Publications by authors named "Augustin Scalbert"

207 Publications

Prediagnostic plasma polyphenol concentrations and colon cancer risk: The JPHC nested case-control study.

Clin Nutr 2022 Jul 8;41(9):1950-1960. Epub 2022 Jul 8.

Division of Cohort Research, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan.

Background & Aims: Epidemiological studies that assessed the associations between dietary polyphenol intakes and colon cancer risk have reported largely null results, possibly due to measurement error associated with dietary assessment. We adopted an objective approach by measuring prediagnostic plasma concentrations of 35 polyphenols and assessing associations with colon cancer risk.

Methods: We conducted a nested-case control study within the Japan Public Health Center-based prospective study (JPHC Study) utilizing plasma samples collected at the time of a five-year follow-up survey between 1995 and 1999. We identified colon cancer cases who developed cancer during the follow-up from the time of blood collection. Controls were matched by age, sex, area code, population size of the area, season of blood collection, year of blood collection, and duration of fasting time before the blood collection. Prediagnostic concentrations of 35 polyphenols from 375 incident colon cancer cases (followed until 2012) and 710 matched controls were measured by tandem mass spectrometry coupled with ultra-high-pressure liquid chromatography. We used multivariable conditional logistic regression models adjusted for established colon cancer risk factors to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: In sexes combined log2-transformed multivariable models, circulating levels of 3,4-dihydroxyphenylpropionic acid (P = 0.02), ferulic acid (P = 0.02), and caffeic acid (P = 0.03) were inversely, and 3-hydroxybenzoic acid (P = 0.03) was positively, associated with colon cancer risk. For men only, circulating levels of 3,4-dihydroxyphenylpropionic acid was inversely, and 3,5-dihydroxyphenylpropionic acid, gallic acid, (+)-epigallocatechin, 3-hydroxybenzoic acid, and epicatechin were positively, associated with colon cancer risk. In women, plasma caffeic acid and ferulic acid concentration were inversely associated with colon cancer risk. However, all these associations were nonsignificant after adjustment for multiple comparisons. The remaining polyphenols were not associated with colon cancer risk.

Conclusion: Coffee-derived 3,4-dihydroxyphenylpropionic acid, ferulic acid, and caffeic acid concentrations were inversely associated with colon cancer risk although the association were nonsignificant after adjustment for multiple comparisons. These results support a possible role of coffee polyphenols in preventing colorectal cancer.
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http://dx.doi.org/10.1016/j.clnu.2022.06.041DOI Listing
July 2022

Air pollution, metabolites and respiratory health across the life-course.

Eur Respir Rev 2022 Sep 10;31(165). Epub 2022 Aug 10.

Dept of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.

Previous studies have explored the relationships of air pollution and metabolic profiles with lung function. However, the metabolites linking air pollution and lung function and the associated mechanisms have not been reviewed from a life-course perspective. Here, we provide a narrative review summarising recent evidence on the associations of metabolic profiles with air pollution exposure and lung function in children and adults. Twenty-six studies identified through a systematic PubMed search were included with 10 studies analysing air pollution-related metabolic profiles and 16 studies analysing lung function-related metabolic profiles. A wide range of metabolites were associated with short- and long-term exposure, partly overlapping with those linked to lung function in the general population and with respiratory diseases such as asthma and COPD. The existing studies show that metabolomics offers the potential to identify biomarkers linked to both environmental exposures and respiratory outcomes, but many studies suffer from small sample sizes, cross-sectional designs, a preponderance on adult lung function, heterogeneity in exposure assessment, lack of confounding control and omics integration. The ongoing EXposome Powered tools for healthy living in urbAN Settings (EXPANSE) project aims to address some of these shortcomings by combining biospecimens from large European cohorts and harmonised air pollution exposure and exposome data.
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http://dx.doi.org/10.1183/16000617.0038-2022DOI Listing
September 2022

Determinants of blood acylcarnitine concentrations in healthy individuals of the European Prospective Investigation into Cancer and Nutrition.

Clin Nutr 2022 Aug 8;41(8):1735-1745. Epub 2022 Jun 8.

Nutrition and Metabolism Branch, International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon, France.

Background & Aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed.

Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed.

Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels.

Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.
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http://dx.doi.org/10.1016/j.clnu.2022.05.020DOI Listing
August 2022

Development and validation of a metabolite score for red meat intake: an observational cohort study and randomized controlled dietary intervention.

Am J Clin Nutr 2022 Aug;116(2):511-522

Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.

Background: Self-reported meat consumption is associated with disease risk but objective assessment of different dimensions of this heterogeneous dietary exposure in observational and interventional studies remains challenging.

Objectives: We aimed to derive and validate scores based on plasma metabolites for types of meat consumption. For the most predictive score, we aimed to test whether the included metabolites varied with change in meat consumption, and whether the score was associated with incidence of type 2 diabetes (T2D) and other noncommunicable diseases.

Methods: We derived scores based on 781 plasma metabolites for red meat, processed meat, and poultry consumption assessed with 7-d food records among 11,432 participants in the EPIC-Norfolk (European Prospective Investigation into Cancer and Nutrition-Norfolk) cohort. The scores were then tested for internal validity in an independent subset (n = 853) of the same cohort. In focused analysis on the red meat metabolite score, we examined whether the metabolites constituting the score were also associated with meat intake in a randomized crossover dietary intervention trial of meat (n = 12, Lyon, France). In the EPIC-Norfolk study, we assessed the association of the red meat metabolite score with T2D incidence (n = 1478) and other health endpoints.

Results: The best-performing score was for red meat, comprising 139 metabolites which accounted for 17% of the explained variance of red meat consumption in the validation set. In the intervention, 11 top-ranked metabolites in the red meat metabolite score increased significantly after red meat consumption. In the EPIC-Norfolk study, the red meat metabolite score was associated with T2D incidence (adjusted HR per SD: 1.17; 95% CI: 1.10, 1.24).

Conclusions: The red meat metabolite score derived and validated in this study contains metabolites directly derived from meat consumption and is associated with T2D risk. These findings suggest the potential for objective assessment of dietary components and their application for understanding diet-disease associations.The trial in Lyon, France, was registered at clinicaltrials.gov as NCT03354130.
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http://dx.doi.org/10.1093/ajcn/nqac094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348983PMC
August 2022

Reproducibility of the blood and urine exposome - a systematic literature review and meta-analysis.

Cancer Epidemiol Biomarkers Prev 2022 Jun 23. Epub 2022 Jun 23.

Hochschule Neubrandenburg - University of Applied Sciences, Neubrandenburg, Germany.

Endogenous and exogenous metabolite concentrations may be susceptible to variation over time. This variability can lead to misclassification of exposure levels and in turn to biased results. To assess the reproducibility of metabolites, the intra-class correlation coefficient (ICC) is computed. A literature search in three databases from 2000 until May 2021 was conducted to identify studies reporting ICCs for blood and urine metabolites. This review includes 192 studies, of which 31 studies are included in the meta-analyses. The ICCs of 359 single metabolites are reported and the ICCs of 10 metabolites were meta-analysed. The reproducibility of the single metabolites ranges from poor to excellent and is highly compound dependent. The reproducibility of BPA (bisphenol A), MEP (mono-ethyl phthalate), MnBP (mono-n-butyl phthalate), MEHP (mono-2-ethylhexyl phthalate), MEHHP (mono(2-ethyl-5-hydroxyhexyl) phthalate), MBzP (mono-benzyl phthalate), MEOHP (mono-(2-ethyl-5-oxohexyl) phthalate), methylparaben and propylparaben, is poor to moderate (ICC median: 0.32; range: 0.15-0.49) and for 25-Hydroxyvitamin D (25(OH)D) excellent (ICC: 0.95; 95% CI: 0.90, 0.99). Pharmacokinetics, mainly the half-life of elimination and exposure patterns, can explain reproducibility. This review describes the reproducibility of the blood and urine exposome, provides a vast dataset of ICC estimates, and hence constitutes a valuable resource for future reproducibility, clinical and epidemiological studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-22-0090DOI Listing
June 2022

Cord blood metabolites and rapid postnatal growth as multiple mediators in the prenatal propensity to childhood overweight.

Int J Obes (Lond) 2022 07 4;46(7):1384-1393. Epub 2022 May 4.

Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO-Piemonte, Torino, Italy.

Background: The mechanisms underlying childhood overweight and obesity are poorly known. Here, we investigated the direct and indirect effects of different prenatal exposures on offspring rapid postnatal growth and overweight in childhood, mediated through cord blood metabolites. Additionally, rapid postnatal growth was considered a potential mediator on childhood overweight, alone and sequentially to each metabolite.

Methods: Within four European birth-cohorts (N = 375 mother-child dyads), information on seven prenatal exposures (maternal education, pre-pregnancy BMI, weight gain and tobacco smoke during pregnancy, age at delivery, parity, and child gestational age), selected as obesogenic according to a-priori knowledge, was collected. Cord blood levels of 31 metabolites, associated with rapid postnatal growth and/or childhood overweight in a previous study, were measured via liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry. Rapid growth at 12 months and childhood overweight (including obesity) between four and eight years were defined with reference to WHO growth charts. Single mediation analysis was performed using the imputation approach and multiple mediation analysis using the extended-imputation approach.

Results: Single mediation suggested that the effect of maternal education, pregnancy weight gain, parity, and gestational age on rapid postnatal growth but not on childhood overweight was partly mediated by seven metabolites, including cholestenone, decenoylcarnitine(C10:1), phosphatidylcholine(C34:3), progesterone and three unidentified metabolites; and the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth. Multiple mediation suggested that the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth and that the mediating role of the metabolites was marginal.

Conclusion: Our findings provide evidence of the involvement of in utero metabolism in the propensity to rapid postnatal growth and of rapid postnatal growth in the propensity to childhood overweight. We did not find evidence supporting a mediating role of the studied metabolites alone between the studied prenatal exposures and the propensity to childhood overweight.
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http://dx.doi.org/10.1038/s41366-022-01108-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239910PMC
July 2022

Assessment of Fruit and Vegetables Intake with Biomarkers in Children and Adolescents and Their Level of Validation: A Systematic Review.

Metabolites 2022 Jan 28;12(2). Epub 2022 Jan 28.

Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology-BIPS, Achterstraße 30, 28359 Bremen, Germany.

Fruit and vegetables (FV) are part of a healthy diet and should be frequently consumed already at a young age. However, intake of FV is difficult to assess in children and adolescents due to various misreporting aspects. Thus, measurement of dietary biomarkers may be a promising alternative to assess FV intake more objectively at young age. To date, dietary biomarkers have been primarily studied in adults, and research focused on their usefulness in children is scarce. However, clinical studies have revealed important differences between children and adults, most importantly in their gut microbiome composition, resulting in differences in postprandial metabolism, as well as in food choices and meal compositions that may influence individual biomarker levels. Therefore, the present review aimed to identify biomarkers of FV intake (BFVI) currently available in children and adolescents and to explore whether there are any differences in the BFVI profile above between children and adolescents and adults. In addition, the current level of validation of BFVI in children and adolescents was examined. In total, 28 studies were eligible for this review, and 18 compounds were identified as potential biomarkers for FV intake in children and adolescents. Carotenoid concentration in skin was a valuable biomarker for total FV intake for both children and adult populations. Common BFVI in blood in adults (e.g., carotenoids and vitamin C) showed inconsistent results in children and adolescents. Biomarkers particularly useful in children included urinary hippuric acid as a biomarker of polyphenolic compound intake originating from FV and the combination of -methylnicotinic acid and acetylornithine as a biomarker of bean intake. Further studies are needed to assess their kinetics, dose-response, and other validation aspects. There is limited evidence so far regarding valid BFVI in children and adolescents. Thus, to put BFVI into practice in children and adolescents, further studies, particularly based on metabolomics, are needed to identify and validate BFVI that can be used in future epidemiological studies.
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http://dx.doi.org/10.3390/metabo12020126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876138PMC
January 2022

Flavonoid intakes inversely associate with COPD in smokers.

Eur Respir J 2022 Aug 10;60(2). Epub 2022 Aug 10.

Institute for Nutrition Research, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.

Introduction: Higher flavonoid intakes are beneficially associated with pulmonary function parameters; however, their association with chronic obstructive pulmonary disease (COPD) is unknown. This study aimed to examine associations between intakes of 1) total flavonoids, 2) flavonoid subclasses and 3) major flavonoid compounds with incident COPD in participants from the Danish Diet, Cancer and Health study.

Methods: This prospective cohort included 55 413 men and women without COPD, aged 50-65 years at recruitment. Habitual flavonoid intakes at baseline were estimated from a food frequency questionnaire using Phenol-Explorer. Danish nationwide registers were used to identify incident cases of COPD. Associations were modelled using restricted cubic splines within Cox proportional hazards models.

Results: During 23 years of follow-up, 5557 participants were diagnosed with COPD. Of these, 4013 were current smokers, 1062 were former smokers and 482 were never-smokers. After multivariable adjustments, participants with the highest total flavonoid intakes had a 20% lower risk of COPD than those with the lowest intakes (quintile 5 quintile 1: HR 0.80, 95% CI 0.74-0.87); a 6-22% lower risk was observed for each flavonoid subclass. The inverse association between total flavonoid intake and COPD was present in both men and women but only in current smokers (HR 0.77, 95% CI 0.70-0.84) and former smokers (HR 0.82, 95% CI 0.69-0.97), not never-smokers. Furthermore, higher flavonoid intakes appeared to lessen, but not negate, the higher risk of COPD associated with smoking intensity.

Conclusion: Dietary flavonoids may be important for partially mitigating the risk of smoking-related COPD. However, smoking cessation should remain the highest priority.
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http://dx.doi.org/10.1183/13993003.02604-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9363846PMC
August 2022

Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.

Int J Cancer 2022 04 11;150(8):1255-1268. Epub 2022 Jan 11.

Public Health Directorate, Asturias, Spain.

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (OR  = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
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http://dx.doi.org/10.1002/ijc.33885DOI Listing
April 2022

Urinary Concentrations of (+)-Catechin and (-)-Epicatechin as Biomarkers of Dietary Intake of Flavan-3-ols in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

Nutrients 2021 Nov 20;13(11). Epub 2021 Nov 20.

Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain.

This study examines the correlation of acute and habitual dietary intake of flavan-3-ol monomers, proanthocyanidins, theaflavins, and their main food sources with the urinary concentrations of (+)-catechin and (-)-epicatechin in the European Prospective Investigation into Cancer and Nutrition study (EPIC). Participants (N = 419, men and women) provided 24-h urine samples and completed a 24-h dietary recall (24-HDR) on the same day. Acute and habitual dietary data were collected using a standardized 24-HDR software and a validated dietary questionnaire, respectively. Intake of flavan-3-ols was estimated using the Phenol-Explorer database. Concentrations of (+)-catechin and (-)-epicatechin in 24-h urine were analyzed using tandem mass spectrometry after enzymatic deconjugation. Simple and partial Spearman's correlations showed that urinary concentrations of (+)-catechin, (-)-epicatechin and their sum were more strongly correlated with acute than with habitual intake of individual and total monomers (acute = 0.13-0.54, < 0.05; and habitual = 0.14-0.28, < 0.01), proanthocyanidins (acute = 0.24-0.49, < 0.001; and habitual = 0.10-0.15, < 0.05), theaflavins (acute = 0.22-0.31, < 0.001; and habitual = 0.20-0.26, < 0.01), and total flavan-3-ols (acute = 0.40-0.48, < 0.001; and habitual = 0.23-0.33, < 0.001). Similarly, urinary concentrations of flavan-3-ols were weakly correlated with both acute ( = 0.12-0.30, < 0.05) and habitual intake ( = 0.10-0.27, < 0.05) of apple and pear, stone fruits, berries, chocolate and chocolate products, cakes and pastries, tea, herbal tea, wine, red wine, and beer and cider. Moreover, all comparable correlations were stronger for urinary (-)-epicatechin than for (+)-catechin. In conclusion, our data support the use of urinary concentrations of (+)-catechin and (-)-epicatechin, especially as short-term nutritional biomarkers of dietary catechin, epicatechin and total flavan-3-ol monomers.
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http://dx.doi.org/10.3390/nu13114157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624971PMC
November 2021

The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium.

PLoS Med 2021 09 20;18(9):e1003786. Epub 2021 Sep 20.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.

Background: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).

Methods And Findings: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.

Conclusions: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
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http://dx.doi.org/10.1371/journal.pmed.1003786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496779PMC
September 2021

Polyphenol Intake and Epithelial Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

Antioxidants (Basel) 2021 Aug 4;10(8). Epub 2021 Aug 4.

Institut Gustave Roussy, 94805 Villejuif, France.

Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake of total, classes and subclasses of polyphenols and EOC risk in a large prospective study. The study was conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 309,129 adult women recruited mostly from the general population. Polyphenol intake was assessed through validated country-specific dietary questionnaires and the Phenol-Explorer database. During a mean follow-up of 14 years, 1469 first incident EOC cases (including 806 serous, 129 endometrioid, 102 mucinous, and 67 clear cell tumours) were identified. In multivariable-adjusted Cox regression models, the hazard ratio in the highest quartile of total polyphenol intake compared with the lowest quartile (HR) was 1.14 (95% CI 0.94-1.39; -trend = 0.11). Similarly, the intake of most classes and subclasses of polyphenols were not related to either overall EOC risk or any EOC subtype. A borderline statistically significant positive association was observed between phenolic acid intake (HR = 1.20, 95% CI 1.01-1.43; -trend = 0.02) and EOC risk, especially for the serous subtype and in women with obesity, although these associations did not exceed the Bonferroni correction threshold. The current results do not support any association between polyphenol intake and EOC in our large European prospective study. Results regarding phenolic acid intake need further investigation.
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http://dx.doi.org/10.3390/antiox10081249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389235PMC
August 2021

Developing the building blocks to elucidate the impact of the urban exposome on cardiometabolic-pulmonary disease: The EU EXPANSE project.

Environ Epidemiol 2021 Aug 1;5(4):e162. Epub 2021 Jul 1.

Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.

By 2030, more than 80% of Europe's population will live in an urban environment. The urban exposome, consisting of factors such as where we live and work, where and what we eat, our social network, and what chemical and physical hazards we are exposed to, provides important targets to improve population health. The EXPANSE (EXposome Powered tools for healthy living in urbAN SEttings) project will study the impact of the urban exposome on the major contributors to Europe's burden of disease: Cardio-Metabolic and Pulmonary Disease. EXPANSE will address one of the most pertinent questions for urban planners, policy makers, and European citizens: "How to maximize one's health in a modern urban environment?" EXPANSE will take the next step in exposome research by (1) bringing together exposome and health data of more than 55 million adult Europeans and OMICS information for more than 2 million Europeans; (2) perform personalized exposome assessment for 5,000 individuals in five urban regions; (3) applying ultra-high-resolution mass-spectrometry to screen for chemicals in 10,000 blood samples; (4) evaluating the evolution of the exposome and health through the life course; and (5) evaluating the impact of changes in the urban exposome on the burden of cardiometabolic and pulmonary disease. EXPANSE will translate its insights and innovations into research and dissemination tools that will be openly accessible via the EXPANSE toolbox. By applying innovative ethics-by-design throughout the project, the social and ethical acceptability of these tools will be safeguarded. EXPANSE is part of the European Human Exposome Network.
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http://dx.doi.org/10.1097/EE9.0000000000000162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367039PMC
August 2021

Higher Habitual Flavonoid Intakes Are Associated with a Lower Incidence of Diabetes.

J Nutr 2021 11;151(11):3533-3542

Institute for Nutrition Research, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.

Background: Higher flavonoid intakes are hypothesized to confer protection against type 2 diabetes mellitus.

Objectives: We aimed to 1) investigate associations between flavonoid intakes and diabetes, 2) examine the mediating impact of body fat, and 3) identify subpopulations that may receive the greatest benefit from higher flavonoid intakes in participants of the Danish Diet, Cancer, and Health Study followed up for 23 y.

Methods: Cross-sectional associations between baseline flavonoid intake, estimated using FFQs and the Phenol Explorer database, and body fat, estimated by bioelectrical impedance, were assessed using multivariable-adjusted linear regression models. Nonlinear associations between flavonoid intake and incident diabetes were examined using restricted cubic splines with multivariable-adjusted Cox proportional hazards models.

Results: Among 54,787 participants (median age: 56 y; IQR: 52-60 y; 47.3% men), 6700 individuals were diagnosed with diabetes. Participants in the highest total flavonoid intake quintile (median, 1202 mg/d) had a 1.52 kg lower body fat (95% CI: -1.74, -1.30 kg) and a 19% lower risk of diabetes (HR: 0.81; 95% CI: 0.75, 0.87) after multivariable adjustments and compared with participants in the lowest intake quintile (median: 174 mg/d). Body fat mediated 57% (95% CI: 42, 83%) of the association between flavonoid intake and incident diabetes. Of the flavonoid subclasses, moderate to high intakes of flavonols, flavanol monomers, flavanol oligo + polymers, and anthocyanins were significantly associated with a lower risk of diabetes. Although associations were not modified by sex, smoking status, BMI, or physical activity (Pinteraction > 0.05 for all), findings on an absolute scale suggest that those at a higher risk (those with obesity) may benefit the most from a higher flavonoid intake.

Conclusions: The findings reported in this study suggest that a diet abundant in flavonoid-rich foods may help ameliorate diabetes risk, in part through a reduction in body fat.
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http://dx.doi.org/10.1093/jn/nxab269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562076PMC
November 2021

Cord blood metabolic signatures predictive of childhood overweight and rapid growth.

Int J Obes (Lond) 2021 10 12;45(10):2252-2260. Epub 2021 Jul 12.

Μedical Research Council Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Introduction: Metabolomics may identify biological pathways predisposing children to the risk of overweight and obesity. In this study, we have investigated the cord blood metabolic signatures of rapid growth in infancy and overweight in early childhood in four European birth cohorts.

Methods: Untargeted liquid chromatography-mass spectrometry metabolomic profiles were measured in cord blood from 399 newborns from four European cohorts (ENVIRONAGE, Rhea, INMA and Piccolipiu). Rapid growth in the first year of life and overweight in childhood was defined with reference to WHO growth charts. Metabolome-wide association scans for rapid growth and overweight on over 4500 metabolic features were performed using multiple adjusted logistic mixed-effect models and controlling the false discovery rate (FDR) at 5%. In addition, we performed a look-up analysis of 43 pre-annotated metabolites, previously associated with birthweight or rapid growth.

Results: In the Metabolome-Wide Association Study analysis, we identified three and eight metabolites associated with rapid growth and overweight, respectively, after FDR correction. Higher levels of cholestenone, a cholesterol derivative produced by microbial catabolism, were predictive of rapid growth (p = 1.6 × 10). Lower levels of the branched-chain amino acid (BCAA) valine (p = 8.6 × 10) were predictive of overweight in childhood. The area under the receiver operator curve for multivariate prediction models including these metabolites and traditional risk factors was 0.77 for rapid growth and 0.82 for overweight, compared with 0.69 and 0.69, respectively, for models using traditional risk factors alone. Among the 43 pre-annotated metabolites, seven and five metabolites were nominally associated (P < 0.05) with rapid growth and overweight, respectively. The BCAA leucine, remained associated (1.6 × 10) with overweight after FDR correction.

Conclusion: The metabolites identified here may assist in the identification of children at risk of developing obesity and improve understanding of mechanisms involved in postnatal growth. Cholestenone and BCAAs are suggestive of a role of the gut microbiome and nutrient signalling respectively in child growth trajectories.
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http://dx.doi.org/10.1038/s41366-021-00888-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455328PMC
October 2021

Longitudinal associations of physical activity with plasma metabolites among colorectal cancer survivors up to 2 years after treatment.

Sci Rep 2021 07 2;11(1):13738. Epub 2021 Jul 2.

Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

We investigated longitudinal associations of moderate-to-vigorous physical activity (MVPA) and light-intensity physical activity (LPA) with plasma concentrations of 138 metabolites after colorectal cancer (CRC) treatment. Self-reported physical activity data and blood samples were obtained at 6 weeks, and 6, 12 and 24 months post-treatment in stage I-III CRC survivors (n = 252). Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQp180 kit). Linear mixed models were used to evaluate confounder-adjusted longitudinal associations. Inter-individual (between-participant differences) and intra-individual associations (within-participant changes over time) were assessed as percentage difference in metabolite concentration per 5 h/week of MVPA or LPA. At 6 weeks post-treatment, participants reported a median of 6.5 h/week of MVPA (interquartile range:2.3,13.5) and 7.5 h/week of LPA (2.0,15.8). Inter-individual associations were observed with more MVPA being related (FDR-adjusted q-value < 0.05) to higher concentrations of arginine, citrulline and histidine, eight lysophosphatidylcholines, nine diacylphosphatidylcholines, 13 acyl-alkylphosphatidylcholines, two sphingomyelins, and acylcarnitine C10:1. No intra-individual associations were found. LPA was not associated with any metabolite. More MVPA was associated with higher concentrations of several lipids and three amino acids, which have been linked to anti-inflammatory processes and improved metabolic health. Mechanistic studies are needed to investigate whether these metabolites may affect prognosis.
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http://dx.doi.org/10.1038/s41598-021-92279-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253824PMC
July 2021

Circulating tryptophan metabolites and risk of colon cancer: Results from case-control and prospective cohort studies.

Int J Cancer 2021 11 12;149(9):1659-1669. Epub 2021 Jul 12.

International Agency for Research on Cancer, Lyon, France.

Dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis; however, epidemiological studies investigating tryptophan metabolites in relation to colorectal cancer risk are limited. We studied associations of plasma tryptophan, serotonin and kynurenine with colon cancer risk in two studies with cancer patients and controls, and in one prospective cohort: ColoCare Study (110 patients/153 controls), the Colorectal Cancer Study of Austria (CORSA; 46 patients/390 controls) and the European Prospective Investigation into Cancer and Nutrition (EPIC; 456 matched case-control pairs). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer risk. Tryptophan was inversely associated with colon cancer risk in ColoCare (OR per 1-SD = 0.44; 95% CI, 0.31-0.64) and EPIC (OR per 1-SD = 0.86; 95% CI, 0.74-0.99). Comparing detectable vs nondetectable levels, serotonin was positively associated with colon cancer in CORSA (OR = 6.39; 95% CI, 3.61-11.3) and EPIC (OR = 2.03; 95% CI, 1.20-3.40). Kynurenine was inversely associated with colon cancer in ColoCare (OR per 1-SD = 0.74; 95% CI, 0.55-0.98), positively associated in CORSA (OR per 1-SD = 1.79; 95% CI, 1.27-2.52), while no association was observed in EPIC. The kynurenine-to-tryptophan ratio was positively associated with colon cancer in ColoCare (OR per 1-SD = 1.38; 95% CI, 1.03-1.84) and CORSA (OR per 1-SD = 1.44; 95% CI, 1.06-1.96), but not in EPIC. These results suggest that higher plasma tryptophan may be associated with lower colon cancer risk, while increased serotonin may be associated with a higher risk of colon cancer. The kynurenine-to-tryptophan ratio may also reflect altered tryptophan catabolism during colon cancer development.
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http://dx.doi.org/10.1002/ijc.33725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429124PMC
November 2021

Associations between dietary amino acid intakes and blood concentration levels.

Clin Nutr 2021 06 27;40(6):3772-3779. Epub 2021 Apr 27.

International Agency for Research on Cancer, Nutrition and Metabolism Section, 69372, Lyon CEDEX 08, France.

Background And Aims: Emerging evidence suggests a role of amino acids (AAs) in the development of various diseases including renal failure, liver cirrhosis, diabetes and cancer. However, mechanistic pathways and the effects of dietary AA intakes on circulating levels and disease outcomes are unclear. We aimed to compare protein and AA intakes, with their respective blood concentrations in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Methods: Dietary protein and AA intakes were assessed via the EPIC dietary questionnaires (DQ) and 24-h dietary recalls (24-HDR). A subsample of 3768 EPIC participants who were free of cancer had blood AA concentrations measured. To investigate how circulating levels relate to their respective intakes, dietary AA intake was examined in quintiles and ANOVA tests were run. Pearson correlations were examined for continous associations between intakes and blood concentrations.

Results: Dietary AA intakes (assessed with the DQ) and blood AA concentrations were not strongly correlated (-0.15 ≤ r ≤ 0.17) and the direction of the correlations depended on AA class: weak positive correlations were found for most essential AAs (isoleucine, leucine, lysine, methionine, threonine, tryptophan, and valine) and conditionally essential AAs (arginine and tyrosine), while negative associations were found for non-essential AAs. Similar results were found when using the 24-HDR. When conducting ANOVA tests for essential AAs, higher intake quintiles were linked to higher blood AA concentrations, except for histidine and phenylalanine. For non-essential AAs and glycine, an inverse relationship was observed. Conditionally-essential AAs showed mixed results.

Conclusions: Weak positive correlations and dose responses were found between most essential and conditionally essential AA intakes, and blood concentrations, but not for the non-essential AAs. These results suggest that intake of dietary AA might be related to physiological AA status, particularly for the essential AAs. However, these results should be further evaluated and confirmed in large-scale prospective studies.
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http://dx.doi.org/10.1016/j.clnu.2021.04.036DOI Listing
June 2021

Flavonoid intake and incident dementia in the Danish Diet, Cancer, and Health cohort.

Alzheimers Dement (N Y) 2021 13;7(1):e12175. Epub 2021 May 13.

School of Medical and Health Sciences Edith Cowan University Perth Australia.

Introduction: Prospective studies investigating flavonoid intake and dementia risk are scarce. The aims of this study were to examine associations between flavonoid intake and the risk of incident dementia and to investigate whether this association differs in the presence of lifestyle risk factors for dementia.

Methods: We examined associations in 55,985 participants of the Danish Diet, Cancer, and Health Study followed for 23 years. The Phenol-Explorer database was used to estimate flavonoid intakes. Information on incident dementia and dementia subtypes was obtained using Danish patient and prescription registries. Hazard ratios (HRs) were calculated using restricted cubic splines in multivariable-adjusted Cox proportional hazards models.

Results: For incident dementia, moderate compared to low intakes of flavonols (HR: 0.90 [0.82, 0.99]), flavanol oligo+polymers (HR: 0.87 [0.79, 0.96]), anthocyanins (HR: 0.84 [0.76, 0.93]), flavanones (HR: 0.89 [0.80, 0.99]), and flavones (HR: 0.85 [0.77, 0.95]) were associated with a lower risk. For vascular dementia, moderate intakes of flavonols (HR: 0.69 [0.53, 0.89]) and flavanol oligo + polymers (HR: 0.65 [0.51, 0.83]) were associated with lower risk. Flavonoid intakes were not significantly associated with Alzheimer's disease or unspecified dementia. The inverse association between total flavonoid intake and incident dementia was stronger in "ever" smokers than in "never" smokers and in those without hypercholesterolemia versus those with hypercholesteremia. Furthermore, the inverse association of vascular dementia with a moderate total flavonoid intake was stronger in "ever" smokers and those who were "normal" to "overweight" versus "never" smokers or those who were "obese," respectively.

Conclusion: A moderate intake of flavonoid-rich foods may help to reduce dementia risk.
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http://dx.doi.org/10.1002/trc2.12175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118115PMC
May 2021

Novel Biomarkers of Habitual Alcohol Intake and Associations With Risk of Pancreatic and Liver Cancers and Liver Disease Mortality.

J Natl Cancer Inst 2021 11;113(11):1542-1550

Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, Utrecht, the Netherlands.

Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed because of measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk.

Methods: Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies.

Results: Two metabolites displayed a dose-response association with self-reported alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54, 95% CI = 1.51 to 4.27) and pancreatic cancer (OR = 1.43, 95% CI = 1.03 to 1.99) in EPIC and liver cancer (OR = 2.00, 95% CI = 1.44 to 2.77) and liver disease mortality (OR = 2.16, 95% CI = 1.63 to 2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19, 95% CI = 1.60 to 2.98) in ATBC.

Conclusions: 2-hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.
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http://dx.doi.org/10.1093/jnci/djab078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562969PMC
November 2021

Habitual flavonoid intake and ischemic stroke incidence in the Danish Diet, Cancer, and Health Cohort.

Am J Clin Nutr 2021 07;114(1):348-357

School of Biomedical Sciences, University of Western Australia, Royal Perth Hospital, Perth, Australia.

Background: Flavonoid-rich foods have antiinflammatory, antiatherogenic, and antithrombotic properties that may contribute to a lower risk of ischemic stroke.

Objectives: We aimed to investigate the relationship between habitual flavonoid consumption and incidence of ischemic stroke in participants from the Danish Diet, Cancer and Health Study.

Design: In this prospective cohort study, 55,169 Danish residents without a prior ischemic stroke [median (IQR) age at enrolment of 56 y (52-60)], were followed for 21 y (20-22). We used Phenol-Explorer to estimate flavonoid intake from food frequency questionnaires obtained at study entry. Incident cases of ischemic stroke were identified from Danish nationwide registries and restricted cubic splines in Cox proportional hazards models were used to investigate relationships with flavonoid intake.

Results: During follow-up, 4237 individuals experienced an ischemic stroke. Compared with participants in Q1 and after multivariable adjustment for demographics and lifestyle factors, those in Q5-for intake of total flavonoids, flavonols, and flavanol oligo + polymers-had a 12% [HR (95% CI): 0.88 (0.81, 0.96)], 10% [0.90 (0.82, 0.98)], and 18% [0.82 (0.75, 0.89)] lower risk of ischemic stroke incidence, respectively. Multivariable (demographic and lifestyle) adjusted associations for anthocyanins and flavones with risk of ischemic stroke were not linear, with moderate but not higher intakes associated with lower risk [anthocyanins Q3 vs. Q1 HR (95% CI): 0.85 (0.79, 0.93); flavones: 0.90 (0.84, 0.97)]. Following additional adjustment for dietary confounders, similar point estimates were observed; however, significance was only retained for anthocyanins and flavanol oligo + polymers [anthocyanins Q3 vs. Q1 HR (95% CI): 0.86 (0.79, 0.94); flavanol oligo + polymers Q5 vs. Q1 0.86 (0.78, 0.94)].

Conclusions: These findings suggest that moderate habitual consumption of healthy flavonoid-rich foods is associated with a lower risk of ischemic stroke and further investigation is therefore warranted.
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http://dx.doi.org/10.1093/ajcn/nqab138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246625PMC
July 2021

Metabolic signatures of greater body size and their associations with risk of colorectal and endometrial cancers in the European Prospective Investigation into Cancer and Nutrition.

BMC Med 2021 04 30;19(1):101. Epub 2021 Apr 30.

International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: The mechanisms underlying the obesity-cancer relationship are incompletely understood. This study aimed to characterise metabolic signatures of greater body size and to investigate their association with two obesity-related malignancies, endometrial and colorectal cancers, and with weight loss within the context of an intervention study.

Methods: Targeted mass spectrometry metabolomics data from 4326 participants enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 17 individuals from a single-arm pilot weight loss intervention (Intercept) were used in this analysis. Metabolic signatures of body size were first determined in discovery (N = 3029) and replication (N = 1297) sets among EPIC participants by testing the associations between 129 metabolites and body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) using linear regression models followed by partial least squares analyses. Conditional logistic regression models assessed the associations between the metabolic signatures with endometrial (N = 635 cases and 648 controls) and colorectal (N = 423 cases and 423 controls) cancer risk using nested case-control studies in EPIC. Pearson correlation between changes in the metabolic signatures and weight loss was tested among Intercept participants.

Results: After adjustment for multiple comparisons, greater BMI, WC, and WHR were associated with higher levels of valine, isoleucine, glutamate, PC aa C38:3, and PC aa C38:4 and with lower levels of asparagine, glutamine, glycine, serine, lysoPC C17:0, lysoPC C18:1, lysoPC C18:2, PC aa C42:0, PC ae C34:3, PC ae C40:5, and PC ae C42:5. The metabolic signature of BMI (OR 1.50, 95% CI 1.30-1.74), WC (OR 1.46, 95% CI 1.27-1.69), and WHR (OR 1.54, 95% CI 1.33-1.79) were each associated with endometrial cancer risk. Risk of colorectal cancer was positively associated with the metabolic signature of WHR (OR: 1.26, 95% CI 1.07-1.49). In the Intercept study, a positive correlation was observed between weight loss and changes in the metabolic signatures of BMI (r = 0.5, 95% CI 0.06-0.94, p = 0.03), WC (r = 0.5, 95% CI 0.05-0.94, p = 0.03), and WHR (r = 0.6, 95% CI 0.32-0.87, p = 0.01).

Conclusions: Obesity is associated with a distinct metabolic signature comprising changes in levels of specific amino acids and lipids which is positively associated with both colorectal and endometrial cancer and is potentially reversible following weight loss.
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http://dx.doi.org/10.1186/s12916-021-01970-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086283PMC
April 2021

Adolescents' dietary polyphenol intake in relation to serum total antioxidant capacity: the HELENA study.

Int J Food Sci Nutr 2022 Feb 15;73(1):71-81. Epub 2021 Apr 15.

Department of Public Health and Primary Care, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.

We evaluated the association between intake of total polyphenols, polyphenol classes and the 10 most consumed individual polyphenols with serum total antioxidant capacity (TAC) in 749 European adolescents (53% girls; 15% overweight; 12.5-17.5 years-old) from the cross-sectional HELENA study of 2006-2007. Dietary polyphenol intake was calculated from two non-consecutive 24-h recalls matched with the Phenol-Explorer database. Multilevel linear models examined the associations between dietary polyphenols and TAC. Polyphenol intake was rather low (median = 321mg/day; p25 = 158; p75 = 536) and TAC was comparable to other literature findings (median = 1.57 mmol/L; p25 = 1.45; p75 = 1.74). Total polyphenol intake, polyphenol classes and the top 10 compounds were not associated with TAC in a linear, quadratic or cubic way in partially or fully confounder-adjusted models. A direct anti-oxidative effect of dietary polyphenol intake was not observed in European adolescents. Polyphenol biomarkers and additional antioxidant measures are needed in future prospective studies to confirm these results.
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http://dx.doi.org/10.1080/09637486.2021.1910631DOI Listing
February 2022

NMR Metabolite Profiles in Male Meat-Eaters, Fish-Eaters, Vegetarians and Vegans, and Comparison with MS Metabolite Profiles.

Metabolites 2021 Feb 20;11(2). Epub 2021 Feb 20.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.

Metabolomics may help to elucidate mechanisms underlying diet-disease relationships and identify novel risk factors for disease. To inform the design and interpretation of such research, evidence on diet-metabolite associations and cross-assay comparisons is needed. We aimed to compare nuclear magnetic resonance (NMR) metabolite profiles between meat-eaters, fish-eaters, vegetarians and vegans, and to compare NMR measurements to those from mass spectrometry (MS), clinical chemistry and capillary gas-liquid chromatography (GC). We quantified 207 serum NMR metabolite measures in 286 male participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford cohort. Using univariate and multivariate analyses, we found that metabolite profiles varied by diet group, especially for vegans; the main differences compared to meat-eaters were lower levels of docosahexaenoic acid, total n-3 and saturated fatty acids, cholesterol and triglycerides in very-low-density lipoproteins, various lipid factions in high-density lipoprotein, sphingomyelins, tyrosine and creatinine, and higher levels of linoleic acid, total n-6, polyunsaturated fatty acids and alanine. Levels in fish-eaters and vegetarians differed by metabolite measure. Concentrations of 13 metabolites measured using both NMR and MS, clinical chemistry or GC were mostly similar. In summary, vegans' metabolite profiles were markedly different to those of men consuming animal products. The studied metabolomics platforms are complementary, with limited overlap between metabolite classes.
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http://dx.doi.org/10.3390/metabo11020121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923783PMC
February 2021

Untargeted Metabolomics Reveals Major Differences in the Plasma Metabolome between Colorectal Cancer and Colorectal Adenomas.

Metabolites 2021 Feb 19;11(2). Epub 2021 Feb 19.

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Sporadic colorectal cancer is characterized by a multistep progression from normal epithelium to precancerous low-risk and high-risk adenomas to invasive cancer. Yet, the underlying molecular mechanisms of colorectal carcinogenesis are not completely understood. Within the "Metabolomic profiles throughout the continuum of colorectal cancer" (MetaboCCC) consortium we analyzed data generated by untargeted, mass spectrometry-based metabolomics using plasma from 88 colorectal cancer patients, 200 patients with high-risk adenomas and 200 patients with low-risk adenomas recruited within the "Colorectal Cancer Study of Austria" (CORSA). Univariate logistic regression models comparing colorectal cancer to adenomas resulted in 442 statistically significant molecular features. Metabolites discriminating colorectal cancer patients from those with adenomas in our dataset included acylcarnitines, caffeine, amino acids, glycerophospholipids, fatty acids, bilirubin, bile acids and bacterial metabolites of tryptophan. The data obtained discovers metabolite profiles reflecting metabolic differences between colorectal cancer and colorectal adenomas and delineates a potentially underlying biological interpretation.
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http://dx.doi.org/10.3390/metabo11020119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922413PMC
February 2021

Targeted Plasma Metabolic Profiles and Risk of Recurrence in Stage II and III Colorectal Cancer Patients: Results from an International Cohort Consortium.

Metabolites 2021 Feb 24;11(3). Epub 2021 Feb 24.

Huntsman Cancer Institute Salt Lake City, Salt Lake City, UT 84112, USA.

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism = 0.04; p = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.
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http://dx.doi.org/10.3390/metabo11030129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996362PMC
February 2021

Pepper Alkaloids and Processed Meat Intake: Results from a Randomized Trial and the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort.

Mol Nutr Food Res 2021 04 2;65(7):e2001141. Epub 2021 Mar 2.

Nutrition and Metabolism Branch, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon, France.

Scope: Processed meat intake has been associated with adverse health outcomes. However, little is known about the type of processed meat more particularly responsible for these effects. This study aims to identify novel biomarkers for processed meat intake.

Methods And Results: In a controlled randomized cross-over dietary intervention study, 12 healthy volunteers consume different processed and non-processed meats for 3 consecutive days each. Metabolomics analyses are applied on post-intervention fasting blood and urine samples to identify discriminating molecular features of processed meat intake. Nine and five pepper alkaloid metabolites, including piperine, are identified as major discriminants of salami intake in urine and plasma, respectively. The associations with processed meat intake are tested for replication in a cross-sectional study (n = 418) embedded within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Three of the serum metabolites including piperine are associated with habitual intake of sausages and to a lesser extent of total processed meat.

Conclusion: Pepper alkaloids are major discriminants of intake for sausages that contain high levels of pepper used as ingredient. Further work is needed to assess if pepper alkaloids in combination with other metabolites may serve as biomarkers of processed meat intake.
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http://dx.doi.org/10.1002/mnfr.202001141DOI Listing
April 2021

Prospective Identification of Elevated Circulating CDCP1 in Patients Years before Onset of Lung Cancer.

Cancer Res 2021 07 11;81(13):3738-3748. Epub 2021 Feb 11.

MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer-related dysregulation of CDCP1 expression years before diagnosis. SIGNIFICANCE: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611235PMC
July 2021

Diet quality indices and dietary patterns are associated with plasma metabolites in colorectal cancer patients.

Eur J Nutr 2021 Sep 5;60(6):3171-3184. Epub 2021 Feb 5.

Division of Human Nutrition and Health, Wageningen University and Research, P.O. Box 17, 6700 AA, Wageningen, The Netherlands.

Purpose: Emerging evidence suggests that diet is linked to survival in colorectal cancer patients, although underlying mechanisms are not fully understood. The aim of this study was to evaluate whether dietary exposures are associated with metabolite concentrations in colorectal cancer patients.

Methods: Concentrations of 134 metabolites of the Biocrates Absolute p180 kit were quantified in plasma samples collected at diagnosis from 195 stage I-IV colorectal cancer patients. Food frequency questionnaires were used to calculate adherence to the World Cancer Research Fund (WCRF) dietary recommendations and the Dutch Healthy Diet (DHD15) index as well as to construct dietary patterns using Principal Component Analysis. Multivariable linear regression models were used to determine associations between dietary exposures and metabolite concentrations. All models were adjusted for age, sex, body mass index, smoking status, analytical batch, cancer stage, and multiple testing using false discovery rate.

Results: Participants had a mean (SD) age of 66 (9) years, were mostly men (60%), and mostly diagnosed with stage II and III cancer. For the dietary pattern analyses, Western, Carnivore, and Prudent patterns were identified. Better adherence to the WCRF dietary recommendations was associated with lower concentrations of ten phosphatidylcholines. Higher intake of the Carnivore pattern was associated with higher concentrations of two phosphatidylcholines. The DHD15-index, Western pattern, or Prudent pattern were not associated with metabolite concentrations.

Conclusion: In the current study, the WCRF dietary score and the Carnivore pattern are associated with phosphatidylcholines. Future research should elucidate the potential relevance of phosphatidylcholine metabolism in the colorectal cancer continuum.

Clinical Trial Registry: ClinicalTrials.gov Identifier: NCT03191110.
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http://dx.doi.org/10.1007/s00394-021-02488-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354955PMC
September 2021
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