the 24 h urine collections of a cohort of 696 Italian kidney stone formers divided into two subgroups according to their different dietary habits. The link between lithogenic risk parameters and hippuric acid was assessed and this compound was revealed as a valuable biomarker of fruits and vegetables intake in kidney stone formers. A cut-off value of urinary excretion of hippuric acid, 300 mg/24 h, was set as the threshold of discrimination between low and high intake of fruits and vegetables for these patients. These results highlight the importance of monitoring of the excretion hippuric acid in urine to address proper dietary guidelines for the management of stone former patients.