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The infant gut microbiota affects childhood health. This pioneer microbiota may be vulnerable to antibiotic exposures, but could be supported by prebiotic oligosaccharides found in breast milk and some infant formulas. We sought to characterize the effects of several exposures on the neonatal gut microbiota, including human milk oligosaccharides (HMOs), galacto-oligosaccharides (GOS), and infant/maternal antimicrobial exposures. We profiled the stool microbiota of 1023 one-month-old infants from the KOALA Birth Cohort using 16S rRNA gene amplicon sequencing. We quantified 15 HMOs in breast milk from the mothers of 220 infants, using high-performance liquid chromatography-mass spectrometry. Both breastfeeding and antibiotic exposure decreased gut microbial diversity, but each was associated with contrasting shifts in microbiota composition. Other factors associated with microbiota composition included C-section, homebirth, siblings, and exposure to animals. Neither infant exposure to oral antifungals nor maternal exposure to antibiotics during pregnancy were associated with infant microbiota composition. Four distinct groups of breast milk HMO compositions were evident, corresponding to maternal Secretor status and Lewis group combinations defined by the presence/absence of certain fucosylated HMOs. However, we found the strongest evidence for microbiota associations between two non-fucosylated HMOs: 6'-sialyllactose (6'-SL) and lacto-N-hexaose (LNH), which were associated with lower and higher relative abundances of Bifidobacterium, respectively. Among 111 exclusively formula-fed infants, the GOS-supplemented formula was associated with a lower relative abundance of Clostridium perfringens. In conclusion, the gut microbiota is sensitive to some prebiotic and antibiotic exposures during early infancy and understanding their effects could inform future strategies for safeguarding a health-promoting infant gut microbiota.

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).

Scope: Understanding the biological functions of human milk oligosaccharides (HMOs) in shaping gastrointestinal (GI) tract microbiota during infancy is of great interest. A link between HMOs in maternal milk and infant fecal microbiota composition is examined and the role of microbiota in degrading HMOs within the GI tract of healthy, breastfed, 1-month-old infants is investigated. Methods and results: Maternal breast milk and infant feces are from the KOALA Birth Cohort. HMOs are quantified in milk and infant fecal samples using liquid chromatography-mass spectrometry. Fecal microbiota composition is characterized using Illumina HiSeq 16S rRNA gene amplicon sequencing. The composition is associated with gender, delivery mode, and milk HMOs: Lacto-N-fucopentaose I and 2′-fucosyllactose. Overall, Bifidobacterium, Bacteroides, Escherichia–Shigella, and Parabacteroides are predominating genera. Three different patterns in infant fecal microbiota structure are detected. GI degradation of HMOs is strongly associated with fecal microbiota composition, and there is a link between utilization of specific HMOs and relative abundance of various phylotypes (operational taxonomic units). Conclusions: HMOs in maternal milk are among the important factors shaping GI tract microbiota in 1-month-old breastfed infants. An infant's ability to metabolize different HMOs strongly correlates with fecal microbiota composition and specifically with phylotypes within genera Bifidobacterium, Bacteroides, and Lactobacillus.

Objective: Microvascular dysfunction has been suggested as a possible underlying mechanism for the association between uric acid and various diseases, such as hypertension, renal disease and cardiomyopathies. We therefore analysed the association between serum uric acid and skin microvascular function, a model of generalized microvascular function. Methods: A cross-sectional study was performed in 610 individuals [51.8% men; mean age 58.7 +/- 8.6 years; 23.6% with type 2 diabetes (by design)] from The Maastricht Study. We assessed skin capillary density (capillaries/mm(2)) by capillaroscopy at baseline, after 4 min of arterial occlusion, and after 2 min of venous congestion. Capillary recruitment after arterial occlusion and during venous congestion was expressed as the absolute change in capillary density after recruitment and as the percentage change in capillary density from baseline. Results: Crude linear regression analyses showed that serum uric acid [per +1 standard deviation (SD) of 74 mu mol/l] was not associated with baseline capillary density [beta = -0.21 (95% confidence interval, 95% CI -1.61 to 1.19) P = 0.765], while an inverse association was found between uric acid and absolute change in capillary density after arterial occlusion [beta = -1.15 (95% CI -2.36 to 0.06) P = 0.062] and during venous congestion [beta = -1.41 (95% CI -2.68 to -0.14) P = 0.029]. However, after adjustment for sex, age and glucose metabolism status, these associations were no longer statistically significant. In addition, we found no association between uric acid and percentage capillary recruitment after arterial occlusion [beta = -1.66 (95% CI -3.97 to 0.65) P = 0.159] or during venous congestion [beta = -2.02 (95% CI -4.46 to 0.42) P = 0.104] in unadjusted analyses; multivariable analyses gave similar results. Conclusion: These results do not support the hypothesis that generalized microvascular dysfunction (as estimated in skin microcirculation) is the underlying mechanis

Objective:Arterial stiffness may be a mechanism to explain the association between uric acid and cardiovascular disease. We aimed to analyse associations between serum uric acid and regional and local arterial stiffness, and assess potential differences related to sex and glucose metabolism status.Methods:A cross-sectional study was performed in 614 adults [52.6% men; mean age 58.7 +/- 8.5 years; 23.2% type 2 diabetes mellitus (by design)] from The Maastricht Study. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), distensibility, and compliance coefficient of the carotid and femoral artery, and carotid artery Young's elastic modulus.Results:Higher uric acid (per SD of 74 mu mol/l) was associated with greater stiffness indicated by a significantly higher cfPWV [beta = 0.216 (95% confidence interval 0.061, 0.372); P = 0.006] and lower carotid distensibility coefficient [beta = -0.633 (95% confidence interval -1.099, -0.166); P = 0.008] after adjustment for sex, age, and glucose metabolism status. Associations lost significance after adjusting for mean arterial pressure, BMI, waist, smoking status, heart rate, total : high-density lipoprotein cholesterol ratio, triglycerides, estimated glomerular filtration rate, use of lipid-lowering, antihypertensive, and diabetes medication, and use of secondary uricosurics. No associations were found between uric acid and carotid compliance coefficient, carotid Young's elastic modulus, or stiffness of the femoral artery. A significant interaction (P <0.10) with glucose metabolism status was found for cfPWV. However, none of the stratified associations were significant. There was no interaction with sex.Conclusion:Uric acid was not significantly associated with stiffness of the aorta, or the carotid or femoral artery among adults aged 40-75 years without and with type 2 diabetes mellitus.

ObjectiveTo investigate whether the intestinal microbiota composition in early infancy is associated with subsequent weight development in children.MethodsAnalyses were conducted within the KOALA Birth Cohort Study (n=2834). This cohort originates from two recruitments groups, pregnant women with a conventional lifestyle (no selection based on lifestyle) and pregnant women recruited through alternative channels (organic shops, anthroposophic clinicians/midwives, Steiner schools, and relevant magazines). From 909 one-month-old infants fecal samples were collected and analyzed by qPCR targeting bifidobacteria, Bacteroides fragilis-group, Clostridium difficile, Escherichia coli, lactobacilli, and total bacteria counts. Between the ages of 1-10 years, parent-reported weight and height was collected at 7 time points. Age- and gender-standardized Body Mass Index (BMI) z-scores were calculated. Data were analyzed using Generalized Estimating Equation.ResultsColonization with B. fragilis-group was borderline significantly associated with a higher BMI z-score of 0.15 (95% CI: -0.02 to 0.31), in the conventional subcohort. After stratification for fiber intake (pforinteraction 0.003), colonization with B. fragilis-group was associated with a 0.34 higher BMI z-score among children with a low fiber intake in this subcohort (95% CI: 0.17 to 0.53). Higher counts among colonized children were positively associated with BMI z-score only in children within the conventional subcohort and a high fiber diet (BMI z-score 0.08; 95% CI: 0.01 to 0.14), but inversely associated in children with a low fiber diet (BMI z-score -0.05; 95% CI: -0.10 to 0.00), and in children recruited through alternative channels (BMI z-score -0.10; 95% CI: -0.17 to -0.03). The other bacteria were not associated with BMI z-scores, regardless of subcohort.ConclusionUsing a targeted approach, we conclude that the intestinal microbiota, particularly the B. fragilis-group, is associated with childhood weight develop

Studies on the occurrence of gout show a large range in estimates. However, a clear insight into the factors responsible for this variation in estimates is lacking. Therefore, our aim was to review the literature on the prevalence and incidence of gout systematically and to obtain insight into the degree of and factors contributing to the heterogeneity. We searched MEDLINE, EMBASE, and Web of Science (January 1962 to July 2012) to identify primary studies on the prevalence and incidence of gout in the general population. Data were extracted by two persons on sources of clinical heterogeneity, methodological heterogeneity, and variation in outcome reporting. Meta-analysis and meta-regression analysis were performed for the prevalence of gout. Of 1,466 articles screened, 77 articles were included, of which 71 reported the prevalence and 12 the incidence of gout. The pooled prevalence (67 studies; N = 12,226,425) based on a random effects model was 0.6 % (95 % CI 0.4; 0.7), however there was a high level of heterogeneity (I2 = 99.9 %). Results from a mixed-effects meta-regression model indicated that age (p = 0.019), sex (p < 0.001), continent (p < 0.001), response rate (p = 0.016), consistency in data collection (p = 0.002), and case definition (p < 0.001) were significantly associated with gout prevalence and jointly accounted for 88.7 % of the heterogeneity. The incidence in the total population ranged from 0.06 to 2.68 per 1,000 person-years. In conclusion, gout is a common disease and the large variation in the prevalence data on gout is explained by sex, continent on which the study was performed, and the case definition of gout.

Background: Nutritional supplements designed to increase adenosine 5'-triphosphate (ATP) concentrations are commonly used by athletes as ergogenic aids. ATP is the primary source of energy for the cells, and supplementation may enhance the ability to maintain high ATP turnover during high-intensity exercise. Oral ATP supplements have beneficial effects in some but not all studies examining physical performance. One of the remaining questions is whether orally administered ATP is bioavailable. We investigated whether acute supplementation with oral ATP administered as enteric-coated pellets led to increased concentrations of ATP or its metabolites in the circulation. Methods: Eight healthy volunteers participated in a cross-over study. Participants were given in random order single doses of 5000 mg ATP or placebo. To prevent degradation of ATP in the acidic environment of the stomach, the supplement was administered via two types of pH-sensitive, enteric-coated pellets (targeted at release in the proximal or distal small intestine), or via a naso-duodenal tube. Blood ATP and metabolite concentrations were monitored by HPLC for 4.5 h (naso-duodenal tube) or 7 h (pellets) post-administration. Areas under the concentration vs. time curve were calculated and compared by paired-samples t-tests. Results: ATP concentrations in blood did not increase after ATP supplementation via enteric-coated pellets or naso-duodenal tube. In contrast, concentrations of the final catabolic product of ATP, uric acid, were significantly increased compared to placebo by similar to 50% after administration via proximal-release pellets (P = 0.003) and naso-duodenal tube (P = 0.001), but not after administration via distal-release pellets. Conclusions: A single dose of orally administered ATP is not bioavailable, and this may explain why several studies did not find ergogenic effects of oral ATP supplementation. On the other hand, increases in uric acid after release of ATP in the proximal part

Plant lignans are converted to enterolignans that have antioxidant and weak estrogen-like activities, and therefore they may lower cardiovascular disease and cancer risks. OBJECTIVE: We investigated whether the intakes of 4 plant lignans (lariciresinol, pinoresinol, secoisolariciresinol, and matairesinol) were inversely associated with coronary heart disease (CHD), cardiovascular diseases (CVD), cancer, and all-cause mortality. DESIGN: The Zutphen Elderly Study is a prospective cohort study in which 570 men aged 64-84 y were followed for 15 y. We recently developed a database and used it to estimate the dietary intakes of 4 plant lignans. Lignan intake was related to mortality with the use of Cox proportional hazards analysis. RESULTS: The median total lignan intake in 1985 was 977 microg/d. Tea, vegetables, bread, coffee, fruit, and wine were the major sources of lignan. The total lignan intake was not related to mortality. However, the intake of matairesinol was inversely associated with CHD, CVD, and all-cause mortality (P

Enterolignans ( enterodiol and enterolactone) can potentially reduce the risk of certain cancers and cardiovascular diseases. Enterolignans are formed by the intestinal microflora after the consumption of plant lignans. Until recently, only secoisolariciresinol and matairesinol were considered enterolignan precursors, but now several new precursors have been identified, of which lariciresinol and pinoresinol have a high degree of conversion. Quantitative data on the contents in foods of these new enterolignan precursors are not available. Thus, the aim of this study was to compile a lignan database including all four major enterolignan precursors. Liquid chromatography-tandem mass spectrometry was used to quantify lariciresinol, pinoresinol, secoisolariciresinol and matairesinol in eighty-three solid foods and twenty-six beverages commonly consumed in The Netherlands. The richest source of lignans was flaxseed (301 129 μ g/100 g), which contained mainly secoisolariciresinol. Also, lignan concentrations in sesame seeds (29 331 μ g/100 g, mainly pinoresinol and lariciresinol) were relatively high. For grain products, which are known to be important sources of lignan, lignan concentrations ranged from 7 to 764 μ g/100 g. However, many vegetables and fruits had similar concentrations, because of the contribution of lariciresinol and pinoresinol. Brassica vegetables contained unexpectedly high levels of lignans (185-2321 μ g/100 g), mainly pinoresinol and lariciresinol. Lignan levels in beverages varied from 0 (cola) to 91 μ g/100 ml (red wine). Only four of the 109 foods did not contain a measurable amount of lignans, and in most cases the amount of lariciresinol and pinoresinol was larger than that of secoisolariciresinol and matairesinol. Thus, available databases largely underestimate the amount of enterolignan precursors in foods.

Plant polyphenols, a large group of natural antioxidants, are serious candidates in explanations of the protective effects of vegetables and fruits against cancer and cardiovascular diseases. Epidemiologic studies are useful for evaluation of the human health effects of long-term exposure to physiologic concentrations of polyphenols, but reliable data on polyphenol contents of foods are still scarce. The aim of this review is to summarize available epidemiologic data on the health effects of polyphenols, focusing on the flavonoid subclasses of flavonols, flavones, and catechins and on lignans. Data obtained to date suggest beneficial effects of both flavonoids and lignans on cardiovascular diseases but not on cancer, with the possible exception of lung cancer. There is a need for more research on stroke and lung diseases such as asthma and chronic obstructive pulmonary disease. Most studies to date have included only flavonols and flavones. With data becoming available for other polyphenols, these compounds should be included in future studies. Careful design of prospective studies is important to offset some of the major drawbacks of epidemiologic studies, including residual confounding (by smoking and other dietary factors) and exposure assessment.

Quercetin is an important dietary flavonoid with putative beneficial effects in the prevention of cancer and CVD. The in vivo bioactivity of quercetin depends on its bioavailability, which varies widely between foods. We used an in situ rat intestinal perfusion model to study whether differential small intestinal hydrolysis of the sugar moiety of five naturally occurring quercetin glycosides determines the small intestinal uptake and subsequent biliary excretion of quercetin. After 30 min perfusion, a decrease of intact quercetin glycoside in perfusate was observed for quercetin-3-O-beta-glucoside (20.9 (SEM 1-4) mumol/l) and quercetin-4'-O-beta-glucoside (23.5 (SEM 1-6) mumol/l), but not of quercetin-3-O-beta-galactoside, quercetin-3-O-beta-rhamnoside and quercetin-3-O-alpha-arabinopyranoside. Appearance of free quercetin in perfusate and conjugated quercetin metabolites (quercetin, isorhammetin, and tamarixetin) in portal and peripheral plasma and bile were also significantly greater after treatment with quercetin-3-O-beta-glucoside or quercetin-4'-O-beta-glucoside compared with any of the other glycosides. Thus, the type of sugar moiety is a major determinant of the small intestinal absorption of quercetin glycosides, but the position (3 or 4') of the glucose moiety does not further influence absorption. The poor bioavailability of important dietary quercetin glycosides has implications for their in vivo bioactivities.

Catechins are polyphenolic compounds in plant foods that belong to the family of flavonoids. Due to their strong antioxidant activity and their capacity to influence mammalian enzyme systems, catechins were hypothesized to affect risk of cardiovascular diseases and cancer in humans. After optimizing the extraction and quantification of six major catechins from foods, a database containing catechin contents of more than 130 commonly consumed plant foods and beverages was created. Catechin levels varied between 5 and 610 mg/kg and were particularly high in tea, chocolate, fruits and red wine. Among 6,200 participants of the Dutch National Food Consumption Survey 1998, the average catechin intake was 50 mg/day. Catechin intake increased with age, and the intake was higher in women (60 mg/day) than in men (40 mg/day). Tea was the main catechin source in all age groups. The role of catechins in chronic disease prevention was studied in two prospective cohort studies: the Zutphen Elderly Study (~800 Dutch men, 65-84 years old, followed since 1985) and the Iowa Women's Health Study (~34,000 postmenopausal American women, 55-69 years old, followed since 1986). In Zutphen, a high intake of catechins was associated with a 51% lower risk of coronary heart disease (CHD) mortality, but not with myocardial infarction incidence or stroke. In Iowa, a 24% lower risk of CHD mortality was found in the highest quintile of intake of (+)-catechin and (-)-epicatechin, catechins typical of foods other than tea. Catechins derived from tea were not associated with CHD mortality. Lung cancer incidence was studied in both the Zutphen Elderly Study and the Iowa Women's Health Study. Whereas in Zutphen a borderline significant inverse association with lung cancer was found for catechins from foods other than tea, particularly apple, catechins were not associated with lung cancer in Iowa. The incidence of other cancers studied in Zutphen - total epithelial cancer and epithelial cancers other that