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This dataset contains the supplementary tables with fasting and postprandial plasma metabolomics data of chapters 5 and 7 from Anouk Gijbels' PhD thesis, "Precision nutrition for cardiometabolic health: insights from human dietary intervention studies". The research in this thesis aimed to contribute to a better understanding of the role of metabolic heterogeneity in response to diet, with a specific focus on tissue-specific insulin resistance. In addition, we aimed to contribute to a better understanding of the mechanisms by which diet affects metabolic health by investigating postprandial metabolism.

Nutrition can play a pivotal role in preventing and sometimes even reversing obesity and associated diseases. Traditionally, the effects of nutrition on health were assessed by the use of a few single biomarkers, known as classical biomarkers of a disease state. While the low hanging fruits of diet-induced effects on health have been identified using these markers, new approaches are needed to assess the more subtle diet-induced effects of nutrition on health. Hence, there is a need for more sensitive and comprehensive diet effect biomarkers. Developments in the omics field have paved the way to explore and identify these new biomarkers. Additionally, these omics techniques are being used to improve measurements of dietary intake, by providing objective measurements for short and long term dietary intake, called exposure biomarkers. In this thesis, we identified both diet effect and exposure biomarkers, by performing several human intervention studies with varying dietary exposures and study designs, and by using various omics approaches.In these human intervention studies combined, we found that metabolomics is a powerful tool to identify diet effect biomarkers, next to its effective use to identify exposure biomarkers. In addition, we observed that compliance with a dietary intervention, as reflected by an increase in exposure biomarkers, does not always translate into a response in diet effect biomarkers. Furthermore, despite clear significant effects at the intervention group level, we observed large inter-individual differences in response in the diet effect biomarkers. These inter-individual differences might eventually provide leads for personalised dietary advice in the future. This thesis also confirmed the ambiguity that exists among the different biomarker categories, and highlighted the relevance to explore whether a biomarker is an exposure, effect, or health biomarker, or can reflect multiple conditions. We also showed that although many potential exposure biomarkers have been identified in the literature, well-validated exposure biomarkers are missing, and thereby hamper their current use in nutrition research. Lastly, we showed that microRNA expression in the subcutaneous adipose tissue can be affected by diet and weight-loss. However, before microRNAs can provide a useful addition to the omics arsenal within nutrition research, several challenges need to be overcome, such as the current limited knowledge on the interaction between microRNA, genome, and health. If these challenges can be overcome, the future of microRNA analysis within nutrition research holds strong promise.&nbsp

The recently completed EU-funded BACCHUS Integrated Project (grant number: 312090) has focused on identification of cause-and-effect relationships between consumption of bioactive peptides and polyphenols and physiological effects on cardiovascular health. An important BACCHUS output is a toolkit to support the needs of small- and medium-sized enterprises (SMEs) in the food sector considering making health claims on their products. The toolkit draws together best practice guides, a bioactives database, an intake assessment tool and an e-learning platform. This paper focuses on the Best Practice Guide for Human Dietary Intervention Studies. The toolkit has been developed with SMEs in mind but this guidance is likely to have value far beyond the needs of businesses, in particular being a useful resource for students, early-career scientists and others new to the design and implementation of dietary intervention studies. The aim of this article is to share the principles of the guide with a broader audience.

Background: It is well-known that the saturated fatty acid stearic acid (C18:0) lowers LDL-cholesterol and HDL-cholesterol concentrations as compared with palmitic acid (C16:0). As related to CHD risk, the decrease in LDL-cholesterol is beneficial, while the decrease in HDL-cholesterol is controversial. Recent evidence suggests that not increased HDL-cholesterol concentrations, but the ability of the HDL particles to perform cholesterol efflux from macrophages (cholesterol efflux capacity; CEC) may protect against CHD risk. Therefore, our primary objective was to examine the effects of palmitic acid versus stearic acid on CEC of the HDL fraction during the fasted state. Secondary objectives were effects on fasting lipids, (apo)lipoproteins, and cholesteryl ester transfer protein (CETP). Study design and population: This study was a double-blind, randomized, crossover study with two four-week isocaloric intervention periods, during which subjects received products enriched with palmitic acid or stearic acid. Difference between palmitic acid and stearic acid intakes were 6% of total energy. Thirty-four healthy men and women (61.5u00b15.7 years, BMI: 25.4u00b12.5 kg/m2) completed the study.Results: CEC was not significantly different between the diets. Compared with palmitic acid, stearic acid lowered concentrations of total-cholesterol, LDL-cholesterol, HDL-cholesterol, and apolipoprotein-A1. No significant differences were observed in apolipoprotein-B100 and triacylglycerol concentrations. CETP mass was higher on the stearic acid diet. Conclusion: Although concentrations of HDL-cholesterol and apolipoprotein-A1 were lower on the stearic acid diet, CEC was not significantly different. CETP may be involved in the observed decrease in HDL-cholesterol. Stearic acid lowered total- and LDL-cholesterol, without lowering the total number of apoB100-containing lipoproteins.This study was funded by Unilever R&D Vlaardingen (before divesting its spreads business and since July 2, 2018 operating under the name Upfieldu2122).

Isoprostanoids are a group of non-enzymatic oxidized lipids from polyunsaturated fatty acids. They are commonly used as biomarkers for oxidative damage, to assess in vivo lipid peroxidation in diseases related to the vascular system and neurodegeneration. Currently, there is a mismatch with the outcome in the use of these biomarkers in intervention studies, particularly when testing the effect of antioxidants such as vitamins C and E, or zinc, or a cocktail of these, with other food components. Much of this is because the biomarkers, the method of measurement, and the duration of supplementation are unsuitable. In this review, we will highlight the formation of isoprostanoids from their respective fatty acids, and their application as biomarkers for oxidative damage in vivo, considering human dietary intervention studies evaluating plasma and urine, using mass spectrometry techniques.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine formed during ordinary cooking, and is subsequently metabolically activated by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). Respective genes encoding for these enzymes, display polymorphic distribution in the human population and are thus believed to cause interindividual differences in cancer risk susceptibility. The present study investigated the influence of dietary exposure and CYP1A2 and NAT2 genotypes and phenotypes on differential urinary PhIP excretion levels in 71 human volunteers after consumption of either a high (7.4 ng/g) or low (1.7 ng/g) dose of PhIP. Urinary PhIP excretion levels were found to reflect recent dietary exposure levels, with average levels of 174% (high dose group) and 127% (low dose group), as compared to pre-feed levels. Urinary caffeine metabolite ratios were significantly different between the two NAT2 genotypes, whereas for CYP1A2, the apparent difference in metabolic ratios between the genotypes was statistically non-significant. Significant correlations were firstly found between the CYP1A2-164A-->C (CYP1A2*1F) polymorphism and differential urinary PhIP excretion levels. Although the found correlations are driven primarily by a small number of subjects possessing the homozygous variant constellation, the strong influence of this genotype indicates that the CYP1A2*1F polymorphism could play an important role in human cancer risk susceptibility.

Increase in low density lipoprotein (LDL) oxidation is hypothesized to be causally associated with increasing risk of atherosclerosis and coronary heart disease. In recent epidemiological studies, tissue and serum levels of lycopene, a carotenoid available from tomatoes, have been found to be inversely related to risk of coronary heart disease. A study was undertaken to investigate the effect of dietary supplementation of lycopene on LDL oxidation in 19 healthy human subjects. Dietary lycopene was provided using tomato juice, spaghetti sauce, and tomato oleoresin for a period of 1 wk each. Blood samples were collected at the end of each treatment. Serum lycopene was extracted and measured by high-performance liquid chromatography using an absorbance detector. Serum LDL was isolated by precipitation with buffered heparin, and thiobarbituric acid-reactive substances (TBARS) and conjugated dienes (CD) were measured to estimate LDL oxidation. Both methods, to measure LDL oxidation LDL-TBARS and LDL-CD, were in good agreement with each other. Dietary supplementation of lycopene significantly increased serum lycopene levels by at least twofold. Although there was no change in serum cholesterol levels (total, LDL, or high-density lipoprotein), serum lipid peroxidation and LDL oxidation were significantly decreased. These results may have relevance for decreasing the risk for coronary heart disease.

Folic acid (pteroylmonoglutamic acid) has historically been used as the reference folate in human intervention studies assessing the relative bioavailability of dietary folate. Recent studies using labelled folates indicated different plasma response kinetics to folic acid than to natural (food) folates, thus obviously precluding its use in single-dose experiments. Since differences in tissue distribution and site of biotransformation were hypothesised, the question is whether folic acid remains suitable as a reference folate for longer-term intervention studies, where the relative bioavailability of natural (food) folate is assessed based on changes in folate status. Healthy adults aged 18–65 years (n163) completed a 16-week placebo-controlled intervention study in which the relative bioavailability of increased folate intake (453 nmol/d) from folate-rich foods was assessed by comparing changes in plasma and erythrocyte folate concentration with changes induced by an equal reference dose of supplemental (6S)-5-methyltetrahydrofolic acid or folic acid. The relative increase in plasma folate concentration in the food group was 31 % when compared with that induced by folic acid, but 39 % when compared with (6S)-5-methyltetrahydrofolic acid. The relative increase in erythrocyte folate concentration in the food group when compared with that induced by folic acid was 43 %, and 40 % when compared with (6S)-5-methyltetrahydrofolic acid. When recent published observations were additionally taken into account it was concluded that, in principle, folic acid should not be used as the reference folate when attempting to estimate relative natural (food) folate bioavailability in longer-term human intervention studies. Using (6S)-5-methyltetrahydrofolic acid as the reference folate would avoid future results' validity being questioned.

SCOPE: It has been proposed that endogenously formed N-nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as critical factor in the formation of NOCs, we evaluated the impact of replacing the additive sodium nitrite (E251) by botanical extracts in the PHYTOME project. METHOD AND RESULTS: A human dietary intervention study was conducted in which healthy subjects consumed 300 grams of meat for two weeks, in subsequent order: conventional processed red meat, white meat, and processed red meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of red meat products enriched with phytochemicals leads to a significant reduction in the faecal excretion of NOCs, as compared to traditionally processed red meat products. Gene expression changes identify cell proliferation as main affected molecular mechanism. High nitrate levels in drinking water in combination with processed red meat intake further stimulates NOC formation, an effect that could be mitigated by replacement of E251 by natural plant extracts. CONCLUSION: These findings suggest that addition of natural extracts to conventionally processed red meat products may help to reduce CRC risk, which is mechanistically supported by gene expression analyses.

Consumption of walnuts has slowed breast cancer growth and/or reduced the risk of mammary cancer in mice. The benefit against cancer was associated with altered expression of genes for cancer growth and survival. We hypothesized that walnut consumption would alter gene expression in pathologically confirmed breast cancers of women in a direction that would be expected to decrease breast cancer growth and survival, as was seen in mice. The study was a nonplacebo, 2-arm, clinical trial. Women with breast lumps large enough for research and pathology biopsies were recruited and randomized to walnut consuming or control groups. Immediately after biopsy collection, women in the walnut group began to consume 2 oz of walnuts per day until follow-up surgery. Pathological studies confirmed that lumps were breast cancer in all women who remained in the trial. At surgery, about 2 weeks after biopsy, additional specimens were taken from the breast cancers. Changes in gene expression in the surgical specimen compared to baseline were determined in each individual woman in walnut-consuming (n = 5) and control (n = 5) groups. RNA sequencing expression profiling revealed that expression of 456 identified genes was significantly changed in the tumor due to walnut consumption. Ingenuity Pathway Analysis showed activation of pathways that promote apoptosis and cell adhesion, and inhibition of pathways that promote cell proliferation and migration. These results support the hypothesis that, in humans, walnut consumption could suppress growth and survival of breast cancers.

Background: Weight loss (WL) is often followed by weight regain after an energy-restricted dietary intervention (DI). When people are following a diet, the volume of an adipocyte decreases by loss of triglycerides, which creates stress between the cell contents and the surrounding extracellular matrix (ECM). Previously, we observed that genetic variations in ECM genes are associated with an increased risk of weight regain. Objective: We investigated the relation between the expression of ECM genes during WL and a period of weight stabilization (WS) and the risk of weight regain. Design: In this randomized controlled trial, 61 healthy overweight or obese participants followed either a 5-wk very-low-calorie diet (VLCD; 500 kcal/d) or a 12-wk low-calorie diet (1250 kcal/d) (WL period) with a subsequent 4-wk WS period and a 9-mo follow-up. The WL and WS periods combined were considered the DI. Abdominal subcutaneous adipose tissue biopsy samples were collected for microarray analysis. Gene expression changes for a broad set of ECM-related genes were correlated with the weight-regain percentage (WR%). Results: A total of 26 of the 277 genes were significantly correlated with WR% during WL, WS, or the DI periods. Most correlations were observed in the VLCD group during the WS period. Four genes code for leukocyte-specific receptors. These and other genes belong to a group of 26 genes, among which the expression changes were highly correlated (r ≥ 0.7, P ≤ 0.001). This group could be divided into 3 subclusters linking to 2 biological processes-leukocyte integrin gene activity and ECM remodeling-and a link to insulin sensitivity was also apparent. Conclusions: Our present findings indicate the importance of adipose tissue leukocytes for the risk of weight regain. ECM modification also seems to be involved, and we observed a link to insulin sensitivity. This trial was registered at clinicaltrials.gov as NCT01559415.

Background Nitrate is converted to nitrite in the human body and subsequently can react with amines and amides in the gastrointestinal tract to form N-nitroso compounds (NOCs), which are known to be carcinogenic in animals. Humans can be exposed to nitrate via consumption of drinking water and diet, especially green leafy vegetables and cured meat. The contribution of nitrate from drinking water in combination with meat intake has not been investigated thoroughly. Therefore, in the present pilot study, we examined the effect of nitrate from drinking water, and its interaction with the consumption of white and processed red meat, on the endogenous formation of NOCs, taking into account the intake of vitamin C, a nitrosation inhibitor. Methods Twenty healthy subjects were randomly assigned to two groups consuming either 3.75 g/kg body weight (maximum 300 g per day) processed red meat or unprocessed white meat per day for two weeks. Drinking water nitrate levels were kept low during the first week (N-nitroso compounds (ATNC), compliance markers, and genotoxic potential in human colonic Caco-2 cells. Results Urinary nitrate excretion was significantly increased during the high drinking water nitrate period for both meat types. Furthermore, levels of compliance markers for meat intake were significantly increased in urine from subjects consuming processed red meat (i.e. 1-Methylhistidine levels), or unprocessed white meat (i.e. 3-Methylhistidine). ATNC levels significantly increased during the high drinking water nitrate period, which was more pronounced in the processed red meat group. Genotoxicity in Caco-2 cells exposed to faecal water resulted in increased genotoxicity after the interventions, but results were only significant in the low drinking water nitrate period in subjects consuming processed red meat. Furthermore, a positive correlation was found between the ratio of nitrate/vitamin C intake (including drinking water) and the level of ATNC in faecal water of subjects in the processed red meat group, but this was not statistically significant. Conclusions Drinking water nitrate significantly contributed to the endogenous formation of NOC, independent of the meat type consumed. This implies that drinking water nitrate levels should be taken into account when evaluating the effect of meat consumption on endogenous formation of NOC. Trial registration Dutch Trialregister: 29707. Registered 19th of October 2018. Retrospectively registered.

Consumption of nitrate-rich beetroot juice (BRJ) by athletes induces a number of beneficial physiological health effects, which are linked to the formation of nitric oxide (NO) from nitrate. However, following a secondary pathway, NO may also lead to the formation of N-nitroso compounds (NOCs), which are known to be carcinogenic in 39 animal species. The extent of the formation of NOCs is modulated by various other dietary factors, such as vitamin C. The present study investigates the endogenous formation of NOCs after BRJ intake and the impact of vitamin C on urinary NOC excretion. In a randomized, controlled trial, 29 healthy recreationally active volunteers ingested BRJ with or without additional vitamin C supplements for one week. A significant increase of urinary apparent total N-nitroso Compounds (ATNC) was found after one dose (5 to 47 nmol/mmol: p &lt, 0.0001) and a further increase was found after seven consecutive doses of BRJ (104 nmol/mmol: p &lt, 0.0001). Vitamin C supplementation inhibited ATNC increase after one dose (16 compared to 72 nmol/mmol, p &lt, 0.01), but not after seven daily doses. This is the first study that shows that BRJ supplementation leads to an increase in formation of potentially carcinogenic NOCs. In order to protect athlete&rsquo, s health, it is therefore important to be cautious with chronic use of BRJ to enhance sports performances.

Nutritional management of blood glucose levels is a strategic target in the prevention and management of type 2 diabetes mellitus (T2DM). To implement such an approach it is essential to understand the effect of food on glycaemic regulation and on the underlying metabolic derangements. This comprehensive review summarises the results from human dietary interventions exploring the impact of dietary components on blood glucose levels. Included are the major macronutrients; carbohydrate, protein and fat, micronutrient vitamins and minerals, non-nutrient phytochemicals and additional foods including low-calorie sweeteners, vinegar and alcohol. Based on the evidence presented in this review, it is clear that dietary components have significant and clinically relevant effects on blood glucose modulation. An integrated approach that includes reducing excess body weight, increased physical activity along with a dietary regime to regulate blood glucose levels will not only be advantages in T2DM management, but will benefit the health of the population and limit the increasing worldwide incidence of T2DM.