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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    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.

    Mucus and gut barrier in health and disease
    Sovran, B. - \ 2015
    Wageningen University. Promotor(en): Jerry Wells; P. de Vos, co-promotor(en): J. Dekker. - Wageningen : Wageningen University - ISBN 9789462574892 - 233
    slijm - spijsverteringskanaal - darmen - muizen - probiotica - eilandjes van peyer - colitis - transcriptomen - immunohistologie - veroudering - geslacht (sex) - homeostase - gezondheid - ziekten - mucus - digestive tract - intestines - mice - probiotics - peyer patches - colitis - transcriptomes - immunohistology - senescence - sex - homeostasis - health - diseases

    This publication describes his work as a PhD student in the Host-Microbe Interactomics Chair group at Wageningen University within the Gastrointestinal Health theme. It has been completed under the supervision of Prof. Dr Jerry M Wells, Dr Jan Dekker and the TIFN project leader, Prof. Dr Paul de Vos.

    Mucus serves as a protective layer between the intestinal content and the intestinal wall. It facilitates the passage of the luminal content through the intestine, reducing the risk of mechanical damage to the intestinal epithelium. The overarching goal of this thesis was to investigate the role of mucus in the maintenance of the intestinal immune barrier and the effects of ageing and gender differences on mucus production and the gut barrier.

    We found by using a mouse model that decreased mucus production leads to changes in microbiota and mucosal stress responses, without the appearance of pathology, demonstrating the importance of mucus in intestinal homeostasis. The mucus barrier was shown to deteriorate during aging but this could be prevented with specific probiotics. Furthermore gender-specific differences in the effects of ageing on the mucosal barrier were found. Increased knowledge on these mechanisms might contribute significantly to disease prevention and treatment, for instance by optimizing gender-specific dietary and pharmacological requirements.

    The study presented in this thesis was performed within the framework of Top Institute Food and Nutrition, within the GH002 project.

    The impact of dietary fibers on dendritic cell responses in vitro is dependent on the differential effects of the fibers on intestinal epithelial cells
    Bermudez-Brito, M. ; Sahasrabudhe, N.M. ; Rösch, C. ; Schols, H.A. ; Faas, M.M. ; Vos, P. de - \ 2015
    Molecular Nutrition & Food Research 59 (2015)4. - ISSN 1613-4125 - p. 698 - 710.
    immune function - receptor 2 - health - homeostasis - modulation - mortality - polysaccharides - activation - mechanisms - prebiotics
    Scope In the present study, the direct interaction of commonly consumed fibers with epithelial or dendritic cells (DCs) was studied. Methods and results The fibers were characterized for their sugar composition and chain length profile. When in direct contact, fibers activate DCs only mildly. This was different when DCs and fibers were co-cultured together with supernatants from human epithelial cells (Caco spent medium). Caco spent medium enhanced the production of IL-12, IL-1Ra, IL-6, IL-8, TNF-a, MCP-1 (monocyte chemotactic protein), and MIP-1a but this was strongly attenuated by the dietary fibers. This attenuating effect on proinflammatory cytokines was dependent on the interaction of the fibers with Toll-like receptors as it was reduced by Pepinh-myd88. The interaction of galacto-oligosaccharides, chicory inulin, wheat arabinoxylan, barley ß-glucan with epithelial cells and DCs led to changes in the production of the Th1 cytokines in autologous T cells, while chicory inulin, and barley ß-glucan reduced the Th2 cytokine IL-6. The Treg-promoting cytokine IL-10 was induced by galacto-oligosaccharides whereas chicory inulin decreased the IL-10 production. Conclusions Our results suggest that dietary fibers can modulate the host immune system not only by the recognized mechanism of effects on microbiota but also by direct interaction with the consumer's mucosa. This modulation is dietary fiber type dependent.
    Precise control of plant stem cell activity through parallel regulatory inputs
    Bennett, T. ; Toorn, A. van; Willemsen, V. ; Scheres, B. - \ 2014
    Development 141 (2014). - ISSN 0950-1991 - p. 4055 - 4064.
    arabidopsis-thaliana root - transcription factor - shoot apex - meristem - gene - differentiation - organization - maintenance - homeostasis - sombrero
    The regulation of columella stem cell activity in the Arabidopsis root cap by a nearby organizing centre, the quiescent centre, has been a key example of the stem cell niche paradigm in plants. Here, we investigate interactions between transcription factors that have been shown to regulate columella stem cells using a simple quantification method for stem cell activity in the root cap. Genetic and expression analyses reveal that the RETINOBLASTOMA-RELATED protein, the FEZ and SOMBRERO NAC-domain transcription factors, the ARF10 and ARF16 auxin response factors and the quiescent centre-expressed WOX5 homeodomain protein each provide independent inputs to regulate the number of columella stem cells. Given the tight control of columella development, we found that these inputs act in a surprisingly parallel manner. Nevertheless, important points of interaction exist; for example, we demonstrate the repression of SMB activity by non-autonomous action of WOX5. Our results suggest that the developmental progression of columella stem cells may be quantitatively regulated by several more broadly acting transcription factors rather than by a single intrinsic stem cell factor, which raises questions about the special nature of the stem cell state in plants.
    High relative air humidity influences mineral accumulation and growth in iron deficient soybean plants
    Roriz, M. ; Carvalho, S.M.P. ; Wilton Vasconcelos, M. - \ 2014
    Frontiers in Plant Science 5 (2014). - ISSN 1664-462X - 24 p.
    metabolic-responses - greenhouse plants - nutrient-uptake - human-nutrition - seed treatment - chlorosis - homeostasis - roots - salinity - crops
    Iron (Fe) deficiency chlorosis (IDC) in soybean results in severe yield losses. Cultivar selection is the most commonly used strategy to avoid IDC but there is a clear interaction between genotype and the environment; therefore, the search for quick and reliable tools to control this nutrient deficiency is essential. Several studies showed that relative humidty (RH) may influence the long distance transport of mineral elements and the nutrient status of plants. Thus, we decided to analyze the response of an ‘Fe-efficient’ (EF) and an ‘Fe-inefficient’ (INF) soybean accession grown under Fe-sufficient and deficient conditions under low (60%) and high (90%) RH, evaluating morphological and physiological parameters. Furthermore, the mineral content of different plant organs was analyzed. Our results showed beneficial effects of high RH in alleviating IDC symptoms as seen by increased SPAD values, higher plant dry weight, increased plant height, root length and leaf area. This positive effect of RH in reducing IDC symptoms was more pronounced in the EF accession. Also, Fe content in the different plant organs of the EF accession grown under deficient conditions increased with RH. The lower partitioning of Fe to roots and stems of the EF accessions relative to dry matter also supported our hypothesis, suggesting a greater capacity of this accession in Fe translocation to the aerial parts under Fe deficient conditions, when grown under high RH.
    Increasing protein intake modulates lipid metabolism in healthy young men and women consuming a high-fat hypercaloric diet 1-3
    Rietman, A. ; Schwarz, J. ; Blokker, B.A. ; Siebelink, E. ; Kok, F.J. ; Afman, L.A. ; Tome, D. ; Mensink, M.R. - \ 2014
    The Journal of Nutrition 144 (2014)8. - ISSN 0022-3166 - p. 1174 - 1180.
    energy-expenditure - hepatic steatosis - adipose-tissue - liver fat - quantification - disease - rats - homeostasis - accurate - insulin
    The objective of this study was to evaluate the effect of increasing protein intake, at the expense of carbohydrates, on intrahepatic lipids (IHLs), circulating triglycerides (TGs), and body composition in healthy humans consuming a high-fat, hypercaloric diet. A crossover randomized trial with a parallel control group was performed. After a 2-wk run-in period, participants were assigned to either the control diet [n = 10; 27.8 energy percent (en%) fat, 16.9 en% protein, 55.3 en% carbohydrates] for 4 wk or a high-fat, hypercaloric diet (n = 17; >2 MJ/d) crossover trial with 2 periods of 2 wk, with either high-protein (HP) (37.7 en% fat, 25.7 en% protein, 36.6 en% carbohydrates) or normal-protein (NP) (39.4 en% fat, 15.4 en% protein, 45.2 en% carbohydrates) content. Measurements were performed after 2 wk of run-in (baseline), 2 wk of intervention (period 1), and 4 wk of intervention (period 2). A trend toward lower IHL and plasma TG concentrations during the HP condition compared with the NP condition was observed (IHL: 0.35 ± 0.04% vs. 0.51 ± 0.08%, P = 0.08; TG: 0.65 ± 0.03 vs. 0.77 ± 0.05 mmol/L, P = 0.07, for HP and NP, respectively). Fat mass was significantly lower (10.6 ± 1.72 vs. 10.9 ± 1.73 kg; P = 0.02) with the HP diet than with the NP diet, whereas fat-free mass was higher (55.7 ± 2.79 vs. 55.2 ± 2.80 kg; P = 0.003). This study indicated that an HP, high-fat, hypercaloric diet affects lipid metabolism. It tends to lower the IHL and circulating TG concentrations and significantly lowers fat mass and increases fat-free mass compared with an NP, high-fat, hypercaloric diet. This trail was registered at www.clinicaltrails.gov as NCT01354626.
    Vitamin D-tour : cognition and depression: the role of vitamin D and its interplay with glucose homeostasis
    Brouwer-Brolsma, E.M. - \ 2014
    Wageningen University. Promotor(en): Lisette de Groot; Edith Feskens, co-promotor(en): Teun Schuurman; Wilma Steegenga. - Wageningen : Wageningen University - ISBN 9789462571082 - 215
    vitamine d - depressie - glucose - homeostase - gezondheid - hersenen - vitaminetekorten - vitamin d - depression - glucose - homeostasis - health - brain - vitamin deficiencies

    According to recent estimations approximately 35.6 million people have dementia worldwide. Globally, 350 million people experience one or more depressive episodes during their life. As the therapeutic options for dementia and depression are limited, these conditions form a major challenge for public health and society. More and more researchers have initiated research on potential preventive factors for dementia and depression, including the potential effects of nutritional factors. The aim of this PhD-thesis was to study the role of vitamin D and its potential interplay with glucose homeostasis, in the development of cognitive decline and depression, using epidemiological data as well experimental animal data.

    Chapter 2 recapitulates a debate between vitamin D experts that was organized to make a step towards the harmonization on the formulation of optimal vitamin D intake levels and serum 25(OH)D concentrations across Europe. It was concluded that based on the current evidence-base 25(OH)D concentrations ≥50 nmol/L are sufficient with respect to optimal bone health. For health outcomes beyond bone health evidence was considered insufficient to formulate optimal levels. In order to achieve and maintain a 25(OH)D concentration ≥50 nmol/L, older adults aged ≥65 years were recommended to adhere to a vitamin D intake of 20 μg/day.

    Chapter 3 shows that there is a high prevalence of 25(OH)D inadequacy in a population of Dutch older adults that participated in the B-PROOF study (n=2857), namely 45% had 25(OH)D concentrations <50 nmol/L. Mean vitamin D intake was 4.9±2.9 µg/day and only 20% of the participants reported to use vitamin D containing supplements. Exploration of the determinants of 25(OH)D status showed significant associations between vitamin D ‘raising’ SNPs (n=2530), higher sun exposure (n=1012), vitamin D intake (n=596) and higher 25(OH)D concentrations. Including all the potential relevant predictors in one model explained 35% of the variance in 25(OH)D status (R2=0.35).

    In chapter 4 the associations between 25(OH)D status and global cognitive performance (n=116), depressive symptoms (n=118), and surrogate markers of glucose intolerance (n=593) were evaluated using data of European adults aged 70-75 years. None of the associations reached significance.

    Studying the potential role of vitamin D in domain-specific cognitive performance and depression in 127 Dutch pre-frail and frail older adults aged ≥65 years (chapter 5), showed an association between 25(OH)D concentration and executive functioning, and a tendency towards an association with information processing speed. Stratification for ‘low’ and ‘high’ fasting glucose concentrations did not suggest an interaction between vitamin D and glucose homeostasis in the association with domain-specific cognitive performance. Moreover, adding fasting glucose or insulin did not substantially influence the associations between 25(OH)D status and domain-specific cognitive performance, and hence a mediation effect of glucose homeostasis was considered unlikely.

    We furthermore observed associations of 25(OH)D status with attention and working memory (n=787) (chapter 6), depression (n=2839) (chapter 7) and grey matter volume of the brain (n=217) (chapter 8) in a population community-dwelling Dutch older adults aged ≥65 years. Again, these studies did not provide evidence that the associations were modified or mediated by glucose intolerance. However, it should be emphasized that glucose intolerance in these three chapters was defined sub-optimally, specifically using blood samples that may have been collected in a non-fasting state, or by using self-reported diabetes data. Hence, the mediation and interaction effects should be interpreted cautiously.

    Finally, chapter 9 shows the results of a proof of principle study on the effect of a long-term vitamin D deficiency on cognitive decline and emotional reactivity in old C57BL/6j mice. Modest tendencies were shown for a relation between vitamin D and spatial learning, but these tendencies did not reach significance. Vitamin D deficiency did not affect recognition memory, spatial memory or emotional reactivity. Mice that received a higher dietary fat load, which was given to induce an impaired glucose tolerance, did not respond differently to a vitamin D deficiency than mice that received a low fat diet did.

    Overall, it is concluded that the evidence for an effect of vitamin D on cognitive performance/decline, depression or brain volume is insufficient to formulate disease specific cut-off values for vitamin D intake or 25(OH)D status. However, given the high prevalence of 25(OH)D concentrations <50 nmol/L we do call for a more active promotion of the current vitamin D intake recommendations.

    Expression of the iron hormone hepcidin distinguished different types of anemia in African children
    Pasricha, S.R. ; Atkinson, S.H. ; Armitage, A.E. ; Khandwala, S. ; Veenemans, J. ; Cox, S.E. ; Eddowes, L.A. ; Hayes, T. ; Doherty, C.P. ; Demir, A.Y. ; Tijhaar, E.J. ; Verhoef, H. ; Prentice, A.M. ; Drakesmith, H. - \ 2014
    Science Translational Medicine 6 (2014)235. - ISSN 1946-6234 - 7 p.
    randomized controlled-trials - deficiency anemia - chronic disease - serum hepcidin - round-robin - ferritin - malaria - supplementation - homeostasis - hemoglobin
    Childhood anemia is a major global health problem resulting from multiple causes. Iron supplementation addresses iron deficiency anemia but is undesirable for other types of anemia and may exacerbate infections. The peptide hormone hepcidin governs iron absorption; hepcidin transcription is mediated by iron, inflammation, and erythropoietic signals. However, the behavior of hepcidin in populations where anemia is prevalent is not well established. We show that hepcidin measurements in 1313 African children from The Gambia and Tanzania (samples taken in 2001 and 2008, respectively) could be used to identify iron deficiency anemia. A retrospective secondary analysis of published data from 25 Gambian children with either postmalarial or nonmalarial anemia demonstrated that hepcidin measurements identified individuals who incorporated >20% oral iron into their erythrocytes. Modeling showed that this sensitivity of hepcidin expression at the population level could potentially enable simple groupings of individuals with anemia into iron-responsive and non–iron-responsive subtypes and hence could guide iron supplementation for those who would most benefit.
    Early-life environmental variation affects intestinal microbiota and immune development in new-born piglets
    Schokker, D.J. ; Zhang, J. ; Zhang, L.L. ; Vastenhouw, S.A. ; Heilig, H.G.H.J. ; Smidt, H. ; Rebel, J.M.J. ; Smits, M.A. - \ 2014
    PLoS ONE 9 (2014)6. - ISSN 1932-6203
    phylogenetic microarray analysis - large gene lists - gut microbiota - staphylococcus-aureus - innate immunity - responses - homeostasis - diversity - cytoscape - system
    Background - Early-life environmental variation affects gut microbial colonization and immune competence development; however, the timin Early-life environmental variation affects gut microbial colonization and immune competence development; however, the timing and additional specifics of these processes are unknown. The impact of early-life environmental variations, as experienced under real life circumstances, on gut microbial colonization and immune development has not been studied extensively so far. We designed a study to investigate environmental variation, experienced early after birth, to gut microbial colonization and intestinal immune development. Methodology/Principal Findings - To investigate effects of early-life environmental changes, the piglets of 16 piglet litters were divided into 3 groups per litter and experimentally treated on day 4 after birth. During the course of the experiment, the piglets were kept with their mother sow. Group 1 was not treated, group 2 was treated with an antibiotic, and group 3 was treated with an antibiotic and simultaneously exposed to several routine, but stressful management procedures, including docking, clipping and weighing. Thereafter, treatment effects were measured at day 8 after birth in 16 piglets per treatment group by community-scale analysis of gut microbiota and genome-wide intestinal transcriptome profiling. We observed that the applied antibiotic treatment affected the composition and diversity of gut microbiota and reduced the expression of a large number of immune-related processes. The effect of management procedures on top of the use of an antibiotic was limited. Conclusions/Significance - We provide direct evidence that different early-life conditions, specifically focusing on antibiotic treatment and exposure to stress, affect gut microbial colonization and intestinal immune development. This reinforces the notion that the early phase of life is critical for intestinal immune development, also under regular production circumstances. g and additional specifics of these processes are unknown. The impact of early-life environmental variations, as experienced under real life circumstances, on gut microbial colonization and immune development has not been studied extensively so far. We designed a study to investigate environmental variation, experienced early after birth, to gut microbial colonization and intestinal immune development. Methodology/Principal Findings To investigate effects of early-life environmental changes, the piglets of 16 piglet litters were divided into 3 groups per litter and experimentally treated on day 4 after birth. During the course of the experiment, the piglets were kept with their mother sow. Group 1 was not treated, group 2 was treated with an antibiotic, and group 3 was treated with an antibiotic and simultaneously exposed to several routine, but stressful management procedures, including docking, clipping and weighing. Thereafter, treatment effects were measured at day 8 after birth in 16 piglets per treatment group by community-scale analysis of gut microbiota and genome-wide intestinal transcriptome profiling. We observed that the applied antibiotic treatment affected the composition and diversity of gut microbiota and reduced the expression of a large number of immune-related processes. The effect of management procedures on top of the use of an antibiotic was limited. Conclusions/Significance We provide direct evidence that different early-life conditions, specifically focusing on antibiotic treatment and exposure to stress, affect gut microbial colonization and intestinal immune development. This reinforces the notion that the early phase of life is critical for intestinal immune development, also under regular production circumstances. Figures
    An evolutionary perspective on differential regulation of zinc and cadmium homeostatis genes in Arabidopsis thaliana and Noccaea caerulescens
    Lin, Y.F. - \ 2014
    Wageningen University. Promotor(en): Maarten Koornneef, co-promotor(en): Mark Aarts. - Wageningen : Wageningen University - ISBN 9789461738950 - 220
    arabidopsis thaliana - zink - cadmium - homeostase - genen - evolutie - nucleotidenvolgordes - tolerantie - arabidopsis thaliana - zinc - cadmium - homeostasis - genes - evolution - nucleotide sequences - tolerance

    Some plants can tolerate and accumulate unusually high levels of toxic metals, and the analysis of such plants can provide insights into the ecology of environments that are polluted with heavy metals due to human industrial activities. The study of heavy metal hyperaccumulators such as Noccaea caerulescens can show how plants cope with excess metals and increase their fitness when growing in metalliferous environments. In this thesis, I compared the molecular mechanisms of zinc (Zn) homeostasis and cadmium (Cd) response in the hyperaccumulator species N. caerulescens and its non-accumulator relative Arabidopsis thalianaby investigating the regulation of the ZNT1/ZIP4gene that promotes Zn uptake and Zn/Cd tolerance.I also studied the ecological advantages of metal hyperaccumulators in nature and determined the DNA sequences of the N. caerulescens transcriptometo find candidate genes that control metal hyperaccumulation and provide an evolutionary perspective on the emergence of this trait.

    The functional characterization of the N. caerulescens and A. thaliana Zn-transporter genes NcZNT1 and AtZIP4 (and their promoters) showed how their differential expression pattern contributed to their role in metal tolerance and accumulation. The NcZNT1 gene is induced by Zn deficiency and the NcZNT1 protein is localized in the plasma membrane. Transgenic N. caerulescens roots containing a transgene for the green fluorescent protein (GFP) driven by the NcZNT1promoter revealed GFP fluorescence localized to pericycle and vascular tissues. This suggests that NcZNT1 contributes to metal loading into the xylem and long-distance metal transport. The overexpression of NcZNT1 in A. thaliana increased Zn and Cd tolerance and the capacity to accumulate these metals compared to wild-type plants. These results suggest that NcZNT1 plays an important role in Zn and Cd hypertolerance and hyperaccumulation in N. caerulescens, where it is expressed in both Zn-sufficient and Zn-excess conditions. The differential activity of the NcZNT1 and AtZIP4 promoters in N. caerulescens and A. thaliana implies that different cis-regulatory elements and trans-regulatory factors are present in both species.

    The ecological advantage of hyperaccumulators in metal-contaminated soils was investigated by studying a natural nas1mutant, in which the Nicotianamine Synthase1 gene is disrupted by a transposon insertion. This mutant allele was found in three natural N. caerulescens populations, which were compared to wild-type plants in terms of phenotype and adaptive advantage. Although the transposon disrupted the gene, the loss of NAS1 gene activity was compensated by enhanced expression of NAS3 and NAS4, resulting in increased nicotianamine (NA) production, which enhanced the Zn and Cd accumulation in the nas1 mutants. This increased their metal sensitivity compared to wild-type plants, but also made them more toxic towards Pieris rapae caterpillars, which developed more slowly and gained less weight when fed on mutant plants exposed to excess Zn or Cd. Therefore, the possible selective advantage of the nas1 mutant in nature is high metal accumulation and the protection of plants from herbivores. Differences in nas1 allele frequency among the three natural populations suggests that nas1 alleles experience different degrees of natural selection or may be at different stages on the route to fixation.

    Molecular evolutionary studies involve the identification of candidate genes that play a role in adaptation. Therefore, a comprehensive set of transcript sequences was obtained from N. caerulescens accession Ganges (GA) by 454 pyrosequencing. In total, the collected 23,836 isotigs (putative transcripts) were grouped into 20,378 isogroups and 93.2% of them could be matched to Brassicaceae protein sequences, which allowedtheir functional annotation. A total of 87 isogroups was annotated as metal homeostasis related genes, including metal transporter families, metal chelator biosynthesis families, and metal tolerance gene families, which are candidate genes for the molecular analysis of heavy metal homeostasis mechanisms. A group of genes required for the synthesis of glucosinolates, which are important secondary metabolites that protect plants against herbivores, were also shown to be expressed in N. caerulescens. The METALLOTHIONEIN3 (MT3) gene was found to have been duplicated in the N. caerulescens genome, when compared to related Brassicaceae. These transcript sequences will provide an important tool to annotate the genome sequence of the N. caerulescensGanges accession, which is in progress. This genome sequence will also be the basis of genome comparisons between the different N. caerulescens accessions that have different levels of metal accumulation and metal tolerance and which may therefore differ in terms of gene expression levels or modes of actions that affect metal homeostasis.

    Crosstalk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity
    Everard, A. ; Belzer, C. ; Geurts, L. ; Ouwerkerk, J.P. ; Druart, C. ; Bindels, L.B. ; Guiot, Y. ; Derrien, M.M.N. ; Muccioli, G.G. ; Delzenne, N.M. ; Vos, W.M. de; Cani, P.D. - \ 2013
    Proceedings of the National Academy of Sciences of the United States of America 110 (2013)22. - ISSN 0027-8424 - p. 9066 - 9071.
    gut microbiota - body-weight - inflammation - mice - endotoxemia - homeostasis - disease - system - bifidobacteria - metabolism
    Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders
    The gut microbiota elicits a profound metabolic reorientation in the mouse jejunal mucosa during conventionalisation
    Aidy, S. El; Merrifield, C.A. ; Derrien, M. ; Baarlen, P. van; Hooiveld, G.J. ; Levenez, F. ; Dore, J. ; Dekker, J. ; Holmes, E. ; Claus, S.P. ; Reijngoud, D.J. ; Kleerebezem, M. - \ 2013
    Gut 62 (2013). - ISSN 0017-5749 - p. 1306 - 1314.
    inflammatory-bowel-disease - gastric bypass - amino-acid - glutamate - intestine - surgery - mice - biosynthesis - homeostasis - expression
    OBJECTIVE: Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region. DESIGN: Germ-free mice aged 8-10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, (1)H NMR metabonomics and microbiota phylogenetic profiling analyses were used. RESULTS: The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4-30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus. CONCLUSION: This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance.
    Identification of traits and QTLs contributing to salt tolerance in barley (Hordeum vulgare L.)
    Nguyen Viet Long, L. - \ 2012
    Wageningen University. Promotor(en): Richard Visser, co-promotor(en): Gerard van der Linden; Oene Dolstra. - S.l. : s.n. - ISBN 9789461734099 - 137
    hordeum vulgare - gerst - zouttolerantie - loci voor kwantitatief kenmerk - groei - plantensamenstelling - genotypen - chromosomen - homeostase - plantenveredeling - hordeum vulgare - barley - salt tolerance - quantitative trait loci - growth - plant composition - genotypes - chromosomes - homeostasis - plant breeding

    Salinity is the most severe abiotic stress perceived by plants and affects about 800 million hectares of land worldwide, including 20% of the world’s highly productive irrigated land. Significant crop yield losses are observed due to salinity. Salinization is increasing because of poor irrigation management and climate change. Improving salt tolerance in crops is for these reasons an important target for plant breeding in the near future. However, salinity tolerance in plants is not easy to breed for due to its interaction with many physiological processes controlled by many genes and their interaction with the environment. Barley is a good model crop to study different mechanisms conferring salt tolerance in cereals. A traditional QTL mapping approach in combination with a new association mapping method allowed us to efficiently explore the genetics and genetic diversity of salt tolerance in barley. Improvements of the association mapping technology highly increased detection power and mapping accuracy. The traits and QTLs identified in this thesis point out both osmotic and ionic stress tolerant genes as important targets for salt tolerance breeding. This thesis provides tools to plant breeders for the application of marker-assisted introgression breeding of salt tolerance genes in their breeding programs. Some QTLs were found to be syntenic with the important QTLs/genes for salt tolerance found in wheat and rice such as Na+ and K+ transporter gene families. Other QTLs were new and suggest the presence of novel genes that play an important role in plant ion homeostasis, transportation of Cl- and Ca2+ and osmotic tolerance. We demonstrated that association mapping can be a powerful approach to dissect the complexity of salt tolerance in barley. The newly available high-density SNP map of barley and the barley genome sequence in the near future further increases the accuracy of mapping studieswith the association panel and will greatly facilitate the cloning of the genes underlying salt tolerance in barley. This thesis thus contributes to better a understanding of the physiological and genetic basis of salt tolerance and improved breeding strategies for the development of salt tolerant varieties.

    Structural, functional and molecular analysis of the effects of aging in the small intestine and colon of C57BL/6 J mice.
    Steegenga, W.T. ; Wit, N.J.W. de; Boekschoten, M.V. ; IJssenagger, N. ; Lute, C. ; Keshtkar, S. ; Grootte Bromhaar, M.M. ; Kampman, E. ; Groot, C.P.G.M. de; Muller, M.R. - \ 2012
    BMC Medical Genomics 5 (2012). - ISSN 1755-8794 - 27 p.
    bacterial overgrowth - age-changes - stem-cells - inflammation - mucosa - cancer - vitamin-b-12 - homeostasis - microbiota - patterns
    Background By regulating digestion and absorption of nutrients and providing a barrier against the external environment the intestine provides a crucial contribution to the maintenance of health. To what extent aging-related changes in the intestinal system contribute to the functional decline associated with aging is still under debate. Methods Young (4 M) and old (21 M) male C57BL/6 J mice were fed a control low-fat (10E%) or a high-fat diet (45E%) for 2 weeks. During the intervention gross energy intake and energy excretion in the feces were measured. After sacrifice the small and large intestine were isolated and the small intestine was divided in three equal parts. Swiss rolls were prepared of each of the isolated segments for histological analysis and the luminal content was isolated to examine alterations in the microflora with 16S rRNA Q-PCR. Furthermore, mucosal scrapings were isolated from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing. Results Digestible energy intake was similar between the two age groups on both the control and the high-fat diet. Microarray analysis on RNA from intestinal scrapings showed no marked changes in expression of genes involved in metabolic processes. Decreased expression of Cubilin was observed in the intestine of 21-month-old mice, which might contribute to aging-induced vitamin B12 deficiency. Furthermore, microarray data analysis revealed enhanced expression of a large number of genes involved in immune response and inflammation in the colon, but not in the small intestine of the 21-month-old mice. Aging-induced global hypomethylation was observed in the colon and the distal part of the small intestine, but not in the first two sections of the small intestine. Conclusion In 21-month old mice the most pronounced effects of aging were observed in the colon, whereas very few changes were observed in the small intestine.
    The dynamic interplay of microbiota and mucosa drives establishment of homeostasis in conventionalized mice
    Aidy, S.F. El - \ 2012
    Wageningen University. Promotor(en): Michiel Kleerebezem, co-promotor(en): Peter van Baarlen; Erwin Zoetendal. - S.l. : s.n. - ISBN 9789461731951 - 168
    kiemvrije dieren - muizen - darmmicro-organismen - homeostase - slijmvlies van het spijsverteringskanaal - transcriptomica - metabolomica - germfree animals - mice - intestinal microorganisms - homeostasis - digestive tract mucosa - transcriptomics - metabolomics

    The intimate interplay between gut microbiota, host, and nutrient flow is crucial in defining the health status of the host. During microbial conventionalization of germfree mice, tightly regulated molecular responses assure the establishment of homeostasis and immune tolerance towards the microbiota. To decipher the temporal and regional dynamics of host-microbiota communication during the process of conventionalization, a combination of transcriptomics, (immune-)histology, metabonomics (tissue, urine, and plasma), as well as MITchip (Mouse Intestinal Tract chip) based microbiota profiling was employed. To this end, C57/B6 J germfree mice were conventionalized with mouse fecal microbiota and responses were followed in a time-resolved manner for thirty days. The colonizing microbiota was characterized by a shift from low towards higher diversity of its composition, over the period of conventionalization. Microbial colonization was rapidly (after one day) reflected by increased concentrations of specific urine and jejunal metabolites as well as by biologically relevant changes in jejunal tissue transcriptome profiles. Conversely, ileal and colonic transcriptome responses could be measured later, after four days post-conventionalization, and led towards stable molecular profiles at sixteen and thirty days of conventionalization, albeit with region-specific differences. The major molecular responses included strong induction of innate immune response followed by stimulation of adaptive and regulatory immune functions, as well as modulation of metabolic pathways involved in lipid, carbohydrate, and anabolic metabolism. Conventionalization was characterized by two stages separated by one stage of a single day which, particularly in the colon, resembled a transient stage of inflammation, based on transcriptomes, histology and transiently elevated levels of specific plasma markers. This state coincided with temporal domination of specific microbial groups that have previously been identified as “pathobionts”, suggestive of a transient state of dysbiosis. Extensive transcriptome profile analyses throughout the GI tract enabled the identification of central gene regulatory networks that govern the molecular responses during conventionalization and are proposed to serve as genetic signatures for the control of intestinal homeostasis in mice. Nearly all genes in these regulatory networks have human orthologues, suggesting that the biological findings of this study is also relevant for human intestinal biology. In support of this hypothesis, in the jejunum, the identified gene regulatory network appeared to be strongly associated with human metabolic disorders. This notion also suggests that at least in mice, possibly also in human, there is a prominent role of the proximal small intestine in systemic metabolic control.

    This thesis exemplifies the pivotal role of the dynamic molecular interactions between the microbiota and the intestinal mucosa, in the establishment and maintenance of mucosal homeostasis in healthy mice. The molecular signatures obtained from these studies in mice may provide novel diagnostic tools and/or therapeutic targets in humans for specific disorders associated with intestinal dysbiosis and loss of mucosal homeostasis.

    Keywords: C57/BL6 J mice, conventionalization, transcriptomics, (immune-)histology, metabonomics, microbiota

    Effect of feeding rumen-protected rice bran on mineral status of non-lactating dairy heifers
    Martin-Tereso Lopez, J. ; Distefano, C. ; Laar, H. van; Mulder, K. ; Hartog, L.A. den; Verstegen, M.W.A. - \ 2011
    Journal of Animal Physiology and Animal Nutrition 95 (2011)1. - ISSN 0931-2439 - p. 73 - 80.
    zeolite-a supplementation - magnesium absorption - dry period - phosphorus - cows - calcium - phytate - homeostasis - metabolism - zinc
    Adapting Ca homeostasis of dairy cows before calving can prevent milk fever. Rice bran, treated with formaldehyde to prevent ruminal degradation of phytic acid, was fed to heifers to study its effect on Ca homeostasis. For 3 weeks 18 heifers were supplemented 3 kg of two feeds: placebo (PF) and rice bran (RBF), defining three treatments: control (CRT), low dose (LD) and high dose (HD). In weeks 1 and 3, all animals received 3 kg of PF and in week 2: CRT received 3 kg of PF, LD received 1.5 kg of PF and 1.5 kg of RBF and HD received 3 kg of RBF. Treatments did not affect dry matter intake (DMI). Feed intakes and growth rates indicated that all heifers had nutritional requirements that exceeded their Ca intakes. Serum Ca, urinary Ca, calcitriol or hydroxyproline remained unaffected. Urinary Ca was consistently low indicating high renal Ca reabsorption, which is indicative of insufficient Ca supply. Rice bran feed influenced P, Mg and Zn intakes and serum and urine presence of these minerals. Most heifers already presented an upregulated Ca metabolism, being inadequate to study adaptive changes in Ca homeostasis of multiparous dry cows. This metabolic difference can be explanatory to the very low susceptibility of heifers to milk fever, further supporting the induction of homeostatic adaptation before calving to prevent milk fever. Rice bran feed did not reduce DMI, and was not detrimental to P, Mg or Zn status.
    Identification and functional analysis of two ZIP metal transporters of the hyperaccumulator Thlaspi caerulescens
    Wu, J. ; Zhao, F.J. ; Ghandilyan, A. ; Logoteta, B. ; Olortegui Guzman, M.C. ; Schat, H. ; Wang, X. ; Aarts, M.G.M. - \ 2009
    Plant and Soil 325 (2009)1-2. - ISSN 0032-079X - p. 79 - 95.
    arabidopsis-thaliana - zinc transporter - expression differences - genes - iron - homeostasis - irt1 - sequence - family - accumulation
    Abstract The heavy metal hyperaccumulator Thlaspi caerulescens expresses several ZIP-like genes at higher levels than their orthologues in non-hyperaccumulator species, but it is not clear why. To elucidate the function of the T. caerulescens orthologues of the Arabidopsis thaliana ZIP5 and ZIP6 genes, full-length cDNAs of TcZNT5-LC and TcZNT6-LC were cloned, their expression was examined and genes were expressed in A. thaliana. Transcript level analysis revealed the constitutively high expression of these two genes in T. caerulescens compared to AtZIP5 and AtZIP6 genes and differential expression of both genes when comparing two accessions of T. caerulescens with different metal accumulation properties. Expression of TcZNT5-LC in A. thaliana did not modify Cd or Zn tolerance, but mildly affected the root and shoot Zn concentrations towards a hyperaccumulator shoot to root concentration ratio. A. thaliana zip5 knock-out mutants showed increased tolerance to Cd and decreased seed mineral concentrations. Expression of TcZNT6-LC enhanced the Cd sensitivity of A. thaliana, but no phenotype was observed for the zip6 mutant. In conclusion, the changes in expression of TcZNT5-LC and TcZNT6-LC upon changes in Zn or Cd exposure indicate both genes act in metal homeostasis, but their CaMV 35S-mediated expression in A. thaliana does not create T. caerulescens hyperaccumulator phenotypes
    Lichaam in balans
    Keijer, J. - \ 2009
    Wageningen : Wageningen Universiteit, Wageningen UR - ISBN 9789085852803
    mens - dieren - energiebalans - homeostase - vetweefsel - quetelet index - obesitas - fysiologische functies - voedingsfysiologie - gezondheid - man - animals - energy balance - homeostasis - adipose tissue - body mass index - obesity - physiological functions - nutrition physiology - health
    Receptor for advanced glycation end product polymorphisms and type 2 diabetes: the CODAM study
    Gaens, K.H. ; Kallen, C.J. ; Greevenboek, M.M. van; Feskens, E.J.M. ; Stehouwer, C.D. ; Schalkwijk, C.G. - \ 2008
    Annals of the New York Academy Of Sciences 1126 (2008)1. - ISSN 0077-8923 - p. 162 - 165.
    rage - complications - homeostasis - disease
    Genetic variation in the receptor for advanced glycation end products (RAGE) gene may alter the expression and function of RAGE and affect disease development and outcome. We investigated whether single nucleotide polymorphisms (SNPs) in RAGE were associated with diabetes and parameters of glucose homeostasis. In total, nine SNPs of RAGE were analyzed in individuals with and without type 2 diabetes in CODAM: a cohort study of diabetes and atherosclerosis, Maastricht. A significant difference in genotype frequency of SNP rs3134945 was observed between the nondiabetic control subjects, subjects with impaired glucose metabolism, and diabetic patients. The C allele of this polymorphism was significantly associated with higher fasting glucose concentrations, 2-h postload glucose concentrations, insulin levels, and homeostasis model assessment of insulin resistance. These results indicate that SNP rs3134945 or a locus in linkage disequilibrium with this polymorphism may be involved in the development of insulin resistance and diabetes. Because the functionality of this polymorphism is not known, the mechanism whereby this polymorphism contributes to the development of insulin resistance and diabetes has to be further elucidated.
    The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice
    Wit, N.J.W. de; Vermeulen, J.J. ; Groot, P.J. de; Hooiveld, G.J.E.J. ; Grootte Bromhaar, M.M. ; Jansen, J. ; Müller, M.R. ; Meer, R. van der - \ 2008
    BMC Medical Genomics 1 (2008). - ISSN 1755-8794 - 16 p.
    migration inhibitory factor - impaired glucose-tolerance - activated receptor-alpha - farnesoid-x-receptor - gene-expression - metabolic-syndrome - nuclear receptors - gamma - homeostasis - sensitivity
    Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. The development of these metabolic disorders is frequently studied, but mainly in liver, skeletal muscle, and adipose tissue. To gain more insight in the role of the small intestine in development of obesity and insulin resistance, dietary fat-induced differential gene expression was determined along the longitudinal axis of small intestines of C57BL/6J mice. METHODS: Male C57BL/6J mice were fed a low-fat or a high-fat diet that mimicked the fatty acid composition of a Western-style human diet. After 2, 4 and 8 weeks of diet intervention small intestines were isolated and divided in three equal parts. Differential gene expression was determined in mucosal scrapings using Mouse genome 430 2.0 arrays. RESULTS: The high-fat diet significantly increased body weight and decreased oral glucose tolerance, indicating insulin resistance. Microarray analysis showed that dietary fat had the most pronounced effect on differential gene expression in the middle part of the small intestine. By overrepresentation analysis we found that the most modulated biological processes on a high-fat diet were related to lipid metabolism, cell cycle and inflammation. Our results further indicated that the nuclear receptors Ppars, Lxrs and Fxr play an important regulatory role in the response of the small intestine to the high-fat diet. Next to these more local dietary fat effects, a secretome analysis revealed differential gene expression of secreted proteins, such as Il18, Fgf15, Mif, Igfbp3 and Angptl4. Finally, we linked the fat-induced molecular changes in the small intestine to development of obesity and insulin resistance. CONCLUSIONS: During dietary fat-induced development of obesity and insulin resistance, we found substantial changes in gene expression in the small intestine, indicating modulations of biological processes, especially related to lipid metabolism. Moreover, we found differential expression of potential signaling molecules that can provoke systemic effects in peripheral organs by influencing their metabolic homeostasis. Many of these fat-modulated genes could be linked to obesity and/or insulin resistance. Together, our data provided various leads for a causal role of the small intestine in the etiology of obesity and/or insulin resistance.
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