Publications by authors named "Augustin Scalbert"

192 Publications

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

Int J Obes (Lond) 2021 Jul 12. 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
July 2021

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

Sci Rep 2021 Jul 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 Jul 1. Epub 2021 Jul 1.

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
July 2021

Associations between dietary amino acid intakes and blood concentration levels.

Clin Nutr 2021 Jun 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 May 19. Epub 2021 May 19.

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 due to 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 = 1.51-4.27) and pancreatic cancer (OR = 1.43; 95% CI = 1.03-1.99) in EPIC and liver cancer (OR = 2.00; 95% CI = 1.44-2.77) and liver disease mortality (OR = 2.16; 95% CI = 1.63-2.86) 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 = 1.60-2.98) 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
May 2021

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

Am J Clin Nutr 2021 Jul;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 Apr 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 2021 Apr 15:1-11. 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
April 2021

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 Jul 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 Feb 5. 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
February 2021

Taxonomic Composition and Diversity of the Gut Microbiota in Relation to Habitual Dietary Intake in Korean Adults.

Nutrients 2021 Jan 26;13(2). Epub 2021 Jan 26.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France.

We investigated associations of habitual dietary intake with the taxonomic composition and diversity of the human gut microbiota in 222 Koreans aged 18-58 years in a cross-sectional study. Gut microbiota data were obtained by 16S rRNA gene sequencing on DNA extracted from fecal samples. The habitual diet for the previous year was assessed by a food frequency questionnaire. After multivariable adjustment, intake of several food groups including vegetables, fermented legumes, legumes, dairy products, processed meat, and non-alcoholic beverages were associated with major phyla of the gut microbiota. A dietary pattern related to higher α-diversity (HiαDP) derived by reduced rank regression was characterized by higher intakes of fermented legumes, vegetables, seaweeds, and nuts/seeds and lower intakes of non-alcoholic beverages. The HiαDP was positively associated with several genera of such as , , and (all < 0.05). Among enterotypes identified by principal coordinate analysis based on the β-diversity, the enterotype had higher HiαDP scores and was strongly positively associated with intakes of vegetables, seaweeds, and nuts/seeds, compared to the two other enterotypes. We conclude that a plant- and fermented food-based diet was positively associated with some genera of (e.g., , , and ) reflecting better gut microbial health.
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http://dx.doi.org/10.3390/nu13020366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912254PMC
January 2021

Metabolic Signatures of Healthy Lifestyle Patterns and Colorectal Cancer Risk in a European Cohort.

Clin Gastroenterol Hepatol 2020 Dec 29. Epub 2020 Dec 29.

Escuela Andaluza de Salud Pública, Granada, Spain.

Background & Aims: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer cohort.

Methods: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.

Results: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants.

Conclusions: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
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http://dx.doi.org/10.1016/j.cgh.2020.11.045DOI Listing
December 2020

Higher habitual flavonoid intakes are associated with a lower risk of peripheral artery disease hospitalizations.

Am J Clin Nutr 2020 Nov 24. Epub 2020 Nov 24.

Department of Cardiology, Herlev & Gentofte University Hospital, Copenhagen, Denmark.

Background: The role of nutrition in the primary prevention of peripheral artery disease (PAD), the third leading cause of atherosclerotic cardiovascular disease, is undetermined. Flavonoids may attenuate atherosclerosis and therefore persons who consume flavonoid-rich foods may have a lower risk of developing PAD.

Objectives: We aimed to examine the association between flavonoid intake and PAD hospitalizations and investigate if the association differs according to established risk factors for PAD.

Methods: Baseline data from 55,647 participants of the Danish Diet, Cancer, and Health Study without PAD, recruited from 1993 to 1997, were cross-linked with Danish nationwide registries. Flavonoid intake was calculated from FFQs using the Phenol-Explorer database. Associations were examined using multivariable-adjusted restricted cubic splines based on Cox proportional hazards models.

Results: After a median [IQR] follow-up time of 21 [20-22] y, 2131 participants had been hospitalized for any PAD. The association between total flavonoid intake and total PAD hospitalizations was nonlinear, reaching a plateau at ∼750-1000 mg/d. Compared with the median flavonoid intake in quintile 1 (174 mg/d), an intake of 1000 mg/d was associated with a 32% lower risk of any PAD hospitalization (HR: 0.68; 95% CI: 0.60, 0.77), a 26% lower risk of atherosclerosis (HR: 0.74; 95% CI: 0.62, 0.88), a 28% lower risk of an aneurysm (HR: 0.72; 95% CI: 0.59, 0.88), and a 47% lower risk of a hospitalization for other peripheral vascular disease (HR: 0.53; 95% CI: 0.42, 0.67). A higher total flavonoid intake was also significantly associated with a lower incidence of revascularization or endovascular surgery and lower extremity amputation. The association between total flavonoid intake and PAD hospitalizations differed according to baseline smoking status, alcohol intake, BMI, and diabetes status.

Conclusions: Ensuring the adequate consumption of flavonoid-rich foods, particularly in subpopulations prone to the development of atherosclerosis, may be a key strategy to lower the risk of PAD.
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http://dx.doi.org/10.1093/ajcn/nqaa300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779235PMC
November 2020

Prenatal Exposure to Multiple Air Pollutants, Mediating Molecular Mechanisms, and Shifts in Birthweight.

Environ Sci Technol 2020 11 30;54(22):14502-14513. Epub 2020 Oct 30.

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, Imperial College London, London SW7 2BU, United Kingdom.

Mechanisms underlying adverse birth and later in life health effects from exposure to air pollution during the prenatal period have not been not fully elucidated, especially in the context of mixtures. We assessed the effects of prenatal exposure to mixtures of air pollutants of particulate matter (PM), PM, PM, nitrogen oxides, NO, NO, ultrafine particles (UFP), and oxidative potential (OP) of PM on infant birthweight in four European birth cohorts and the mechanistic underpinnings through cross-omics of metabolites and inflammatory proteins. The association between mixtures of air pollutants and birthweight z-scores (standardized for gestational age) was assessed for three different mixture models, using Bayesian machine kernel regression (BKMR). We determined the direct effect for PM, PM, NO, and mediation by cross-omic signatures (identified using sparse partial least-squares regression) using causal mediation BKMR models. There was a negative association with birthweight z-scores and exposure to mixtures of air pollutants, where up to -0.21 or approximately a 96 g decrease in birthweight, comparing the 75th percentile to the median level of exposure to the air pollutant mixture could occur. Shifts in birthweight z-scores from prenatal exposure to PM, PM, and NO were mediated by molecular mechanisms, represented by cross-omics scores. Interleukin-17 and epidermal growth factor were identified as important inflammatory responses underlyingair pollution-associated shifts in birthweight. Our results signify that by identifying mechanisms through which mixtures of air pollutants operate, the causality of air pollution-associated shifts in birthweight is better supported, substantiating the need for reducing exposure in vulnerable populations.
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http://dx.doi.org/10.1021/acs.est.0c02657DOI Listing
November 2020

Blood polyphenol concentrations and differentiated thyroid carcinoma in women from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Am J Clin Nutr 2020 Oct 6. Epub 2020 Oct 6.

Institute of Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands.

Background: Polyphenols are natural compounds with anticarcinogenic properties in cellular and animal models, but epidemiological evidence determining the associations of these compounds with thyroid cancer (TC) is lacking.

Objectives: The aim of this study was to evaluate the relations between blood concentrations of 36 polyphenols and TC risk in EPIC (the European Prospective Investigation into Cancer and Nutrition).

Methods: A nested case-control study was conducted on 273 female cases (210 papillary, 45 follicular, and 18 not otherwise specified TC tumors) and 512 strictly matched controls. Blood polyphenol concentrations were analyzed by HPLC coupled to tandem MS after enzymatic hydrolysis.

Results: Using multivariable-adjusted conditional logistic regression models, caffeic acid (ORlog2: 0.55; 95% CI: 0.33, 0.93) and its dehydrogenated metabolite, 3,4-dihydroxyphenylpropionic acid (ORlog2: 0.84; 95% CI: 0.71, 0.99), were inversely associated with differentiated TC risk. Similar results were observed for papillary TC, but not for follicular TC. Ferulic acid was also inversely associated only with papillary TC (ORlog2: 0.68; 95% CI: 0.51, 0.91). However, none of these relations was significant after Bonferroni correction for multiple testing. No association was observed for any of the remaining polyphenols with total differentiated, papillary, or follicular TC.

Conclusions: Blood polyphenol concentrations were mostly not associated with differentiated TC risk in women, although our study raises the possibility that high blood concentrations of caffeic, 3,4-dihydroxyphenylpropionic, and ferulic acids may be related to a lower papillary TC risk.
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http://dx.doi.org/10.1093/ajcn/nqaa277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779226PMC
October 2020

Recommendations for standardizing nomenclature for dietary (poly)phenol catabolites.

Am J Clin Nutr 2020 10;112(4):1051-1068

School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United Kingdom.

There is a lack of focus on the protective health effects of phytochemicals in dietary guidelines. Although a number of chemical libraries and databases contain dietary phytochemicals belonging to the plant metabolome, they are not entirely relevant to human health because many constituents are extensively metabolized within the body following ingestion. This is especially apparent for the highly abundant dietary (poly)phenols, for which the situation is compounded by confusion regarding their bioavailability and metabolism, partially because of the variety of nomenclatures and trivial names used to describe compounds arising from microbial catabolism in the gastrointestinal tract. This confusion, which is perpetuated in online chemical/metabolite databases, will hinder future discovery of bioactivities and affect the establishment of future dietary guidelines if steps are not taken to overcome these issues. In order to resolve this situation, a nomenclature system for phenolic catabolites and their human phase II metabolites is proposed in this article and the basis of its format outlined. Previous names used in the literature are cited along with the recommended nomenclature, International Union of Pure and Applied Chemistry terminology, and, where appropriate, Chemical Abstracts Service numbers, InChIKey, and accurate mass.
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http://dx.doi.org/10.1093/ajcn/nqaa204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528558PMC
October 2020

Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study.

Int J Cancer 2021 02 28;148(3):609-625. Epub 2020 Aug 28.

Public Health Directorate, Asturias, Spain.

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.
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http://dx.doi.org/10.1002/ijc.33236DOI Listing
February 2021

The Human Microbiome in Relation to Cancer Risk: A Systematic Review of Epidemiologic Studies.

Cancer Epidemiol Biomarkers Prev 2020 10 29;29(10):1856-1868. Epub 2020 Jul 29.

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

The microbiome has been hypothesized to play a role in cancer development. Because of the diversity of published data, an overview of available epidemiologic evidence linking the microbiome with cancer is now needed. We conducted a systematic review using a tailored search strategy in Medline and EMBASE databases to identify and summarize the current epidemiologic literature on the relationship between the microbiome and different cancer outcomes published until December 2019. We identified 124 eligible articles. The large diversity of parameters used to describe microbial composition made it impossible to harmonize the different studies in a way that would allow meta-analysis, therefore only a qualitative description of results could be performed. Fifty studies reported differences in the gut microbiome between patients with colorectal cancer and various control groups. The most consistent findings were for , and being significantly enriched in fecal and mucosal samples from patients with colorectal cancer. For the oral microbiome, significantly increased and decreased abundance was reported for and , respectively, in patients with oral cancer compared with controls. Overall, although there was a large amount of evidence for some of these alterations, most require validation in high-quality, preferably prospective, epidemiologic studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541789PMC
October 2020

An overview and update on the epidemiology of flavonoid intake and cardiovascular disease risk.

Food Funct 2020 Aug;11(8):6777-6806

School of Biomedical Sciences, University of Western Australia, Royal Perth Hospital Research Foundation, Perth, Australia. and School of Medical and Health Sciences, Edith Cowan University, Perth, Australia and Institute for Global Food Security, Queen's University, Belfast, Northern Ireland.

There is an accumulating body of literature reporting on dietary flavonoid intake and the risk of cardiovascular disease (CVD) in prospective cohort studies. This makes apparent the need for an overview and update on the current state of the science. To date, at least 27 prospective cohorts (in 44 publications) have evaluated the association between estimated habitual flavonoid intake and CVD risk. At this time, the totality of evidence suggests long-term consumption of flavonoid-rich foods may be associated with a lower risk of fatal and non-fatal ischemic heart disease (IHD), cerebrovascular disease, and total CVD; disease outcomes which are principally, though not exclusively, composed of cases of atherosclerotic CVD (ASCVD). To date, few studies have investigated outcome specific ASCVD, such as peripheral artery disease (PAD) or ischemic stroke. Of the flavonoid subclasses investigated, evidence more often implicates diets rich in anthocyanins, flavan-3-ols, and flavonols in lowering the risk of CVD. Although inferences are restricted by confounding and other inherent limitations of observational studies, causality appears possible based on biological plausibility, temporality, and the relative consistency of the reported associations. However, whether the associations observed represent a benefit of the isolated bioactives per se, or are a signal of the bioactives acting in concert with the co-occurring nutrient matrix within flavonoid-bearing foods, are issues of consideration. Thus, the simple interpretation, and the one most relevant for dietary advice, is that consumption of flavonoid-rich foods or diets higher in flavonoids, appear nutritionally beneficial in the prevention of CVD.
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http://dx.doi.org/10.1039/d0fo01118eDOI Listing
August 2020

Citrus intake and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Eur J Epidemiol 2020 Nov 24;35(11):1057-1067. Epub 2020 Jul 24.

CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Citrus intake has been suggested to increase the risk of skin cancer. Although this relation is highly plausible biologically, epidemiologic evidence is lacking. We aimed to examine the potential association between citrus intake and skin cancer risk. EPIC is an ongoing multi-center prospective cohort initiated in 1992 and involving ~ 520,000 participants who have been followed-up in 23 centers from 10 European countries. Dietary data were collected at baseline using validated country-specific dietary questionnaires. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI). During a mean follow-up of 13.7 years, 8448 skin cancer cases were identified among 270,112 participants. We observed a positive linear dose-response relationship between total citrus intake and skin cancer risk (HR = 1.10, 95% CI 1.03-1.18 in the highest vs. lowest quartile; P = 0.001), particularly with basal cell carcinoma (BCC) (HR = 1.11, 95% CI 1.02-1.20, P = 0.007) and squamous cell carcinoma (SCC) (HR = 1.23, 95% CI 1.04-1.47, P = 0.01). Citrus fruit intake was positively associated with skin cancer risk (HR = 1.08, 95% CI 1.01-1.16, P = 0.01), particularly with melanoma (HR = 1.23, 95% CI 1.02-1.48; P = 0.01), although with no heterogeneity across skin cancer types (P = 0.21). Citrus juice was positively associated with skin cancer risk (P = 0.004), particularly with BCC (P = 0.008) and SCC (P = 0.004), but not with melanoma (P = 0.02). Our study suggests moderate positive linear dose-response relationships between citrus intake and skin cancer risk. Studies with available biomarker data and the ability to examine sun exposure behaviors are warranted to clarify these associations and examine the phototoxicity mechanisms of furocoumarin-rich foods.
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http://dx.doi.org/10.1007/s10654-020-00666-9DOI Listing
November 2020

Multi-omics Analysis Reveals Adipose-tumor Crosstalk in Patients with Colorectal Cancer.

Cancer Prev Res (Phila) 2020 10 12;13(10):817-828. Epub 2020 Jul 12.

International Agency for Research on Cancer (IARC), Lyon, France.

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma () visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition-as in fibrosis and metastasis-and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 () colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted..
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877796PMC
October 2020

Metabolic Signatures of 10 Processed and Non-processed Meat Products after In Vitro Digestion.

Metabolites 2020 Jul 3;10(7). Epub 2020 Jul 3.

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

The intake of processed meat has been associated with several adverse health outcomes such as type II diabetes and cancer; however, the mechanisms are not fully understood. A better knowledge of the metabolite profiles of different processed and non-processed meat products from this heterogeneous food group could help in elucidating the mechanisms associated with these health effects. Thirty-three different commercial samples of ten processed and non-processed meat products were digested in triplicate with a standardized static in vitro digestion method in order to mimic profiles of small molecules formed in the gut upon digestion. A metabolomics approach based on high-resolution mass spectrometry was used to identify metabolite profiles specific to the various meat products. Processed meat products showed metabolite profiles clearly distinct from those of non-processed meat. Several discriminant features related to either specific ingredients or processing methods were identified. Those were, in particular, syringol compounds deposited in meat during smoking, biogenic amines formed during meat fermentation and piperine and related compounds characteristic of pepper used as an ingredient. These metabolites, characteristic of specific processed meat products, might be used as potential biomarkers of intake for these foods. They may also help in understanding the mechanisms linking processed meat intake and adverse health outcomes such as cancer.
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http://dx.doi.org/10.3390/metabo10070272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408382PMC
July 2020

Metabolic tracking of isoflavones in soybean products and biosamples from healthy adults after fermented soybean consumption.

Food Chem 2020 Nov 11;330:127317. Epub 2020 Jun 11.

Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, South Korea. Electronic address:

Fermentation may enhance the nutritional properties of foods by increasing metabolite bioactivity or bioavailability. This study explored the effect of fermentation on isoflavone bioavailability and metabolism. Isoflavone metabolites were tracked in foods and biospecimens of healthy adults after fermented soybean (FS) or non-fermented soybean (NFS) consumption in a randomized, controlled, crossover intervention study. The change in soybean isoflavones caused by fermentation resulted in faster absorption and higher bioavailability after consumption of FS. Although the urinary level of total isoflavone metabolites was similar after the consumption of the two diets, urinary genistein 7-O-sulfate was derived as a discriminant metabolite for the FS diet by partial least squares discriminant analysis. This study suggests that an isoflavone conjugate profile might be a more appropriate marker than total isoflavone levels for discriminating between the consumption of FS and NFS diets.
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http://dx.doi.org/10.1016/j.foodchem.2020.127317DOI Listing
November 2020

A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.

Metabolism 2020 09 15;110:154292. Epub 2020 Jun 15.

Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, United Kingdom; Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium. Electronic address:

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited.

Methods: To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations.

Results: This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns.

Conclusions: Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight.
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http://dx.doi.org/10.1016/j.metabol.2020.154292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450273PMC
September 2020

A metabolomic study of red and processed meat intake and acylcarnitine concentrations in human urine and blood.

Am J Clin Nutr 2020 08;112(2):381-388

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

Background: Acylcarnitines (ACs) play a major role in fatty acid metabolism and are potential markers of metabolic dysfunction with higher blood concentrations reported in obese and diabetic individuals. Diet, and in particular red and processed meat intake, has been shown to influence AC concentrations but data on the effect of meat consumption on AC concentrations is limited.

Objectives: To investigate the effect of red and processed meat intake on AC concentrations in plasma and urine using a randomized controlled trial with replication in an observational cohort.

Methods: In the randomized crossover trial, 12 volunteers successively consumed 2 different diets containing either pork or tofu for 3 d each. A panel of 44 ACs including several oxidized ACs was analyzed by LC-MS in plasma and urine samples collected after the 3-d period. ACs that were associated with pork intake were then measured in urine (n = 474) and serum samples (n = 451) from the European Prospective Investigation into Cancer and nutrition (EPIC) study and tested for associations with habitual red and processed meat intake derived from dietary questionnaires.

Results: In urine samples from the intervention study, pork intake was positively associated with concentrations of 18 short- and medium-chain ACs. Eleven of these were also positively associated with habitual red and processed meat intake in the EPIC cross-sectional study. In blood, C18:0 was positively associated with red meat intake in both the intervention study (q = 0.004, Student's t-test) and the cross-sectional study (q = 0.033, linear regression).

Conclusions: AC concentrations in urine and blood were associated with red meat intake in both a highly controlled intervention study and in subjects of a cross-sectional study. Our data on the role of meat intake on this important pathway of fatty acid and energy metabolism may help understanding the role of red meat consumption in the etiology of some chronic diseases. This trial was registered at Clinicaltrials.gov as NCT03354130.
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http://dx.doi.org/10.1093/ajcn/nqaa140DOI Listing
August 2020