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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    Gut dysbacteriosis and intestinal disease: mechanism and treatment
    Meng, X. ; Zhang, G. ; Cao, H. ; Yu, D. ; Fang, X. ; Vos, W.M. de; Wu, H. - \ 2020
    Journal of Applied Microbiology (2020). - ISSN 1364-5072
    gut microbiome - immune response - intestinal diseases - prebiotics - probiotics

    The gut microbiome functions like an endocrine organ, generating bioactive metabolites, enzymes or small molecules that can impact host physiology. Gut dysbacteriosis is associated with many intestinal diseases including (but not limited to) inflammatory bowel disease, primary sclerosing cholangitis-IBD, irritable bowel syndrome, chronic constipation, osmotic diarrhoea and colorectal cancer. The potential pathogenic mechanism of gut dysbacteriosis associated with intestinal diseases includes the alteration of composition of gut microbiota as well as the gut microbiota–derived signalling molecules. The many correlations between the latter and the susceptibility for intestinal diseases has placed a spotlight on the gut microbiome as a potential novel target for therapeutics. Currently, faecal microbial transplantation, dietary interventions, use of probiotics, prebiotics and drugs are the major therapeutic tools utilized to impact dysbacteriosis and associated intestinal diseases. In this review, we systematically summarized the role of intestinal microbiome in the occurrence and development of intestinal diseases. The potential mechanism of the complex interplay between gut dysbacteriosis and intestinal diseases, and the treatment methods are also highlighted.

    Non-digestible polysaccharides to support the intestinal immune barrier: in vitro models to unravel molecular mechanisms
    Tang, Yongfu - \ 2017
    Wageningen University. Promotor(en): H.J. Wichers, co-promotor(en): J.J. Mes; C.C.F.M. Govers. - Wageningen : Wageningen University - ISBN 9789463437134 - 166
    polysaccharides - health - immunomodulatory properties - homeostasis - intestinal diseases - human nutrition research - polysacchariden - gezondheid - immunomodulerende eigenschappen - homeostase - darmziekten - voedingsonderzoek bij de mens

    Non-digestible polysaccharides (NDPs) are considered as important ingredients to support health. Among these health effects, immunomodulatory effects raised interests in the past decade. The intestine is the primary organ that interact with NDPs. The intestinal epithelial cells (IECs) form a dynamic physical barrier and together with associated immune cells determine for a large part our immune homeostasis. Studying the direct interaction between NDPs and intestinal and immune cells could help us to uncover the mechanism by which NDPs exert immunomodulatory effects and how NDPs can differ in this activity. In this thesis, we investigated the immunomodulatory effects of NDPs through interaction with intestinal immune cells using in vitro methods in order to characterise the NDPs and preselect NDPs with differential activity for further in vivo evaluations.

    The intestinal immune barrier is formed by various IECs and immune cells, which are introduced and their specific functions discussed in Chapter 1. NDPs could interact directly with both IECs and immune cells that sample in or from the lumen. The majority of IECs are enterocytes and most relevant immune cells responsible for sampling in the lumen have been characterised as macrophages, which leads us to focus on these cell types by in vitro approaches. In addition, basic information on NDPs and current status on health effects of NDPs both in vitro and in vivo are discussed.

    In Chapter 2, the direct response of IEC to NDPs stimulation was investigated. IECs form the largest surface of the body that, with a crucial role as barrier also, perform a role in signalling towards immune cells. We used 21-day transwell cultured Caco-2 to resemble the small intestinal enterocytes that form largest part of this intestinal layer. We first characterized the chemical composition of five NDPs which revealed different mono sugar composition, linkages of backbone and side chains and a wide range of MW (from 17 KDa to 2100 KDa). The NDPs could reduce translocation of FITC-Dextran of 4 kDa across the epithelial layer, potentially through physical interference. Gene expression analysis indicated the induction of unique gene expression characteristics in Caco-2 cells upon exposure to different NDPs. An arabinoxylan preparation from wheat and a lentinan-containing extract from shiitake mushrooms showed upregulation of gene expression of the NF-κB family and chemokines CCL20 and CXCL10. Besides these immune related changes by some NDPs, we also observed changes in receptor expression (like TLR2, CD14 and GPCRs) and other pathways, amongst which the cholesterol biosynthesis pathway.

    Macrophages, as the resident population of immune cells penetrating between or associating with close contact with the IECs, are generally classified as inflammatory (M1) or as tolerant (M2) macrophages. In Chapter 3, we set up a macrophage differentiation method based on primary blood cells and selected and validated M1 and M2 specific gene expression markers. Next, we analysed the effect when macrophages are exposed to NDPs and compared the resulting macrophages with M1 and M2 macrophages. Based on M1 and M2 markers we identified an alternative subset that we named MNDP. This MNDP was further studied by microarray analysis and revealed a commonly modulated set of genes, involved in migration, metabolic processes, cell cycle, and inflammatory immune function.

    In Chapter 4, we further functionally characterize these MNDP in comparison to M1 and M2 macrophages based on a set of functional assays. NDP-treated macrophages showed no IDO activity and showed an inhibited antigen uptake and processing capacity compared to M1 and M2 macrophages. Also their phagocytic capacity was reduced compared to both M1 and M2 macrophages. Furthermore, the alternative expression pattern for NDP-treated macrophages, as demonstrated by gene expression, was confirmed by protein measurements. The signature mix of the chemokines CCL1, CCL5, CCL20, CCL24, CXCL8, and IL1β secreted by MNDP, and in particular when macrophages were treated with Naxus, was shown to induce a recruitment of monocytes.

    As macrophage plasticity could be essential for intestinal immune homeostasis, resolving activity of inflammatory responses upon a challenge is important. Besides, redirecting differentiation and function of tolerant macrophages can also be beneficial to the intestinal immune status. In Chapter 5, we analysed plasticity of M1 and M2 macrophages to NDPs exposure. Macrophage plasticity was demonstrated as M1 and M2 could be skewed to an alternative subset indicated by a dedicated set of gene expression markers, selected to characterize M1, M2 and MNDP macrophages. In addition, phagocytosis and antigen processing capacity of both M1 and M2 were decreased by the NDP Naxus. Besides, Naxus could change the secretion of cytokines by macrophages that previously were differentiated towards M1 and M2. For M2, this resulted in an increase of recruitment of monocytes by M2 macrophages.

    In Chapter 6, we discussed the important findings in each chapter of this thesis together with current literature, and gave a general perspective on this research line focussing on the immunomodulating activity of NDPs and the direction for future research. We suggested NDPs in terms of Naxus as candidate for guiding investigations in ex vivo and in vivo studies for immunomodulation of intestinal disease.

    An apple a day... : de rol van voeding in transmurale zorg
    Witteman, Ben J.M. - \ 2015
    Wageningen : Wageningen University - ISBN 9789462571990 - 32
    ziekenhuiszorg - voedsel - chronische darmontstekingen - darmziekten - prikkelbaar colon - coeliakie - narcose - ondervoeding - vasten - darmen - hospital care - food - inflammatory bowel diseases - intestinal diseases - irritable colon - coeliac syndrome - narcosis - undernutrition - fasting - intestines
    'De gemiddelde levensverwachting stijgt in Nederland. Nochtans worden we op jongere leeftijd met chronische aandoeningen geconfronteerd. De kans hierop neemt de komende jaren sterk toe: van 1 miljoen nu naar 1,5 miljoen in 2020. Hierdoor zullen we geconfronteerd worden met voedingsproblemen waarbij een chronische ziekte een rol speelt. Aangepaste voeding, op grond van de onderliggende pathofysiologie, kan naast preventie van progressie van ziekte ook leiden tot een eerder klinisch herstel. De darm als gate-keeper van het lichaam speelt hierbij een belangrijke rol. Voedingsonderzoek bij deze doelgroep, gericht op verbetering van de darmgezondheid kan de patiënt een beter welzijn geven en de gezondheidszorg mogelijk goedkoper maken.'
    The genus Romboutsia : genomic and functional characterization of novel bacteria dedicated to life in the intestinal tract
    Gerritsen, J. - \ 2015
    Wageningen University. Promotor(en): Hauke Smidt; Willem de Vos, co-promotor(en): G.T. Rijkers. - Wageningen : Wageningen University - ISBN 9789462572423 - 280
    darmmicro-organismen - voeding en gezondheid - microbiota van het spijsverteringskanaal - darmziekten - moleculaire technieken - probiotica - intestinal microorganisms - nutrition and health - gastrointestinal microbiota - intestinal diseases - molecular techniques - probiotics
    The genus Romboutsia: genomic and functional characterization of novel bacteria dedicated to life in the intestinal tract

    PhD thesis Jacoline Gerritsen, 2015


    Humans, like other mammals, are not single-species organisms, but they constitute in fact very complex ecosystems. The extensive network of host-microbe and microbe-microbe interactions is tremendously important for our health, and we are just starting to unravel the mechanisms by which microbes contribute to host health and disease.

    Especially the intestinal tract of both humans and mammals contains an enormous diversity of microbial species of which many still remain to be cultured and characterized. There are numerous diseases for which aberrations in composition and diversity of the intestinal microbiota have been reported. Probiotic microorganism defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” have the potential to modulate the intestinal microbiota and thereby contribute to health and well-being. To this end, the relative abundance of a specific bacterial phylotype, named CRIB, was found to be associated with probiotic-induced changes in gut microbiota and decreased severity of pancreatitis and associated sepsis in an experimental rat model for acute pancreatitis studies. Later, a representative of this phylotype (strain CRIB) was isolated, and characterized using a polyphasic taxonomic approach. The taxonomy of several closely related members of the family Peptostreptococcaceae was revised in order to provide a valid systematic name to the isolate, for which Romboutsia ilealis was chosen. It was found that the majority of Romboutsia-associated 16S rRNA gene sequences have an intestinal origin, however, the specific roles that Romboutsia species play in the intestinal tract are largely unknown. To gain more insight in metabolic and functional capabilities of members of the genus Romboutsia, efforts towards the isolation of additional representatives were undertaken. This ultimately led to the isolation of a human small intestine-derived representative (strain FRIFI) of another novel Romboutsia species which was given the name R. hominis. Characterization of both novel species of intestinal origin, i.e. R. ilealis and R. hominis, belonging to the genus Romboutsia at the genomic and functional level provided first insights into the genetic diversity within the genus Romboutsia and their adaptation to a life in the (upper) intestinal tract. To this end, Romboutsia species are flexible anaerobes that are adapted to a nutrient-rich environment in which carbohydrates and exogenous sources of amino acids and vitamins are abundantly available.

    Microbiomic approaches such as those employed in this study can be used to pinpoint specific commensal microbes that might have a beneficial effect on the health of the host. In addition, the combination of genomic and functional analyses with single organisms and complex communities can be used to identify microbial functionalities that are related to health and disease, which in turn can be used to select potential probiotic strains based on specific functional properties. Ultimately, these approaches will lead to the characterization of (new) beneficial commensal microbes that exert health-promoting effects, with the ultimate possibility for them to be exploited as next-generation probiotics.

    Evaluatie van de voedingsstatus van Nederlandse patiënten met chronische inflammatoire darmziekten : een pilotonderzoek
    Berg, M.C. van den; Plas, M. ; Mares, W. ; Witteman, B.J.M. ; Klein Gunnewiek, J.M.T. ; Vries, J.H.M. de - \ 2014
    Nederlands Tijdschrift voor Voeding en Dietetiek 60 (2014)1. - ISSN 1875-9955 - p. S1 - S12.
    voedingstoestand - darmziekten - chronische darmontstekingen - ondervoeding - patiënten - voeding en gezondheid - nutritional state - intestinal diseases - inflammatory bowel diseases - undernutrition - patients - nutrition and health
    Introductie Het doel van deze pilotstudie was het verkrijgen van inzicht in de voedingsstatus van Nederlandse patiënten met chronische inflammatoire darmziekten (IBD). Methoden De voedingsstatus werd onderzocht op basis van MUST-score, handknijpkracht, micronutriëntstatus in het bloed en voedingsinname. Daarnaast werden leeftijd, geslacht, ziektebeeld, ziekteactiviteit, kwaliteit van leven en medicatiegebruik geïnventariseerd en gecorreleerd aan ziekteactiviteit. Resultaten 41 personen met IBD (17 mannen en 24 vrouwen, 19-74 jaar), onder wie 22 met colitis ulcerosa en 19 met de ziekte van Crohn, namen deel aan het onderzoek. 4 deelnemers hadden volgens de MUST-score een verhoogd risico op ondervoeding. Van 4 deelnemers was de handknijpkracht onder de referentiewaarde. 14 personen hadden een tekort aan vitamine D, 3 aan selenium, 3 aan foliumzuur, 1 aan vitamine B12 en 1 aan magnesium. De micronutriëntconcentraties verschilden niet tussen deelnemers met verschillende ziektebeelden, MUST-scores of handknijpkracht. Serum vitamine B1 verschilde als enige micronutriënt tussen mannen en vrouwen (p=0,047). Foliumzuurconcentraties waren hoger bij hogere ziekteactiviteit (p=0,022) en bij lagere kwaliteit van leven (p=0,030). Serumspiegels van vitamine D en vitamine E waren hoger voor deelnemers boven de leeftijdsmediaan dan voor deelnemers daaronder (50 jaar, respectievelijk: p
    RegIII proteins as gatekeepers of the intestinal epithelium
    Loonen, L.M.P. - \ 2013
    Wageningen University. Promotor(en): Jerry Wells, co-promotor(en): Peter van Baarlen. - S.l. : s.n. - ISBN 9789461736727 - 205
    eiwitten - darmen - darmslijmvlies - darmziekten - colitis - bacterieziekten - immuunsysteem - verdedigingsmechanismen - muizen - diermodellen - microbiologie - immuniteit - geneeskunde - proteins - intestines - intestinal mucosa - intestinal diseases - colitis - bacterial diseases - immune system - defence mechanisms - mice - animal models - microbiology - immunity - medicine

    Mammalian RegIII proteins are expressed in the intestine and in the pancreas in response to inflammation or infection. In the mouse intestine, expression of RegIIIβ and RegIIIγ is increased by microbial colonization, inflammation and infection. At the outset of this thesis human PAP and mouse RegIIIγ were reported to be bactericidal for Gram-positive bacteria. Additionally, human PAP had been shown to attenuate NF-κbsignallingin human monocytes and epithelial cells and administration of anti-PAP antibodies increased inflammation in an experimental rat model of acute pancreatitis. The overarching goals of this thesis were to find out more about the protective role of mouse RegIIIβ and RegIIIγ in the intestine and explore their protective role in colitis and bacterial infection.

    In Chapter 2 we investigated expression of RegIIIβ and RegIIIγ in intestine of Muc2 knockout (-/-) mice, which develop colitis after about 4 weeks, due to the absence of a secreted mucus layer in the small intestine or colon. RegIII proteins were expressed in Paneth cells, enterocytes and goblet cells pointing to a new function for goblet cells in innate immunity. Ang4 expression was confined to Paneth cells and goblet cells. Absence of Muc2 increased expression levels of RegIIIβ, RegIIIγ, and Ang4 and colitis appeared first in the distal colon where the RegIII expression is lowest.

    In Chapter 3 we investigated the distinct phases of colitis development in Muc2-/- mice from before weaning to 4 and 8 weeks of age, also taking into account the effect that mucin deficiency has in the ileum. Gene set enrichment approaches showed increased expression of innate and adaptive immune pathways associated with colitis over time, whereas in the ileum many immune signalling pathways were down-regulated. Nevertheless, RegIIIβ and RegIIIγ were significantly upregulated, suggesting their proposed antimicrobial and/or anti-inflammatory activities might be related to the suppression of immune pathways and avoidance of immune-mediated damage. Furthermore, we showed that RegIIIβ could specifically bind to mucin and fucosylated glycans in vitro, which may serve to inhibit bacterial binding to membrane bound mucins on the epithelium, and also enable RegIIIβ to be retained in the secreted mucin.

    An in vitro approach was used in Chapter 4, where we investigated the activities of RegIIIγ and RegIIIβby expressing and purifying recombinant proteins. Both proteins were insoluble when expressed in E. coli but RegIIIβ could be expressed and secreted in baculovirus as a soluble protein. As previous work reported that RegIII proteins were bactericidal even when produced as inclusion bodies in E. coli and refolded, we followed similar procedures to obtain soluble RegIII proteins. In our hands both the E. coli and baculovirus produced proteins bound strongly to both Gram-positive and Gram-negative bacteria after processing of an N-terminal pro-peptide by trypsin, but lacked any appreciable bactericidal activity. Furthermore these proteins did not influence the growth of Salmonella enteritidis andListeria monocytogenes. Attempts to crystallize the proteins were unsuccessful but structural models of the protein were generated based on the crystal structure of human PAP. These models were used to dock known ligands of RegIIIγ or RegIIIβ. Only one ligand is known for RegIIIγ, which is peptidoglycan, but for RegIIIβ the ligands include peptidoglycan, lipid A and the fucose-containing glycans identified in chapter 3. RegIIIβ was predicted to have two different binding sites which would allow it to bind to mucins and bacteria simultaneously, thereby preventing penetrating of the mucus.

    In Chapter 5 a RegIIIβ-/- mouse was used to study the role of the protein during infection with Gram-negative Salmonella enteritidis or Gram-positive Listeria monocytogenes. Whereas recovery of S. enteritidis orL. monocytogenes from faeces was similar in RegIIIβ-/- and wild type (WT) mice, significantly higher numbers of viable S. enteritidis, but not L. monocytogenes, were recovered from the colon, mesenteric lymph nodes, spleen, and liver of the RegIIIβ-/- than the WT mice. The results suggest that mouse RegIIIβ plays a protective role against intestinal translocation of the Gram-negative bacterium S. enteritidis but not against the Gram-positive bacterium L. monocytogenes.

    In Chapter 6, the generation of a RegIIIγ-/- mouse is described. One of the main phenotypic differences between the RegIIIγ-/- and WT was an altered distribution of the ileal mucus and increased bacterial contact with the epithelium. Additionally, measurement of innate immune markers in the mucosa suggested heightened inflammation in the RegIIIγ-/- mice. Compared to WT mice, RegIIIγ-/- mice infected with S. enteritidis and L. monocytogenes showed an increase of mucosal inflammatory markers indicating protective, anti-microbial roles of RegIIIγ in defense against both Gram-positive and Gram-negative bacteria.

    Chapter 7summarizes and discusses the key results of the thesis in the context of the wider literature and possible directions for future research

    Streptococcus suis is aanwezig in het maagdarmkanaal van biggen op Varkens Innovatie Centrum Sterksel
    Wisselink, H.J. ; Smits, C.B. ; Dirx-Kuijken, N.C.P.M.M. ; Raymakers, R. ; Peet-Schwering, C.M.C. van der - \ 2011
    Lelystad : Central Veterinary Institute - 15
    varkenshouderij - biggen - biggenvoeding - voersamenstelling - agrarische bedrijfsvoering - streptococcus suis - darmziekten - bacterieziekten - pig farming - piglets - piglet feeding - feed formulation - farm management - streptococcus suis - intestinal diseases - bacterial diseases
    Onderzocht is welke aanpassingen aan het voer, zowel wat betreft voersamenstelling als voermanagement, bijdragen aan het verminderen van het aantal biggen met klinische verschijnselen van Streptococcus suis. Daartoe is op Varkens Innovatie Centrum Sterksel een voedingsexperiment met gespeende biggen uitgevoerd.
    Intestinal health: Key to maximise growth performance in livestock
    Verstegen, M.W.A. ; Beever, D.E. ; Collet, S. - \ 2007
    Wageningen : Wageningen Academic Publishers - 300
    vee - diergezondheid - darmen - spijsverteringskanaal - immuunsysteem - immuniteit - darmziekten - veevoeding - diervoeding - besmetters - eiwitexpressieanalyse - voedingsfysiologie - prestatieniveau - dierlijke productie - livestock - animal health - intestines - digestive tract - immune system - immunity - intestinal diseases - livestock feeding - animal nutrition - contaminants - proteomics - nutrition physiology - performance - animal production
    Livestock production is changing worldwide. It is also the case that the ban on antibiotic growth promoters in Europe, the shift in animal production centres to Brazil or Eastern Europe, increase in demand for traceability and natural production, and the emergence of new diseases, are all forcing livestock producers to adapt new husbandry, management, nutrition and healthcare techniques. Food safety is an explosive political issue - the expectations and demands of the informed consumer have altered perceptions of risk and brought food safety to the very front and centre of politics. The changes in legislation on the use of feed additives will impact livestock production, location of production and feed formulation. Veterinarians and producers look for alternatives to maintain intestinal health and maximise animal performance, whilst still complying with stringent EU legislation. This book reviews the changes in livestock production and some of the clinical and sub-clinical disease challenges faced in pig, poultry or ruminant production. The book discusses bacterial challenges such as E.coli, Salmonella. Clostridia and Campylobacter, as well as viral diseases such as circovirus or avian influenza. One of the key elements in determining intestinal health is the use of molecular technologies in determining the composition of the intestinal microflora in poultry, pigs and ruminants. The interaction between innate, cellular and humoral immunity and the effects on antigen recognition and immune response will impact overall performance and ultimately the profit for producers. The understanding of Glycomics and the role of carbohydrates in cell-to-cell communication is crucial in overcoming sub-clinical challenges in modern livestock production. ISBN-13: 978-90-76998-91-6 Price (¿): 85.00 Price ($): 113.00 Publication date: 2007-12-01 (yyyy-mm-dd)
    Het effect van voersamenstelling op bacteriële darmaandoeningen bij varkens = The effect of feed composition on bacterial intestinal diseases in pigs
    Meulen, J. van der; Peet-Schwering, C.M.C. van der - \ 2007
    Lelystad : Animal Sciences Group (Rapport / Animal Sciences Group, Divisie Veehouderij 83) - 14
    varkens - dierhouderij - diervoeding - voersamenstelling - koolhydraten - darmziekten - diergezondheid - bacterieziekten - dysenterie - varkensdysenterie - colitis - enteritis - salmonellose - pigs - animal husbandry - animal nutrition - feed formulation - carbohydrates - intestinal diseases - animal health - bacterial diseases - dysentery - swine dysentery - colitis - enteritis - salmonellosis
    Feed composition, and especially carbohydrate composition, may affect the development of enteric bacterial diseases. Also the kind of feed ingredients (soybean or not) and feed treatment (milling size, pelletizing, fermentation) may be important. A more coarse grinding, no pelletizing and fermentation may be preferable in the reduction of the development of enteric bacterial diseases.
    Gene expression profiling of chicken intestinal host responses
    Hemert, S. van - \ 2007
    Wageningen University. Promotor(en): Martien Groenen; Mari Smits, co-promotor(en): Annemarie Rebel. - [S.l.] : S.n. - ISBN 9789085045816 - 159
    kippen - genexpressie - darmen - darmziekten - ziekteresistentie - experimentele infectie - immuniteitsreactie - immunologie - genetica - fowls - gene expression - intestines - intestinal diseases - disease resistance - experimental infection - immune response - immunology - genetics
    Chicken lines differ in genetic disease susceptibility. The scope of the research described in this thesis was to identify genes involved in genetic disease resistance in the chicken intestine. Therefore gene expression in the jejunum was investigated using a microarray approach. An intestine specific cDNA microarray was generated from a normalized and subtracted library. Gene expression in young chickens was studied using two different disease models, malabsorption syndrome and Salmonella enteritidis . For each model two different chicken lines were studied, which differed in susceptibility to the specific diseases. Gene expression differences between the chicken lines were found under control and under infected conditions. In the studies described here the main focus was on genes that could be involved in disease susceptibility. Large differences between the chicken lines with different genetic backgrounds were found in their gene expression responses to the infections. After malabsorption syndrome the more susceptible chicken line regulated immune related genes, genes involved in food absorption and genes with unknown functions. The chicken line most susceptible for salmonella upregulated genes involved in inflammation, or with unknown functions, whereas the more resistant chicken line regulated genes involved in acute phase response, the fibrinogen system, actin polymerisation, and also genes with unknown functions. Most gene expression responses to both infection models were found 1 day post infection. Gene expression differences between the two chicken lines lead to the hypothesis that immunological differences could be the basis of differences in susceptibility for Salmonella . Therefore the two chicken lines were studied for the phagocytic properties of intestinal mononuclear cells and these properties were different for the two chicken lines. Also, a decrease in the number of CD4 + T-cells and macrophages in response to the Salmonella infection was found only in one chicken line. In both chicken lines the number of CD8 + T-cells increased, but faster in the susceptible chicken line. So genetic background influences intestinal gene expression responses and immunological responses.
    Diet, lifestyle, and molecular alterations that drive colorectal carcinogenesis
    Diergaarde, B. - \ 2004
    Wageningen University. Promotor(en): Frans Kok, co-promotor(en): Ellen Kampman. - [S.I.] : S.n. - ISBN 9789085041030
    carcinoom - neoplasma's - darmziekten - maagdarmziekten - levensstijl - voedselhygiëne - voedingstoestand - consumptiepatronen - gezondheid - genetische stoornissen - milieufactoren - carcinoma - neoplasms - intestinal diseases - gastrointestinal diseases - lifestyle - food hygiene - nutritional state - consumption patterns - health - genetic disorders - environmental factors
    Environmental factors have been repeatedly implicated in the etiology of colorectal cancer, and much is known about the molecular events involved in colorectal carcinogenesis. The relationships between environmental risk factors and the molecular alterations that drive colorectal carcinogenesis are less dear. Further insight into these relationships may prove useful for the development of etfective colorectal cancer prevention and/or treatment strategies. In this thesis, we examine associations between dietary and lifestyle factors previously reported to be associated with colorectal cancer risk and the molecular alterations known to play important roles in colorectal carcinogenesis.

    Data from a case-control study of sporadic colorectal polyps (278 cases; 414 polyp-free controls) were used to evaluate associations between dietary factors and truncating APC mutations in adenomas. High intake of red meat and fat seemed to increase the risk of polyps without truncating APC mutation (APC-) in particular, whereas high intake of carbohydrates seemed to especially decrease the risk of APC.polyps.

    Associations between dietary factors and truncating APC mutations in colorectal carcinomas were investigated in a population-based case-control study (184 cases; 259 controls) of sporadic colon cancer. Consumption of vegetables lowered the risk of tumors with truncating APC mutation (APC+) asweilas APC- tumors, most explicitly of the last. Alcohol intake was associated with an increased risk of APC.tumorsonly, whereas meat, fish and fat seemed to especially increase the risk of APC+ tumors. The same study population was used to evaluate associations between dietary factors and MSI, hMLH I expression and hMLH J hypermethylation. Intake of red meat seemed to increase the risk of MSI-LIMSS carcinomas in particular, whereas alcohol intake appeared to increase the risk of MSI-H tumors. Fruit consumption seemed to especially decrease the risk of MSI-H tumors with hypermethylated hMLHJ. Associations between cigarette smoking and mutations in the APC, K-ras and p53 genes, p53 overexpression, and MSI were also assessed in this study population. Our data suggest that smoking­related colon carcinomas develop through a p53 overexpression-negative pathway and that smoking results in colon tumor cells with transversion mutations in particular.

    Finally, we used data from a case-control study of HNPCC-associated colorectal tumors (145 cases; 103 tumor-free controls) to gain insight into the etfects of environmental factors on colorectal tumor risk in individuals with HNPCC. Fruit consumption and dietary fiber intake lowered the risk of ever developing HNPCC-associated colorectal tumors, whereas cigarette smoking and alcohol consumption seemed to increase this risk. This suggests that also HNPCC-associated outcomes may be modified by environmental factors.
    Voeding in relatie tot darmstoornissen bij kalkoenen
    Veldkamp, T. ; Ferket, P.R. - \ 1999
    Praktijkonderzoek voor de Pluimveehouderij 10 (1999)4. - ISSN 0924-9087 - p. 11 - 14.
    spijsverteringsstoornissen - darmen - kalkoenen - voer - darmziekten - pluimveevoeding - diergezondheid - digestive disorders - intestines - turkeys - feeds - intestinal diseases - poultry feeding - animal health
    In dit artikel wordt de relatie weergegeven tussen voedingsfactoren en diverse stoornissen in het darmstelsel. Het betreft een bewerking van een artikel over Nutrition and gut health of turkeys van Dr. Ferket.
    Dietary modulation of the resistance to intestinal infections
    Bovee-Oudenhoven, I.M.J. - \ 1998
    Agricultural University. Promotor(en): J.T.M. Wouters; R. van der Meer. - S.l. : Bovee-Oudenhoven - ISBN 9789054859796 - 127
    darmziekten - ziekteresistentie - gezondheidsvoedsel - intestinal diseases - disease resistance - health foods

    Gastrointestinal infections are still a major health problem, not only in developing countries. Even in Europe and the United States about 10-15 % of the population contracts an intestinal infection each year, mostly of foodborne origin. The growing resistance of pathogens to antibiotics stresses the importance to prevent and treat intestinal infections by other means. Modulation of the diet to improve host resistance to foodborne infections might be an attractive, alternative approach.

    The diet determines the composition of intestinal contents, which in turn affects the gastrointestinal survival of pathogens, the protective endogenous microflora and the epithelial barrier function. These parameters ultimately determine the susceptibility of the host to intestinal infectious disease. Scientific interest in dietary modulation of the resistance to intestinal infections is just emerging. Notwithstanding the results of numerous in-vitro studies, strictly controlled infection studies showing the importance of the diet (supplemented with pre- or probiotics) to inhibit or ameliorate intestinal infections in-vivo are scarce. Even less is known about the potential protective effect of dietary calcium on the resistance to intestinal infections. At the same time, evidence accumulates showing that calcium is likely an antipromoter of colon carcinogenesis.

    In the intestine, calcium forms an insoluble complex with phosphate which strongly binds bile acids and fatty acids. In soluble form, these surfactants are highly irritating to the intestinal epithelium. Therefore, precipitation of bile acids and fatty acids by calcium phosphate decreases luminal cytotoxicity, resulting in diminished epithelial cell damage and reduced epithelial proliferation. This may also be relevant for host resistance to intestinal infections. A reduced epithelial cell damage may strengthen the mucosal barrier function. In addition, it can be speculated that the decreased cytotoxicity of intestinal contents by calcium phosphate may stimulate growth of the protective endogenous microflora and improve its antagonistic activity towards invading pathogens. Figure 1 summarizes the hypothetical mechanism by which dietary calcium phosphate may decrease the severity of an intestinal infection, for instance caused by salmonella.

    The strictly-controlled experimental studies described in this thesis mainly focused on the proposed protective effect of dietary calcium phosphate on the resistance to intestinal infections. The rat was chosen as animal model and the invasive pathogen Salmonella enteritidis as infective agent. Salmonellosis is one of the most common foodborne, bacterial infections in the world and its pathology in humans and rodents is quite similar. The first study of this thesis investigated the application of urinary nitrate excretion as a marker of intestinal bacterial translocation (chapter 2).

    To study dietary modulation of host resistance to translocation of pathogens a non-invasive, sensitive and quantifiable marker is needed. Classical organ cultures do not meet those criteria. Nitric oxide (NO) is produced by inducible nitric oxide synthase of phagocytes upon contact with bacteria or cell wall components of bacteria, like lipopolysaccharides. To prevent damage to host cells, NO is rapidly oxidized to nitrite and nitrate (summed as NO x ) and these are quantitatively excreted in urine. It was shown that intraperitoneally injected S. enteritidis lipopolysaccharides transiently increased the urinary NO x output within a certain dose-range. Concomitant administration of a competitive inhibitor of nitric oxide synthase (N G-nitro-L-arginine methyl ester) almost completely abolished the rise in NO x excretion. Importantly, increasing the oral dose of viable S. enteritidis resulted in a time- and dose-dependent exponential increase in urinary NO x excretion. Translocation was a prerequisite for provoking a NO x response, because neither orally administered, heat-killed S. enteritidis nor non-invasive, enterotoxigenic Escherichia coli (data not shown) induced an increase in NO x excretion above base-line level. Total urinary NO x excretion after infection of the rats with viable S. enteritidis and weight of the mesenteric lymph nodes were highly correlated.

    After validation of this new translocation marker, the effect of different milk products (low-calcium milk, milk, milk acidified with hydrochloric acid, and pasteurized yogurt) on the resistance of rats to S. enteritidis was studied (chapter 3). Compared with the low-calcium milk group, all high-calcium groups had an increased colonization resistance, as judged by the strongly reduced fecal salmonella excretion in time. The yogurt-fed rats had the best colonization resistance. Before infection, the bile acid concentration and cytotoxicity of fecal water of the low-calcium milk group were significantly higher than those of the high-calcium groups. The reduced resistance of the low-calcium milk group corresponded with strong infection-induced disturbances of normal intestinal physiology. For instance, the apparent iron absorption was reduced and considerable increases in cytotoxicity of fecal water, fecal mucin and alkaline phosphatase excretion were observed in this group. The least infection-induced changes in luminal parameters were noticed in the yogurt-fed rats. Surprisingly, no infection-induced increase in urinary NO x excretion was observed in this study (data not shown).

    As the milk-based diets differed in several respects, another strictly controlled infection study was performed with rats on purified diets differing only in calcium phosphate (20, 60 and 180 mmol/kg) content (chapter 4). Compared with the low-calcium group, the medium- and high-calcium group shedded 10-1000 times less salmonella in their feces and thus had a substantially improved colonization resistance. Calcium supplementation also reduced translocation of salmonella, considering the diminished urinary NO x excretion and decreased viable salmonella counts in the ileal Peyer's patches and spleen. As shown earlier, the bile acid concentration and cytotoxicity of fecal water were decreased by dietary calcium phosphate. This resulted in an increased fecal output of several bacterial mass markers, indicating a stimulation of the endogenous microflora. Besides an enhanced fecal dry weight excretion, dietary calcium phosphate also increased fecal nitrogen, phospholipid and organic phosphate output.

    The non-digestible disaccharide lactulose is well-fermented by the intestinal microflora and has been used successfully in the treatment of certain intestinal infections. The organic acids (e.g. lactic acid) formed during bacterial lactulose fermentation probably play an important role in this protection. Nevertheless, excess acid production may damage the intestinal epithelium and even impair the mucosal barrier function. Considering the above-mentioned resistance-enhancing effects of dietary calcium phosphate and its ability to increase the intestinal buffering capacity, the possible superiority of a combination of dietary lactulose and calcium phosphate to improve host resistance was studied (chapter 5).

    S. enteritidis appeared to be very sensitive to lactic acid in-vitro, whereas Lactobacillus acidophilus (as a representative of the protective endogenous microflora) was unaffected. The infection experiment showed that dietary lactulose decreased fecal shedding of salmonella, thus increased the colonization resistance. The protective effects of lactulose were limited to the cecum and colon because this disaccharide did not decrease translocation of salmonella, as measured by urinary NO x excretion. In agreement with the study described above, calcium phosphate significantly inhibited translocation of salmonella. It is known that mucosal invasion of salmonella mainly takes place in the ileum, a region of the intestinal tract with a relatively less dense bacterial population. Obviously, the fermentation of lactulose in the ileum is limited and not sufficient to prevent translocation of salmonella. Supplementation of a lactulose diet with calcium phosphate reversed the unfavorable increased cytotoxicity of fecal water. In addition, calcium phosphate stimulated lactulose fermentation, as judged by the reduced lactulose excretion in feces and increased fecal lactic acid, ammonia, and nitrogen excretion.

    Finally, it was investigated whether the calcium phosphate-induced protection against colonization and translocation of salmonella was mediated by a stimulation of the intestinal lactobacilli (chapter 6). In-vitro, L. acidophilus was rapidly killed by physiologically relevant concentrations of fatty acids and (un)conjugated bile acids. In contrast, even high concentrations of these surfactants did not affect the viability of S. enteritidis . Calcium phosphate-supplementation reduced the cytotoxicity and the concentration of bile acids and fatty acids in ileal contents and fecal water of rats. Moreover, calcium phosphate notably changed the composition of ileal bile acids into a less cell-damaging direction. Consequently, significantly increased numbers of lactobacilli were detected in ileal contents, on the ileal mucosa and in feces of non-infected, calcium phosphate-supplemented animals. At the same time, the calcium phosphate group had less viable salmonella in ileal contents, on the ileal mucosa and in feces. In accordance, the infection-induced urinary NO x excretion was diminished by calcium phosphate supplementation.

    Interactive effects between dietary fat and a vegetables-fruit mixture on colorectal carcinogenesis
    Rijnkels, J.M. - \ 1998
    Agricultural University. Promotor(en): J.H. Koeman; G.M. Alink; R.A. Woutersen. - S.l. : Rijnkels - ISBN 9789054858171 - 128
    darmziekten - maagdarmziekten - carcinoom - neoplasma's - voedsel - voedingsmiddelen - vetten - groenten - fruitgewassen - intestinal diseases - gastrointestinal diseases - carcinoma - neoplasms - food - foods - fats - vegetables - fruit crops

    Several dietary compounds are associated with colorectal cancer risk. These include the amount of dietary fat, which is positively associated with colorectal cancer, and a variety of vegetables and fruit, which are suggested to possess anticarcinogenic potential. Because diet is complex and dietary factors most probably interact, it is likely that these interactive effects between dietary components, rather then the effects of individual components, may account for a large part in the risk for developing colorectal cancer.

    The results of the studies performed by Alink et al. (1993) demonstrated that it is of paramount importance to study interactive effects between dietary components in evaluating the effects of total diet in colorectal carcinogenesis. They showed that the effects of a vegetables-fruit mixture on DMH-induced colorectal carcinogenesis in rats maintained on complete human diets, was modulated by the presence of other dietary components, such as the amount of dietary fat or fried meat.

    To investigate these observations by Alink et al. in more detail, we performed three long-term animal studies, which have been described in detail in Part I of the present thesis. In these studies, interactive effects between dietary fat (20 and 40 energy%) and a vegetables-fruit mixture (19.5% wt/wt) were studied on 1,2-dimethylhydrazine (DMH)- and N-methyl-N'-nitro-N-nitroso-guanidine (MNNG)-induced colorectal carcinogenesis in rats, and in ApcMin mice, which are genetic susceptible for developing multiple intestinal neoplasia (Chapters 1, 2, and 3). The composition and amount of fat (40e%) and of the vegetables-fruit mixture were based on regular amounts consumed in The Netherlands.

    The animal diets used for these studies were balanced for protein and micronutrient content. The diets differed only in the amount of fat/carbohydrate and the presence of specific plant constituents when a vegetables-fruit mixture was included in the diets. Notwithstanding the use of the same experimental diets in all three studies, the results were remarkably different.

    A vegetables-fruit mixture added to high-fat (40e%) diets resulted in a distinct protection of colorectal carcinogenesis in the MNNG-study, whereas in the DMH study no effect of the vegetables-fruit mixture was observed. In ApcMin mice the vegetables-fruit mixture enhanced rather then inhibited tumor development. Furthermore, a diet high in fat (40e%) enhanced colorectal carcinogenesis in the DMH-study and, although less pronounced, in the MNNG-study, whereas in the ApcMin mice no effect was observed.

    Finally, a vegetables-fruit mixture added to low-fat diets did not result in protection against colorectal cancer development in the MNNG-study, whereas when added to a high-fat diet an inhibitory effect was found. In male ApcMin mice, the same mixture added to low-fat diets decreased the number of small intestinal tumors, whereas it increased the number of small intestinal neoplasia when added to high-fat diets.

    To examine the differences observed between the effects of the vegetables-fruit mixture observed in the DMH-model and those in the MNNG-model in more detail, an experiment was designed, in which the inhibitory potency of a vegetables-fruit mixture was investigated on either the initiation or the promotion phase, using azoxymethane (AOM) to induce colorectal carcinogenesis and using both low- and high-fat diets (Chapter 4). In this study no protection of this mixture on colorectal carcinogenesis was observed either when present during the initiation or during the promotion phase, irrespective of the fat content.

    In conclusion, the variation in the results of the aforementioned studies can most probably be ascribed to methodological differences, such as differences in DMH and MNNG metabolism, route of administration and type of DNA damage. Apart from these differences, genetic susceptibility may play a role. Taken these methodological differences into account the present results do not consistently show that dietary fat has modulated the tumor preventive properties of a vegetables-fruit mixture in colorectal carcinogenesis (Alink et al., 1993).

    The second part of the thesis describes the results of studies into the interactive effects between dietary fat and the vegetables-fruit mixture on (anti)carcinogenic mechanisms. Hepatic xenobiotic enzyme activities (ethoxyresorufine-O-deethylation (EROD), pentoxyresorufine-O-deethylation (PROD), N-nitrosodimethylamine-demethylase (NDMA-d), cytosolic glutathion-S-transferase (GST), UDP-glucuronyl transferase (UDP-GT)) and immune parameters in spleen and mesenteric lymph nodes (NK cell activity, lymphocyte stimulation test, mixed lymphocyte reaction) were measured in rats of the long-term DMH-study (Chapter 5).

    Overall, it was shown that both a vegetables-fruit mixture and dietary fat had no effect on the enzyme activities and immune function. In a short-term (seven weeks) animal study, DMH-treatment appeared to influence hepatic and colonic xenobiotic enzyme activities (EROD, PROD, NDMA-d, UDP-GT and GST) rather strongly (Chapter 6).

    Furthermore, interaction between dietary fat and the vegetables-fruit mixture was observed on colonic NDMA-d activity. Finally, interactive effects between stearic acid, indole-3-carbinol and crude extracts of the vegetables-fruit mixture were studied in vitro (Chapter 7). Both indole-3-carbinol, an isolated plant constituent, and vegetables-fruit extracts, a complex mixtures of plant constituents, modulated the effects of stearic acid on cytotoxicity, gap junctional intercellular communication, and cytochrome P450-IA (EROD) activity. The effects of indole-3-carbinol and extracts of the vegetables-fruit mixture were partly influenced by the order at which these components with stearic acid were added to the cells as well as by the type of cells used.

    In general, the results of the studies described in Part II of this thesis supports the hypothesis that interaction between dietary constituents may influence their modulating effect on colorectal carcinogenesis.

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