Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Diet quality and colorectal tumor risk in persons with Lynch syndrome
    Eijkelboom, Anouk H. ; Brouwer, Jesca G.M. ; Vasen, Hans F.A. ; Bisseling, Tanya M. ; Koornstra, Jan J. ; Kampman, Ellen ; Duijnhoven, Fränzel J.B. van - \ 2020
    Cancer Epidemiology 69 (2020). - ISSN 1877-7821
    colorectal cancer - colorectal tumors - diet - healthy diet - hereditary non-polyposis colorectal cancer - Lynch syndrome - risk factors

    Background: Persons with Lynch syndrome (LS) have an increased risk of developing colorectal tumors (CRTs). Adherence to diet quality indices associated with colorectal cancer (CRC) risk in the general population has not been studied before in LS. Methods: Dietary habits of 490 participants with LS from a prospective cohort study was collected using a food frequency questionnaire. The Dutch Healthy Diet index 2015 (DHD15-index) and Dietary Approaches to Stop Hypertension (DASH) were used to score food-based diet quality. Diet quality scores were divided into tertiles where a higher tertile reflects a higher diet quality. Multivariable Cox proportional hazard regression models were used to estimate the association between the DHD15-index, DASH score and CRT risk. Results: During a median follow-up time of 53.4 months, 210 participants (42.9%) developed CRTs. The DHD-index and DASH score were not associated with CRT risk; hazard ratios for highest vs. lowest tertile were 1.00 (95% Confidence Interval (CI): 0.67-1.48) and 1.11 (95% CI: 0.74-1.69), respectively. No linear trends across the DHD-index and DASH score tertiles were observed (P-trend = 0.97 and 0.83 respectively). Conclusion: In contrast to observations in the general population, no evidence for an association between the food-based DHD15-index or DASH score and CRT risk was observed in persons with LS. Further studies are needed investigating the association between diet quality and mechanisms leading to the development of LS-associated tumors.

    Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk
    Thomas, Minta ; Sakoda, Lori C. ; Hoffmeister, Michael ; Rosenthal, Elisabeth A. ; Lee, Jeffrey K. ; Duijnhoven, Franzel J.B. van; Platz, Elizabeth A. ; Wu, Anna H. ; Dampier, Christopher H. ; Chapelle, Albert de la; Wolk, Alicja ; Joshi, Amit D. ; Burnett-Hartman, Andrea ; Gsur, Andrea ; Lindblom, Annika ; Castells, Antoni ; Win, Aung Ko ; Namjou, Bahram ; Guelpen, Bethany Van; Tangen, Catherine M. ; He, Qianchuan ; Li, Christopher I. ; Schafmayer, Clemens ; Joshu, Corinne E. ; Ulrich, Cornelia M. ; Bishop, D.T. ; Buchanan, Daniel D. ; Schaid, Daniel ; Drew, David A. ; Muller, David C. ; Duggan, David ; Crosslin, David R. ; Albanes, Demetrius ; Giovannucci, Edward L. ; Larson, Eric ; Qu, Flora ; Mentch, Frank ; Giles, Graham G. ; Hakonarson, Hakon ; Hampel, Heather ; Stanaway, Ian B. ; Figueiredo, Jane C. ; Huyghe, Jeroen R. ; Minnier, Jessica ; Chang-Claude, Jenny ; Hampe, Jochen ; Harley, John B. ; Visvanathan, Kala ; Curtis, Keith R. ; Offit, Kenneth ; Li, Li ; Marchand, Loic Le; Vodickova, Ludmila ; Gunter, Marc J. ; Jenkins, Mark A. ; Slattery, Martha L. ; Lemire, Mathieu ; Woods, Michael O. ; Song, Mingyang ; Murphy, Neil ; Lindor, Noralane M. ; Dikilitas, Ozan ; Pharoah, Paul D.P. ; Campbell, Peter T. ; Newcomb, Polly A. ; Milne, Roger L. ; MacInnis, Robert J. ; Castellví-Bel, Sergi ; Ogino, Shuji ; Berndt, Sonja I. ; Bézieau, Stéphane ; Thibodeau, Stephen N. ; Gallinger, Steven J. ; Zaidi, Syed H. ; Harrison, Tabitha A. ; Keku, Temitope O. ; Hudson, Thomas J. ; Vymetalkova, Veronika ; Moreno, Victor ; Martín, Vicente ; Arndt, Volker ; Wei, Wei Qi ; Chung, Wendy ; Su, Yu Ru ; Hayes, Richard B. ; White, Emily ; Vodicka, Pavel ; Casey, Graham ; Gruber, Stephen B. ; Schoen, Robert E. ; Chan, Andrew T. ; Potter, John D. ; Brenner, Hermann ; Jarvik, Gail P. ; Corley, Douglas A. ; Peters, Ulrike ; Hsu, Li - \ 2020
    American Journal of Human Genetics 107 (2020)3. - ISSN 0002-9297 - p. 432 - 444.
    cancer risk prediction - colorectal cancer - machine learning - polygenic risk score

    Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

    The association between circulating levels of vitamin D and inflammatory markers in the first 2 years after colorectal cancer diagnosis
    Wesselink, Evertine ; Balvers, Michiel ; Bours, Martijn J.L. ; Wilt, Johannes H.W. de; Witkamp, Renger F. ; Baar, Harm van; Geijsen, Anne J.M.R. ; Halteren, Henk van; Keulen, Eric T.P. ; Kok, Dieuwertje E. ; Kouwenhoven, Ewout A. ; Ouweland, Jody van den; Zutphen, Moniek van; Weijenberg, Matty P. ; Kampman, Ellen ; Duijnhoven, Fränzel J.B. van - \ 2020
    Therapeutic Advances in Gastroenterology 13 (2020). - ISSN 1756-283X
    25(OH)D - colorectal cancer - cytokines - inflammatory markers - interleukin 6

    Background: Calcitriol, the active form of vitamin D, may inhibit colorectal cancer (CRC) progression, which has been mechanistically linked to an attenuation of a pro-inflammatory state. The present study investigated the associations between circulating 25 hydroxy vitamin D3 (25(OH)D3) levels and inflammatory markers (IL10, IL8, IL6, TNFα and hsCRP) in the 2 years following CRC diagnosis. Methods: Circulating 25(OH)D3 levels and inflammatory markers were assessed at diagnosis, after 6, 12 and 24 months from 798 patients with sporadic CRC participating in two prospective cohort studies. Associations between 25(OH)D3 levels and individual inflammatory markers as well as a summary inflammatory z-score were assessed at each time point by multiple linear regression analyses. To assess the association between 25(OH)D3 and inflammatory markers over the course of 2 years, linear mixed model regression analyses were conducted. Results: Higher 25(OH)D3 levels were associated with lower IL6 levels at diagnosis, at 6 months after diagnosis and over the course of 2 years (β −0.06, 95% CI −0.08 to −0.04). In addition, 25(OH)D3 levels were inversely associated with the summary inflammatory z-score at diagnosis and over the course of 2 years (β −0.17, 95% CI −0.25 to −0.08). In addition, a significant inverse association between 25(OH)D3 levels and IL10 was found over the course of 2 years. Intra-individual analyses showed an inverse association between 25(OH)D3 and IL10, IL6 and TNFα. No statistically significant associations between 25(OH)D3 and IL8 and hsCRP levels were observed. Conclusions: Serum 25(OH)D3 levels were inversely associated with the summary inflammatory z-score and in particular with IL6 in the years following CRC diagnosis. This is of potential clinical relevance as IL6 has an important role in chronic inflammation and is also suggested to stimulate cancer progression. Further observational studies should investigate whether a possible 25(OH)D3-associated reduction of inflammatory mediators influences treatment efficacy and CRC recurrence.

    Single Nucleotide Polymorphisms in 25-Hydroxyvitamin D3 1-Alpha-Hydroxylase (CYP27B1) Gene : The Risk of Malignant Tumors and Other Chronic Diseases
    Latacz, Maria ; Snarska, Jadwiga ; Kostyra, Elżbieta ; Fiedorowicz, Ewa ; Savelkoul, Huub F.J. ; Grzybowski, Roman ; Cieślińska, Anna - \ 2020
    Nutrients 12 (2020)3. - ISSN 2072-6643
    breast cancer - chronic diseases - colorectal cancer - CYP27B1 - multiple sclerosis - prostate cancer - single nucleotide polymorphism - vitamin D

    : Vitamin D is widely known for its roles in the promotion of apoptosis and differentiation, with simultaneous inhibition of proliferation, inflammation, angiogenesis, invasion, and metastasis. Modern literature lacks complete information on polymorphisms in CYP27B1, the only enzyme capable of vitamin D activation. This review presents gathered data that relate to genetic variants in CYP27B1 gene in correlation to multiple diseases, mostly concerning colorectal, prostate, breast, lung, and pancreatic cancers, as well as on other pathologies, such as non-Hodgkin's lymphoma, oral lichen planus, or multiple sclerosis.

    One-carbon metabolites, B-vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients: Results from the ColoCare Study
    Kiblawi, Rama ; Holowatyj, Andreana N. ; Gigic, Biljana ; Brezina, Stefanie ; Geijsen, Anne J.M.R. ; Ose, Jennifer ; Lin, Tengda ; Hardikar, Sheetal ; Himbert, Caroline ; Warby, Christy A. ; Böhm, Jürgen ; Bours, Martijn J.L. ; Duijnhoven, Fränzel J.B. Van; Gumpenberger, Tanja ; Kok, Dieuwertje E. ; Koole, Janna L. ; Roekel, Eline H. Van; Schrotz-King, Petra ; Ulvik, Arve ; Gsur, Andrea ; Habermann, Nina ; Weijenberg, Matty P. ; Ueland, Per Magne ; Schneider, Martin ; Ulrich, Alexis ; Ulrich, Cornelia M. ; Playdon, Mary - \ 2020
    The British journal of nutrition 123 (2020)10. - ISSN 0007-1145 - p. 1187 - 1200.
    B-vitamins - colorectal cancer - CRPangiogenesis - folate - folic acid - inflammation - One-carbon metabolism - Vitamin B

    B-vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- A nd angiogenesis-related chronic diseases, such as colorectal cancer. Yet, the role of one-carbon metabolism in inflammation and angiogenesis among colorectal cancer patients remains unclear.The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed colorectal cancer patients (n=238) in the prospective ColoCare Study, Heidelberg.We cross-sectionally analyzed associations between 12 B-vitamins and one-carbon metabolites and 10 inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesized that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers.We observed that PLP was inversely associated with CRP (r=-0.33, plinear<0.0001), SAA (r=-0.23, plinear=0.003), IL-6 (r=-0.39, plinear <0.0001), IL-8 (r=-0.20, plinear=0.02) and TNFα (r=-0.12, plinear=0.045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r=-0.14), SAA (r=-0.14) and TNFα (r=-0.15) among colorectal cancer patients. Folate catabolite apABG was positively correlated with IL-6 (r= 0.27, plinear<0.0001) and pABG was positively correlated with IL-8 (r= 0.21, plinear<0.0001), indicating higher folate utilization during inflammation.Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among colorectal cancer patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for colorectal cancer patients.

    Systematic meta-Analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer
    Montazeri, Zahra ; Li, Xue ; Nyiraneza, Christine ; Ma, Xiangyu ; Timofeeva, Maria ; Svinti, Victoria ; Meng, Xiangrui ; He, Yazhou ; Bo, Yacong ; Morgan, Samuel ; Castellví-Bel, Sergi ; Ruiz-Ponte, Clara ; Fernández-Rozadilla, Ceres ; Carracedo, Ángel ; Castells, Antoni ; Bishop, Timothy ; Buchanan, Daniel ; Jenkins, Mark A. ; Keku, Temitope O. ; Lindblom, Annika ; Duijnhoven, Fränzel J.B. Van; Wu, Anna ; Farrington, Susan M. ; Dunlop, Malcolm G. ; Campbell, Harry ; Theodoratou, Evropi ; Zheng, Wei ; Little, Julian - \ 2020
    Gut 69 (2020). - ISSN 0017-5749 - p. 1460 - 1471.
    colorectal cancer

    Objective: To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2). Design: We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-Analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-Analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as â € positive' and â € less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin. Results: We initially identified 18 independent variants at 16 loci that were classified as â € positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as â € less-credible positive' SNPs; 72.2% of the â € positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to â € less-credible' positive (reducing the â € positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-Analyses found no evidence to support their associations with CRC risk. Conclusion: The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.

    Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium
    Geijsen, Anne J.M.R. ; Roekel, Eline H. van; Duijnhoven, Fränzel J.B. van; Achaintre, David ; Bachleitner-Hofmann, Thomas ; Baierl, Andreas ; Bergmann, Michael M. ; Boehm, Jürgen ; Bours, Martijn J.L. ; Brenner, Hermann ; Breukink, Stéphanie O. ; Brezina, Stefanie ; Chang-Claude, Jenny ; Herpel, Esther ; Wilt, Johannes H.W. de; Gicquiau, Audrey ; Gigic, Biljana ; Gumpenberger, Tanja ; Hansson, Bibi M.E. ; Hoffmeister, Michael ; Holowatyj, Andreana N. ; Karner-Hanusch, Judith ; Keski-Rahkonen, Pekka ; Keulen, Eric T.P. ; Koole, Janna L. ; Leeb, Gernot ; Ose, Jennifer ; Schirmacher, Peter ; Schneider, Martin A. ; Schrotz-King, Petra ; Stift, Anton ; Ulvik, Arve ; Vogelaar, Jeroen F. ; Wesselink, Evertine ; Zutphen, Moniek van; Gsur, Andrea ; Habermann, Nina ; Kampman, Ellen ; Scalbert, Augustin ; Ueland, Per M. ; Ulrich, Alexis B. ; Ulrich, Cornelia M. ; Weijenberg, Matty P. ; Kok, Dieuwertje E. - \ 2020
    International Journal of Cancer 146 (2020)12. - ISSN 0020-7136 - p. 3256 - 3266.
    colorectal cancer - disease stage - epidemiology - metabolomics - plasma metabolites

    Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I–IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I–IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.

    Editorial : Diet, Inflammation and Colorectal Cancer
    Gessani, Sandra ; Duijnhoven, Fränzel J. Van; Moreno-Aliaga, Maria Jesus - \ 2019
    Frontiers in Immunology 10 (2019). - ISSN 1664-3224
    colorectal cancer - diet - dietary factors - inflammation - obesity
    Concordance with the World Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention and colorectal cancer risk in Morocco : A large, population-based case–control study
    Kinany, Khaoula El; Huybrechts, Inge ; Kampman, Ellen ; Boudouaya, Hanae Abir ; Hatime, Zineb ; Mint Sidi Deoula, Meimouna ; Asri, Achraf El; Benslimane, Abdelilah ; Nejjari, Chakib ; Ibrahimi, Sidi Adil ; Mrabti, Hind ; Abda, Naima ; Alaoui, Rhimou ; Gunter, Marc J. ; Rhazi, Karima El - \ 2019
    International Journal of Cancer (2019). - ISSN 0020-7136
    case–control study, FFQ, Morocco - colorectal cancer - WCRF/AICR recommendations

    The present study aimed to investigate associations between adherence to the recommendations on cancer prevention from the WCRF/AICR and colorectal cancer (CRC) risk in Morocco. Incident CRC cases (n = 1,516) and controls (n = 1,516) matched on age, sex and center, were recruited between September 2009 and February 2017 at five major hospitals located in Morocco. In-person interviews were conducted to assess habitual diet using a validated Food Frequency Questionnaire, physical activity and anthropometric measurements. Adherence to the WCRF/AIRC Recommendations was ranged from 0 (no adherence) to 6 (maximal adherence) and incorporating six WCRF/AICR components (food groups, physical activity and BMI). Multivariable odd ratios (OR A ) and 95% confidence intervals (CI) were calculated using conditional multivariate logistic regression models, with low adherence as referent, adjusting for potential confounding factors. Compared to those with the lowest adherence score, individuals in the highest WCRF/AICR score category had a statistically significant reduced risk for colon cancer (OR A = 0.63, 95% CI 0.53–0.76); rectal cancer (OR A = 0.52, 95% CI 0.43–0.63) and CRC overall (OR A = 0.58, 95% CI 0.51–0.66). For individual score components, when comparing the lowest with the highest adherence category, CRC risk was significantly lower in the highest adherence category for body fatness (OR A = 0.73; 95% CI 0.62–0.85), physical activity (OR A = 0.70; 95% CI 0.60–0.82), plant foods (OR A = 0.50; 95% CI 0.39–0.63) and red/processed meat (OR A = 0.81; 95% CI 0.71–0.92). Our analysis indicated that greater adherence to the WCRF/AICR recommendations for cancer prevention may lower CRC risk in Morocco.

    Plasma metabolites associated with colorectal cancer: A discovery-replication strategy
    Geijsen, Anne J.M.R. ; Brezina, Stefanie ; Keski-Rahkonen, Pekka ; Baierl, Andreas ; Bachleitner-Hofmann, Thomas ; Bergmann, Michael M. ; Boehm, Juergen ; Brenner, Hermann ; Chang-Claude, Jenny ; Duijnhoven, Fränzel J.B. van; Gigic, Biljana ; Gumpenberger, Tanja ; Hofer, Philipp ; Hoffmeister, Michael ; Holowatyj, Andreana N. ; Karner-Hanusch, Judith ; Kok, Dieuwertje E. ; Leeb, Gernot ; Ulvik, Arve ; Robinot, Nivonirina ; Ose, Jennifer ; Stift, Anton ; Schrotz-King, Petra ; Ulrich, Alexis B. ; Ueland, Per Magne ; Kampman, Ellen ; Scalbert, Augustin ; Habermann, Nina ; Gsur, Andrea ; Ulrich, Cornelia M. - \ 2019
    International Journal of Cancer 145 (2019)5. - ISSN 0020-7136 - p. 1221 - 1231.
    colorectal cancer - discovery-replication approach - metabolomics - UHPLC-QTOF-MS

    Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.

    Bowel Biofilms: Tipping Points between a Healthy and Compromised Gut?
    Tytgat, Hanne L.P. ; Nobrega, Franklin L. ; Oost, John van der; Vos, Willem M. de - \ 2019
    Trends in Microbiology 27 (2019)1. - ISSN 0966-842X - p. 17 - 25.
    biofilm - colorectal cancer - microbiota - tipping points

    Bacterial communities are known to impact human health and disease. Mixed species biofilms, mostly pathogenic in nature, have been observed in dental and gastric infections as well as in intestinal diseases, chronic gut wounds and colon cancer. Apart from the appendix, the presence of thick polymicrobial biofilms in the healthy gut mucosa is still debated. Polymicrobial biofilms containing potential pathogens appear to be an early-warning signal of developing disease and can be regarded as a tipping point between a healthy and a diseased state of the gut mucosa. Key biofilm-forming pathogens and associated molecules hold promise as biomarkers. Criteria to distinguish microcolonies from biofilms are crucial to provide clarity when reporting biofilm-related phenomena in health and disease in the gut.

    Oral Nutrition as a Form of Pre-Operative Enhancement in Patients Undergoing Surgery for Colorectal Cancer : A Systematic Review
    Bruns, Emma R.J. ; Argillander, Tanja E. ; Heuvel, Baukje Van Den; Buskens, Christianne J. ; Duijvendijk, Peter Van; Winkels, Renate M. ; Kalf, Annette ; Zaag, Edwin S. Van Der; Wassenaar, Eelco B. ; Bemelman, Willem A. ; Munster, Barbara C. Van - \ 2018
    Surgical Infections 19 (2018)1. - ISSN 1096-2964 - p. 1 - 10.
    colorectal cancer - nutrition - prehabilitation - surgery
    Background: Nutritional status has major impacts on the outcome of surgery, in particular in patients with cancer. The aim of this review was to assess the merit of oral pre-operative nutritional support as a part of prehabilitation in patients undergoing surgery for colorectal cancer. Methods: A systematic literature search and meta-analysis was performed according to the Preferred Reporting of Systematic Reviews and Meta-Analyses (PRISMA) recommendations in order to review all trials investigating the effect of oral pre-operative nutritional support in patients undergoing colorectal surgery. The primary outcome was overall complication rate. Secondary outcomes were incision infection rate, anastomotic leakage rate, and length of hospital stay. Results: Five randomized controlled trials and one controlled trial were included. The studies contained a total of 583 patients with an average age of 63 y (range 23-88 y), of whom 87% had colorectal cancer. Malnourishment rates ranged from 8%-68%. All investigators provided an oral protein supplement. Overall patient compliance rates ranged from 72%-100%. There was no significant reduction in the overall complication rate in the interventional groups (odds ratio 0.82; 95% confidence interval 0.52 - 1.25). Conclusion: Current studies are too heterogeneous to conclude that pre-operative oral nutritional support could enhance the condition of patients undergoing colorectal surgery. Patients at risk have a relatively lean body mass deficit (sarcopenia) rather than an absolute malnourished status. Compliance is an important element of prehabilitation. Targeting patients at risk, combining protein supplements with strength training, and defining standardized patient-related outcomes will be essential to obtain satisfactory results.
    Dietary supplement use and colorectal tumors : from prevention to diagnosis
    Bröring, R.C. - \ 2015
    Wageningen University. Promotor(en): Ellen Kampman, co-promotor(en): Renate Winkels. - Wageningen : Wageningen University - ISBN 9789462575011 - 213
    voedselsupplementen - colorectaal kanker - adenoom - risicoanalyse - risicovermindering - levensstijl - kwaliteit van het leven - cohortstudies - kankerbestrijdende eigenschappen - anticarcinogene eigenschappen - terugval - preventie - food supplements - colorectal cancer - adenoma - risk analysis - risk reduction - lifestyle - quality of life - cohort studies - anticancer properties - anticarcinogenic properties - relapse - prevention

    Background: Expert guidelines formulated by the World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR) advised no use of dietary supplements for cancer prevention. However, it is unclear whether those recommendations also apply to populations at high risk for incident or recurrent colorectal tumors specifically, since dietary supplement use is ubiquitous in western countries where colorectal tumors are common. Furthermore, before the association between dietary supplement use and recurrence and survival in colorectal cancer patients can be examined, more information about the consistency of dietary supplement use is needed, as it is plausible that use varies over time after colorectal cancer diagnosis. This thesis focuses on the association between dietary supplement use and colorectal tumor risk and recurrence in the general population and in high-risk populations, and describes the consistency of use in patients who were diagnosed with colorectal cancer.

    Methods and results: First, we conducted a systematic literature review with meta-analyses of observational studies about the association between dietary supplement use and colorectal cancer risk. Our findings suggested inverse associations between multivitamins (use versus no use: RR=0.92; 95% CI 0.87–0.97, calcium supplements (use versus no use: RR=0.86; 95% CI 0.79–0.95) and colorectal cancer risk, while the association for other supplements and colorectal cancer risk was inconsistent.

    Second, we investigated the role of dietary supplements in recurrence of colorectal adenomas and advanced colorectal adenomas in a prospective cohort study of 565 patients with a history of sporadic colorectal adenomas. Dietary supplement was not associated with total adenoma recurrence (HR=1.03; 95% CI 0.79–1.34).

    Third, dietary supplement use and colorectal adenoma risk was examined in a prospective cohort study among 470 individuals with Lynch syndrome. No associations were found between dietary supplement use (HR=1.18; 95% CI 0.80–1.73) and colorectal adenoma risk in these individuals.

    Finally, in an ongoing prospective cohort study among incident colorectal cancer patients we evaluated whether dietary supplement use was consistent over time. Dietary supplement use was extensively assessed with a detailed self-administered questionnaire at diagnosis, six months and two years post-diagnosis. We observed that dietary supplement use among 160 colorectal cancer patients was common at all time points, but use was inconsistent from diagnosis to two years post-diagnosis.

    Conclusion: The results in this thesis do not point toward a preventive nor a harmful role for dietary supplement use in colorectal tumor risk and recurrence in the general population and in high-risk populations for colorectal cancer. However, dietary supplement use appeared to be inconsistent over time after colorectal cancer diagnosis, and use should be repetitively assessed over time. Since dietary supplement use is rising in countries where colorectal tumors are prevalent and the incidence of colorectal tumors will increase due to screening practices, research on the role of dietary supplement use for primary or tertiary prevention of colorectal tumors should continue in which use should be repetitively and comprehensively assessed.

    Red meat and colon cancer : how dietary heme initiates hyperproliferation
    IJssennagger, N. - \ 2012
    Wageningen University. Promotor(en): Michael Muller, co-promotor(en): Roelof van der Meer. - S.l. : s.n. - ISBN 9789461733931 - 160
    vlees - karteldarmkanker - haem - weefselproliferatie - dieet - colorectaal kanker - darmmicro-organismen - darmslijmvlies - meat - colon cancer - haem - tissue proliferation - diet - colorectal cancer - intestinal microorganisms - intestinal mucosa

    Colorectal cancer is a leading cause of cancer deaths in Western countries. The risk to develop colorectal cancer is associated with the intake of red meat. Red meat contains the porphyrin pigment heme. Heme is an irritant for the colonic wall and it is previously shown that the addition of heme to the diet of rats induces hyperproliferation. Hyperproliferation increases the risk of endogenous mutations, which subsequently increases the risk to develop colon cancer. The aim of this thesis was to elucidate the diet-modulated signaling from an injured surface epithelium to the proliferative stem cells in the crypt to initiate compensatory hyperproliferation.

    In chapter 2 we showed that when heme is added to the diet of mice, there is an increased cytotoxicity of the colonic contents. Heme-fed mice showed decreased apoptosis and increased compensatory epithelial hyperproliferation resulting in hyperplasia. Gene expression levels of mouse colon after heme feeding were analyzed by microarrays and showed 3,710 differentially expressed genes (q<0.01) of which many were involved in proliferation and stress response. Stainings for the enzyme Heme oxygenase-1 and expression levels of heme- and stress-related genes showed that heme affected the epithelial surface cells, but that heme did not reach the crypt cells. Heme caused injury of the surface epithelial cells, and as proliferation originates from the stem cells in the crypts this implied that there must be a signaling mechanism from the injured surface to the stem cells in the crypts to start the hyperproliferation. In chapter 2 several surface to crypt signaling molecules were identified. Heme downregulated inhibitors of proliferation, such as Wnt inhibitory factor 1, Indian hedgehog and Bone morphogenetic protein 2. Furthermore, heme downregulated the cytokine Interleukin-15. Heme upregulated the expression of the growth factors Amphiregulin, Epiregulin and of Cyclooxygenase-2 mRNA in the surface. However, their protein/metabolite levels were not increased as heme induced surface-specific inhibition of translation by increasing the levels of the translation inhibitor 4E-BP1. We concluded that heme induced colonic hyperproliferation and hyperplasia by downregulating the surface to crypt signaling of feedback inhibitors of proliferation.

    Besides many proliferation and stress-related genes, many PPARα target genes were upregulated upon heme feeding. As PPARα is proposed to protect against oxidative stress and lipid peroxidation, we hypothesized in chapter 3 that absence of PPARα leads to more colonic surface injury, which subsequently leads to increased compensatory hyperproliferation in colonic crypts upon heme-feeding. This hypothesis was tested using wild-type and PPARα knockout mice receiving a heme diet. Proliferation levels and gene expression profiles were determined. Heme induced luminal cytotoxicity and lipid peroxidation to the same extent in wild-type and PPARα knockout mice. We showed that PPARα does not play a role in the heme-induced hyperproliferation, as heme induced hyperproliferation both in wild-type as well as in PPARα knockout mice. Stainings for alkaline phosphatase activity and expression levels of Vanin-1 and Nrf2-targets indicated a compromised antioxidant defense in the heme-fed PPARα knockout mice. We concluded that PPARα plays a protective role in colon against oxidative stress, but PPARα does not mediate heme-induced hyperproliferation. This implied that oxidative stress of surface cells is not the main determinant of heme-induced hyperproliferation and hyperplasia.

    Heme was shown to increase both reactive oxygen species as well as cytotoxicity of the colonic contents of mice. So far, the time dependency of the heme-induced oxidative stress and cytotoxic stress on the initiation of hyperproliferation was not studied. Therefore, in chapter 4 the effects of dietary heme on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding were determined. This study showed that the effects of dietary heme on the colonic mucosa can be separated in acute and delayed effects. Acutely, heme increased oxidative stress which caused an increase in lipid peroxidation products. Besides, there was an acute activation of PPARα target genes, most probable induced by the generated oxidized lipids. Nrf2 target genes were activated acutely which played a role in the protection against oxidative stress. Delayed effects which occurred after day 4 of heme feeding, were increased luminal cytotoxicity and the induction of hyperproliferation. This suggested that the cytotoxicity, rather than oxidative stress, induced hyperproliferation. Remarkably, the surface epithelial cells sensed heme after day 4, although heme was present in the colon several hours after ingestion of the heme diet. This suggested that the mucus barrier played a role in the protection of the surface epithelium the first days of heme feeding.

    As the colon is densely populated by bacteria, the microbiota might play a role in modulating the surface to crypt signaling inducing hyperproliferation. To explore the role of the colonic microbiota we simultaneously investigated the effects of dietary heme on colonic microbiota and on the host mucosa of mice (chapter 5). Using 16S rRNA phylogenetic microarrays, it was determined that heme increased Bacteroidetes and decreased Firmicutes in colonic contents. This shift in the microbiota was most likely caused by a selective susceptibility of Gram-positive bacteria to heme cytotoxic fecal water. This susceptibility was not observed for Gram-negative bacteria and allowed the expansion of the Gram-negative community. The increased amount of Gram-negative bacteria, which likely caused an increased mucosal exposure to lipopolysaccharide (LPS), did not elicit a detectable immune reaction in the host mucosa. The absence of an immune reaction might be influenced by the strong upregulation of Secretory leukocyte peptidase inhibitor (Slpi) at gene and protein level, which is known to suppress excessive immune reactions. We showed that there was no functional change in the sensing of the bacteria by the mucosa, as changes in inflammation pathways and Toll- like receptor signaling were not detected. In conclusion, the change in microbiota did not cause the observed hyperproliferation and hyperplasia via inflammation pathways.

    In the study described in chapter 6 we investigated whether microbiota play a causal role in the heme-induced hyperproliferation. In this study mice received a control or a heme diet with or without broad spectrum antibiotics (Abx). Similar to previous experiments, heme induced epithelial hyperproliferation. Interestingly, when heme was administered together with Abx there was no induction of hyperproliferation. Heme induced oxidative stress in the heme group as well as in the heme plus Abx group. Cytotoxicity was also induced in both heme groups. As bacteria were decreased by 100 to 1000 fold in abundance upon Abx treatment it is unlikely that bacteria play a major role in the formation of the cytotoxic factor. Whole genome transcriptomics showed that Abx blocked the heme-induced differential expression of oncogenes, tumor suppressors and cell turnover genes. Moreover, Abx blocked the mucosal sensing of luminal cytotoxicity indicating that Abx increased the mucus barrier. Abx eliminated mucin-degrading bacteria, such as Akkermansia, and sulfate-reducing bacteria (SRBs) that produce sulfide. In-vitro studies showed that sulfide is more potent than N-acetylcysteine and cysteine in splitting disulfide bonds, indicating that SRB generated sulfide can denature mucins and thus open the mucus barrier. This study showed that the microbiota plays an important facilitating role in the heme-induced hyperproliferation and hyperplasia by breaking the mucus barrier and thereby decreasing the protection against luminal irritants such as the toxic heme metabolite.

    Modifiable risk factors and colorectal adenomas among those at high risk of colorectal cancer
    Botma, A. - \ 2011
    Wageningen University. Promotor(en): Ellen Kampman; H.F.A. Vasen, co-promotor(en): F.M. Nagengast. - [S.l.] : S.n. - ISBN 9789461730435 - 127
    colorectaal kanker - risicofactoren - adenoom - quetelet index - tabak roken - alcoholinname - dieet - epidemiologische onderzoeken - cohortstudies - colorectal cancer - risk factors - adenoma - body mass index - tobacco smoking - alcohol intake - diet - epidemiological surveys - cohort studies

    Epidemiological studies have identified several modifiable risk factors for colorectal neoplasms in the general population. However, associations between modifiable risk factors, including body mass index (BMI), smoking, alcohol consumption and dietary patterns, and colorectal neoplasms in two groups at high risk of colorectal cancer, Lynch syndrome patients and sporadic adenoma patients, have been sparsely studied.

    This thesis presents two cohort studies, one of 486 Lynch syndrome patients (the GEOLynch cohort study) and one including data from 565 persons with sporadic adenomas (the POLIEP follow-up study), in which we assessed whether a high BMI, smoking, high alcohol consumption and specific dietary patterns influenced colorectal adenoma development. We also assessed whether the association between BMI and recurrence of sporadic adenomas was modified by polymorphisms in the insulin-like growth factor (IGF) genes.

    First, we observed that excess body weight increased the risk of incident colorectal adenomas in men with Lynch syndrome. Secondly, we showed that current smoking increased the risk of colorectal adenomas in Lynch syndrome in both sexes. Former smokers still showed an elevated risk, but lower than current smokers. Number of years smoked, among ever smokers, was positively associated with colorectal adenomas. A clear association with alcohol consumption was not observed. Thirdly, we identified four dietary patterns in the Lynch syndrome cohort; i) ‘Prudent’, ii) ‘Meat’, iii) ‘Snack’, vi) ‘Cosmopolitan’. The ‘Snack’ pattern was associated with increased adenoma occurrence. The other patterns showed Hazard Ratios in the expected directions based on similar studies in the general population but these were not statistically significantly associated with adenoma occurrence. Additionally, among 565 sporadic adenoma patients, we found that BMI was not associated with adenoma recurrence (n=165), nor with recurrence of advanced adenomas (n=37) after a median of 4.7 years of follow-up. Variation in IGF-axis genes (rs1520220 in IGF1 and rs3213221 in IGF2) influenced the likelihood of colorectal adenoma recurrence. Furthermore, we observed that the association between BMI and adenoma recurrence was modified by variation in the IGF2 gene (rs1004446 and rs1003483). Finally, the three dietary patterns identified (‘Low meat’, ‘Cosmopolitan’, or ‘Refined foods’) among the sporadic adenoma patients did not show marked associations with adenoma recurrence, although the ‘Low meat’ pattern might reduce the risk of advanced recurrences. No significant associations were seen for smoking and alcohol consumption.

    Overall, the results of our Lynch syndrome cohort suggest that modifiable risk factors, e.g. high BMI and smoking, influence colorectal adenoma development in Lynch syndrome patients. On the other hand, these risk factors do not appear to influence recurrence of sporadic colorectal adenomas.

    Fish consumption, does it beneficially affect markers of colorectal carcinogenesis?
    Pot, G.K. - \ 2009
    Wageningen University. Promotor(en): Ellen Kampman; G. Schaafsma, co-promotor(en): Anouk Geelen. - [S.l. : S.n. - ISBN 9789085854456 - 118
    visconsumptie - colorectaal kanker - carcinogenese - fish consumption - colorectal cancer - carcinogenesis
    Background: Fish consumption is possibly associated with a decreased risk of colorectal cancer, as has been shown in several observational studies. However, most of these studies did not discriminate between the effects of oil-rich and lean fish. To date, no randomized controlled trials (RCTs) have examined the possible beneficial effects of fish intake on colorectal cancer risk.
    Aim: The aim of this thesis was to investigate whether fish consumption beneficially affects markers of colorectal carcinogenesis.
    Methods and Results: In a case control study (363 cases, 498 controls), we studied the association of serum n 3 polyunsaturated fatty acid (PUFA) levels as a marker of oil rich fish intake with colorectal adenomas, a precursor lesion of colorectal cancer. We found that individuals with high serum long chain n 3 PUFA levels had a decreased risk of colorectal adenomas (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.46; 0.96), whereas individuals with high serum n 6 PUFA levels had an increased risk of colorectal adenomas (OR 1.68, 95% CI 1.17; 2.42).
    In an RCT, we studied the effects of 3.5g/d fish oil (~1.5g/d n 3 PUFA) for 12 weeks on 19 serum inflammation markers in 77 healthy subjects and found that serum levels of these cytokines and chemokines were not changed.
    Finally, we studied the effects of increasing fish consumption compared with no additional fish, on markers of colorectal carcinogenesis in an RCT. Subjects (n=242), at an increased risk of colorectal cancer and those with no macroscopic signs of disease, were randomly allocated to receive dietary advice (DA) plus either two additional weekly portions of oil rich fish (salmon, ~1.4g/d n 3 PUFA) or lean fish (cod, ~0.09 g/d n 3 PUFA), or only DA for six months. We observed no change in apoptotic and mitotic cell numbers after the 6 months intervention with either salmon or cod compared with DA. Furthermore, colorectal genotoxicity, levels of cytokines and chemokines in colonic biopsies and feces, and fecal calprotectin were also not markedly changed after fish consumption. Only serum C reactive protein (CRP) levels were statistically significantly decreased after consumption of salmon ( 0.5 mg/l, 95% CI 0.9; 0.2) and cod ( 0.4 mg/l, 95% CI 0.7; 0.0) compared with DA.
    Conclusion: The results of this thesis do not provide strong evidence for beneficial effects of fish consumption on markers of colorectal carcinogenesis.

    Fruits and vegetables, detoxification genes and intermediate endpoints in colorectal cancer prevention
    Tijhuis, M.J. - \ 2008
    Wageningen University. Promotor(en): Frans Kok, co-promotor(en): Ellen Kampman; Jac Aarts. - [S.l.] : S.n. - ISBN 9789085047490 - 183
    colorectaal kanker - ziektepreventie - vruchten - groenten - voedselconsumptie - voedselopname - ontgifting - enzymen - genetische variatie - colorectal cancer - disease prevention - fruits - vegetables - food consumption - food intake - detoxification - enzymes - genetic variation
    Het eten van groenten en fruit verkleint mogelijk de kans op dikke darmkanker door te stimuleren dat schadelijke stoffen onschadelijk gemaakt worden (ontgifting). Mensen verschillen in hun ontgiftingsvermogen doordat ze verschillend eten, maar ook door genetische aanleg. In het proefschrift wordt het samenspel onderzocht tussen het eten van groenten en fruit en genetische verschillen in twee typen ontgiftingseiwitten, GST en NQO1. Bij 94 mensen is nagegaan in hoeverre groente- en fruitconsumptie en aangeboren verschillen de hoeveelheid GST- en NQO1-eiwitten in darmweefsel en bloed beïnvloeden. Bij 1450 mensen, van wie de helft darmpoliepen had, is bekeken of het vóórkomen van dit voorstadium van dikke darmkanker samenhangt met groente- en fruitconsumptie en aangeboren verschillen in GST en NQO1. Er bleek geen gunstiger effect van groenten en fruit voor mensen met bepaalde aangeboren verschillen. Er hoeft geen aangepast advies voor groente- en fruitconsumptie te worden gegeven op basis van aangeboren variatie in de onderzochte ontgiftingseiwitten.
    Biomarkers of quercetin-mediated modulation of colon carcinogenesis
    Dihal, A.A. - \ 2007
    Wageningen University. Promotor(en): Ivonne Rietjens, co-promotor(en): R.H. Stierum; Ruud Woutersen. - [S.l.] : S.n. - ISBN 9789085046783 - 240
    biochemische merkers - quercetine - colorectaal kanker - biochemical markers - quercetin - colorectal cancer
    Colorectal cancer (CRC) is hypothesized to be prevented by intake of fruits and vegetables that contain anti-carcinogenic compounds, including theflavonoidquercetinthat is found in apples and onions. In this thesis,quercetin'smechanisms of cancer-preventive action were studied both in vitro and in vivo . The in vitro experiments were performed using the human Caco-2 cell line as a model for CRC, andquercetinstabilized byascorbatein the culture medium. Unexpectedly,ascorbate-stabilizedquercetinshowed enhancement of cellular processes involved in CRC-development, including stimulated cell proliferation, reduced cell differentiation and enhancement of pathways that stimulate cell survival. Furthermore,transcriptomicsshowed thatquercetindownregulatedexpression of genes involved intumorsuppression and phase II metabolism, andupregulatedoncogenes. Comparison with Caco-2 cells exposed toquercetinin the absence ofascorbateshowed the opposite, i.e. anti-carcinogenic effects by thisflavonoid. This led to the hypothesis thatquercetin-induced reactive oxygen species that eradicatetumorcells were scavenged by vitamin C, causingtumorcell survival. Withoutascorbate, these reactive oxygen species may be responsible for anti-carcinogenic effects, pointing to beneficial effects of supposed adverse reactive intermediates.

    Subsequently, the CRC-modulating potency ofquercetinand its conjugaterutinwere investigated in a rat model for CRC.Quercetin, but not its conjugaterutindecreased thetumorincidence, which was associated with the blood plasma levels of this anti-oxidant, but not reflected by the putativepreneoplasticbiomarker lesions, designated aberrant crypt foci. The combination oftranscriptomicsand proteomics showed thatquercetininhibited the potentiallyoncogenicmitogen-activated proteinkinase(Mapk) pathway and enhanced expression oftumorsuppressor genes, cell cycle inhibitors, and genes involved inxenobioticmetabolism. In addition,quercetinaffected the energy production pathways, by increasing mitochondrial fatty acid degradation, and inhibitingglycolysis. This observation provided a new hypothesis pointing at another anti-carcinogenic mechanism forquercetin, based on an alteration in routes for energy metabolism, shifting them infavorof non-tumorlike pathways like mitochondrial fatty acid degradation at the cost of thetumor-likeglycolyticpathway for cellular energy supply.

    Overall, the studies presented in the present thesis provided new hypotheses for the mode of action ofquercetinas an anti-tumoragent, but it appeared that the actual dose needed to exert this beneficial effect amounted to about 60 - 100 times the already relatively high prescribed dose forquercetinsupplements. Therefore, it is concluded that health claims on the use ofquercetinas an anti-cancer agent need better scientific support.
    Towards functional effects of polyphenols : modulation of energy metabolism revealed
    Boer, V.C.J. de - \ 2007
    Wageningen University. Promotor(en): Ivonne Rietjens, co-promotor(en): Jaap Keijer; Peter Hollman. - [S.l.] : S.n. - ISBN 9789085046080 - 184
    quercetine - weefselverdeling - colorectaal kanker - energiemetabolisme - quercetin - tissue distribution - colorectal cancer - energy metabolism
    A diet rich in fruits and vegetables contains high levels of polyphenols (up to 1 gram per day). Epidemiological studies suggest that a high dietary intake of selected polyphenols can be protective against development of cardiovascular heart diseases in humans. In addition, mechanistic studies demonstrate that polyphenols possess beneficial properties ininvitro and animal model systems. Due to the possible beneficial health effects of polyphenols, they are currently being sold extensively as food supplements. However, the basis for most of the health claims attributed to polyphenols in food supplements is often very small. Our objective was to elucidate relevant mechanisms of action of selected polyphenols. We studied the tissue distribution and in vivo physiological effects of quercetin (a polyphenol abundant in the human diet) after chronic dietary exposure, followed by in vitro elucidation of possible biological mechanisms. We revealed lungs as novel tissue target of quercetin and demonstrated that dietary quercetin alters fatty acid catabolism pathways in rats. In addition, dietary quercetin lowered tumor incidence in the colon of rats in a model of colon carcinogenesis. Furthermore, a major in vivo metabolite of quercetin, quercetin 3-O-glucuronide, opposed the effect of quercetin aglycone on SIRT1 activation in vitro , whereas quercetin 3-O-glucuronide attenuated glucose utilization in cultured adipocytes in a similar fashion as quercetin aglycone. Although we used high dietary dosages of quercetin and further studies should elucidate physiological effects of a normal dietary intake of polyphenols, the experiments described in this thesis point to a possible beneficial effect of dietary polyphenols. However, as long as the molecular mechanisms in humans are unknown and the risk of increasing dietary intakes of polyphenols via food supplements is not thoroughly investigated, there is no scientific justification for supplementing the diet with large amounts of polyphenols. Nevertheless, our approach successfully identified modulation of energy metabolism by polyphenols as an important process involved in mediating the possible health effects associated with dietary polyphenol intake.
    Biobeschikbaarheid van enterolignans en hun relatie met chronische ziekten = Bioavailability of enterolignans and their relation with chronic diseases
    Kuijsten, A. - \ 2007
    Wageningen University. Promotor(en): Pieter van 't Veer; Frans Kok, co-promotor(en): Peter Hollman. - [S.l.] : S.n. - ISBN 9789085045823 - 183
    lignanen - colorectaal kanker - adenoom - hartziekten - biologische beschikbaarheid - lijnzaad - ziektepreventie - lignans - colorectal cancer - adenoma - heart diseases - bioavailability - linseed - disease prevention
    Keywords:Lignans; enterodiol; enterolactone; plasma; flaxseed;bioavailability; liquid chromatography; mass spectrometry; case-control studies; prospective studies; colorectal adenomas; colorectal carcinomas; coronary heart diseases

    Lignans are biphenolic compounds that occur in foods of plant origin. Some of the plant lignans can be converted into the enterolignans, enterodiol and enterolactone, by the microorganisms in the colon. Because of their biological activities, enterolignans may affect the development of chronic diseases. It is not sufficiently known to what extent enterolignans become bioavailable, i.e., are absorbed and used for metabolic processes in the body.

    The aim of the present research was to gain further insight in the bioavailability of enterolignans and in their relation with several chronic diseases. To be able to do this, we developed a liquid chromatography-tandem mass spectrometry method using triply 13 C-labeled isotopes for the simultaneous quantification of enterodiol and enterolactone in plasma.

    Enterodiol and enterolactone absorption started 8 to 10 hours after consumption of secoisolariciresinol diglucoside, an isolated plant lignan, and they were eliminated slowly. A substantial part (~40%) of the enterolignans was excreted in urine, and thus had been available in the blood circulation. Because of the slow elimination, enterolignans will accumulate and reach steady state concentrations in plasma when consumed 2 to 3 times a day. As lignans are present in many foods this is very likely to happen. The bioavailability of lignans from flaxseeds, a high lignan source, improved substantially when whole seeds were replaced by crushed or ground seeds. Independent determinants of plasma concentrations of enterolignans were, besides the intake of plant lignans, use of antibiotic therapy, defecation frequency, and body mass index.

    Our data suggest a protective role of enterolignans against colorectal adenomas; the risk reduction was ~2-fold in highest versus lowest quartile of enterolignan plasma concentrations. However, a protective effect could not be confirmed for colorectal carcinomas. Moreover, we observed increased risks (~2.5-fold) in women, especially in postmenopausal women, and in subjects with a high body mass index. This suggests that an estrogen-related hormonal mechanism might be involved. In addition, our data do not support a protective role of enterolignans against the development of nonfatal myocardial infarction.

    In conclusion, a substantial part of the enterolignans enters the blood circulation and is subsequently excreted in urine. Enterolignans might protect against colorectal adenomas. We did not find protective associations for colorectal carcinomas and myocardial infarction. At this point, there is not enough evidence to give recommendations regarding the consumption of foods rich in lignans.
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