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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Structure dependent-immunomodulation by sugar beet arabinans via a SYK tyrosine kinase-dependent signaling pathway
Meijerink, Marjolein ; Rösch, Christiane ; Taverne, Nico ; Venema, Koen ; Gruppen, Harry ; Schols, Henk A. ; Wells, Jerry M. - \ 2018
Frontiers in Immunology 9 (2018)OCT. - ISSN 1664-3224
Arabinans - C-Type lectin receptors - Dietary fiber - Immunomodulation - Pectin - Structure-function relationship

There is much interest in the immunomodulatory properties of dietary fibers but their activity may be influenced by contamination with microbial-Associated molecular patterns (MAMPs) such as lipopolysaccharide (LPS) and lipoteichoic acids, which are difficult to remove completely from biological samples. Bone marrow-derived dendritic cells (BMDCs) from TLR2x4 double-KO mice were shown to be a reliable approach to analyse the immunomodulatory properties of a diverse range of dietary fibers, by avoiding immune cell activation due to contaminating MAMPs. Several of the 44 tested dietary fiber preparations induced cytokine responses in BMDCs from TLR2x4 double-KO mice. The particulate fractions of linear arabinan (LA) and branched arabinan (BA) from sugar beet pectin were shown to be strongly immune stimulatory with LA being more immune stimulatory than BA. Enzymatic debranching of BA increased its immune stimulatory activity, possibly due to increased particle formation by the alignment of debranched linear arabinan. Mechanistic studies showed that the immunostimulatory activity of LA and BA was independent of the Dectin-1 recognition but Syk kinase-dependent.

Mitochondrial dynamics in cancer-induced cachexia
Ende, Miranda van der; Grefte, Sander ; Plas, Rogier ; Meijerink, Jocelijn ; Witkamp, Renger F. ; Keijer, Jaap ; Norren, Klaske van - \ 2018
Biochimica et Biophysica Acta - Reviews on Cancer 1870 (2018)2. - ISSN 0304-419X - p. 137 - 150.
Animal models - Cancer-induced cachexia - Mitochondria - Mitochondrial dynamics - Muscle

Cancer-induced cachexia has a negative impact on quality of life and adversely affects therapeutic outcomes and survival rates. It is characterized by, often severe, loss of muscle, with or without loss of fat mass. Insight in the pathophysiology of this complex metabolic syndrome and direct treatment options are still limited, which creates a research demand. Results from recent studies point towards a significant involvement of muscle mitochondrial networks. However, data are scattered and a comprehensive overview is lacking. This paper aims to fill existing knowledge gaps by integrating published data sets on muscle protein or gene expression from cancer-induced cachexia animal models. To this end, a database was compiled from 94 research papers, comprising 11 different rodent models. This was combined with four genome-wide transcriptome datasets of cancer-induced cachexia rodent models. Analysis showed that the expression of genes involved in mitochondrial fusion, fission, ATP production and mitochondrial density is decreased, while that of genes involved ROS detoxification and mitophagy is increased. Our results underline the relevance of including post-translational modifications of key proteins involved in mitochondrial functioning in future studies on cancer-induced cachexia.

In vitro anti-inflammatory and radical scavenging properties of chinotto (Citrus myrtifolia Raf.) essential oils
Plastina, Pierluigi ; Apriantini, Astari ; Meijerink, Jocelijn ; Witkamp, Renger ; Gabriele, Bartolo ; Fazio, Alessia - \ 2018
Nutrients 10 (2018)6. - ISSN 2072-6643
Antioxidant - Citrus - Inflammation - Macrophages - Nitric oxide

Chinotto (Citrus myrtifolia Raf.) is a widely diffused plant native from China and its fruits have a wide-spread use in confectionary and drinks. Remarkably, only little has been reported thus far on its bioactive properties, in contrast to those of the taxonomically related bergamot (Citrus bergamia Risso). The present study aimed to investigate potential in vitro anti-inflammatory and radical scavenging properties of chinotto essential oils (CEOs) and to establish to what extent their composition and bioactivities are dependent on maturation. Essential oil from half ripe chinotto (CEO2) reduced the production of nitric oxide (NO) and the expression of inflammatory genes, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6), and chemokine monocyte chemotactic protein-1 (MCP-1) by lipopolysaccharide (LPS)-stimulated RAW264,7 macrophages. Limonene, linalool, linalyl acetate, and γ-terpinene were found to be the main components in CEO2. Moreover, CEO2 showed high radical scavenging activity measured as Trolox equivalents (TE) against both 2,2′-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS). These findings show that chinotto essential oil represents a valuable part of this fruit and warrants further in vivo studies to validate its anti-inflammatory potential.

Prebiotic potential of pectin and pectic oligosaccharides to promote anti-inflammatory commensal bacteria in the human colon
Chung, Wing Sun Faith ; Meijerink, Marjolein ; Zeuner, Birgitte ; Holck, Jesper ; Louis, Petra ; Meyer, Anne S. ; Wells, Jerry M. ; Flint, Harry J. ; Duncan, Sylvia H. - \ 2017
FEMS Microbiology Ecology 93 (2017)11. - ISSN 0168-6496
Bacteroides thetaiotaomicron - Eubacterium eligens - Faecalibacterium prausnitzii - Firmicutes - glycosyl hydrolase - pectate lyase
Dietary plant cell wall carbohydrates are important in modulating the composition and metabolism of the complex gut microbiota, which can impact on health. Pectin is a major component of plant cell walls. Based on studies in model systems and available bacterial isolates and genomes, the capacity to utilise pectins for growth is widespread among colonic Bacteroidetes but relatively uncommon among Firmicutes. One Firmicutes species promoted by pectin is Eubacterium eligens. Eubacterium eligens DSM3376 utilises apple pectin and encodes a broad repertoire of pectinolytic enzymes, including a highly abundant pectate lyase of around 200 kDa that is expressed constitutively. We confirmed that certain Faecalibacterium prausnitzii strains possess some ability to utilise apple pectin and report here that F. prausnitzii strains in common with E. eligens can utilise the galacturonide oligosaccharides DP4 and DP5 derived from sugar beet pectin. Faecalibacterium prausnitzii strains have been shown previously to exert anti-inflammatory effects on host cells, but we show here for the first time that E. eligens strongly promotes the production of the anti-inflammatory cytokine IL-10 in in vitro cell-based assays. These findings suggest the potential to explore further the prebiotic potential of pectin and its derivatives to re-balance the microbiota towards an anti-inflammatory profile.
Governance Arrangements for the Adaptation to Climate Change
Termeer, C.J.A.M. ; Buuren, Arwin Van; Dewulf, A.R.P.J. ; Huitema, Dave ; Mees, Heleen L.P. ; Meijerink, Sander ; Rijswick, H.F.M.W. - \ 2017
In: The Oxford Research Encyclopedia of Climate Science Oxford University Press - ISBN 9780190228620 - 31 p.
climate governance - governance arrangements - adaptation to climate change - design principles
Adaptation to climate change is not only a technical issue; above all, it is a matter of governance. Governance is more than government and includes the totality of interactions in which public as well as private actors participate, aiming to solve societal problems. Adaptation governance poses some specific, demanding challenges, such as the context of institutional fragmentation, as climate change involves almost all policy domains and governance levels; the persistent uncertainties about the nature and scale of risks and proposed solutions; and the need to make short-term policies based on long-term projections. Furthermore, adaptation is an emerging policy field with, at least for the time being, only weakly defined ambitions, responsibilities, procedures, routines, and solutions. Many scholars have already shown that complex problems, such as adaptation to climate change, cannot be solved in a straightforward way with actions taken by a hierarchic or monocentric form of governance. This raises the question of how to develop governance arrangements that contribute to realizing adaptation options and increasing the adaptive capacity of society. A series of seven basic elements have to be addressed in designing climate adaptation governance arrangements: the framing of the problem, the level(s) at which to act, the alignment across sectoral boundaries, the timing of the policies, the selection of policy instruments, the organization of the science-policy interface, and the most appropriate form of leadership. For each of these elements, this chapter suggests some tentative design principles. In addition to effectiveness and legitimacy, resilience is an important criterion for evaluating these arrangements. The development of governance arrangements is always context- and time-specific, and constrained by the formal and informal rules of existing institutions.
Lactobacillus plantarum strains can enhance human mucosal and systemic immunity and prevent non-steroidal anti-inflammatory drug induced reduction in T regulatory Cells
Vos, Paul de; Mujagic, Zlatan ; Haan, Bart J. de; Siezen, Roland J. ; Bron, Peter A. ; Meijerink, Marjolein ; Wells, Jerry M. ; Masclee, Ad A.M. ; Boekschoten, Mark V. ; Faas, Marijke M. ; Troost, Freddy J. - \ 2017
Frontiers in Immunology 8 (2017). - ISSN 1664-3224 - 18 p.
Adaptive immunity - Indomethacin - Intestinal mucosal immunity - Lactobacillus plantarum - Non-steroidal anti-inflammatory drug - Probiotics

Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo-controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or WCFS1) or placebo for 7 days. To determine whether L. plantarum can enhance immune response, we compared the effects of three stains on systemic and gut mucosal immunity, by among others assessing memory responses against tetanus toxoid (TT)-antigen, and mucosal gene transcription, in human volunteers during induction of mild immune stressor in the intestine, by giving a commonly used enteropathic drug, indomethacin [non-steroidal anti-inflammatory drug (NSAID)]. Systemic effects of the interventions were studies in peripheral blood samples. NSAID was found to induce a reduction in serum CD4+ /Foxp3 regulatory cells, which was prevented by L. plantarum TIFN101. T-cell polarization experiments showed L. plantarum TIFN101 to enhance responses against TT-antigen, which indicates stimulation of memory responses by this strain. Cell extracts of the specific L. plantarum strains provoked responses after WCFS1 and TIFN101 consumption, indicating stimulation of immune responses against the specific bacteria. Mucosal immunomodulatory effects were studied in duodenal biopsies. In small intestinal mucosa, TIFN101 upregulated genes associated with maintenance of T- and B-cell function and antigen presentation. Furthermore, L. plantarum TIFN101 and WCFS1 downregulated immunological pathways involved in antigen presentation and shared downregulation of snoRNAs, which may suggest cellular destabilization, but may also be an indicator of tissue repair. Full sequencing of the L. plantarum strains revealed possible gene clusters that mightbe responsible for the differential biological effects of the bacteria on host immunity. In conclusion, the impact of oral consumption L. plantarum on host immunity is strain dependent and involves responses against bacterial cell components. Some strains may enhance specific responses against pathogens by enhancing antigen presentation and leukocyte maintenance in mucosa. In future studies and clinical settings, caution should be taken in selecting beneficial bacteria as closely related strains can have different effects. Our data show that specific bacterial strains can prevent immune stress induced by commonly consumed painkillers such as NSAID and can have enhancing beneficial effects on immunity of consumers by stimulating antigen presentation and memory responses.

Cathelicidins inhibit Escherichia coli-induced TLR2 and TLR4 activation in a viability-dependent manner
Coorens, Maarten ; Schneider, Viktoria A.F. ; Groot, A.M. De; Dijk, Albert I.J.M. Van; Meijerink, Marjolein ; Wells, Jerry M. ; Scheenstra, Maaike R. ; Veldhuizen, Edwin J.A. ; Haagsman, Henk P. - \ 2017
The Journal of Immunology 199 (2017)4. - ISSN 0022-1767 - p. 1418 - 1428.

Activation of the immune system needs to be tightly regulated to provide protection against infections and, at the same time, to prevent excessive inflammation to limit collateral damage to the host. This tight regulation includes regulating the activation of TLRs, which are key players in the recognition of invading microbes. A group of short cationic antimicrobial peptides, called cathelicidins, have previously been shown to modulate TLR activation by synthetic or purified TLR ligands and may play an important role in the regulation of inflammation during infections. However, little is known about how these cathelicidins affect TLR activation in the context of complete and viable bacteria. In this article, we show that chicken cathelicidin-2 kills Escherichia coli in an immunogenically silent fashion. Our results show that chicken cathelicidin-2 kills E. coli by permeabilizing the bacterial inner membrane and subsequently binds the outer membrane-derived lipoproteins and LPS to inhibit TLR2 and TLR4 activation, respectively. In addition, other cathelicidins, including human, mouse, pig, and dog cathelicidins, which lack antimicrobial activity under cell culture conditions, only inhibit macrophage activation by nonviable E. coli. In total, this study shows that cathelicidins do not affect immune activation by viable bacteria and only inhibit inflammation when bacterial viability is lost. Therefore, cathelicidins provide a novel mechanism by which the immune system can discriminate between viable and nonviable Gramnegative bacteria to tune the immune response, thereby limiting collateral damage to the host and the risk for sepsis.

Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue
Wang, Ya ; Balvers, Michiel G.J. ; Hendriks, Henk F.J. ; Wilpshaar, Tessa ; Heek, Tjarda van; Witkamp, Renger F. ; Meijerink, Jocelijn - \ 2017
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1862 (2017)9. - ISSN 1388-1981 - p. 823 - 831.
CCL-20 - Docosahexaenoyl serotonin - Endocannabinoids - IL-17 - Inflammatory bowel disease (IBD) - Th17

Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis.

Endocannabinoids derived from n-3 PUFAs - Formation, release and possible roles in inflammation and obesity
Wang, Ya - \ 2017
University. Promotor(en): Renger Witkamp, co-promotor(en): Jocelijn Meijerink; Jean-Paul Vincken. - Wageningen : Wageningen University - ISBN 9789463432016 - 195
polyunsaturated fats - health promotion - obesity - inflammation - cannabinoids - neurology - energy restricted diets - meervoudig onverzadigde vetten - gezondheidsbevordering - obesitas - ontsteking - cannabinoïden - neurologie - energiearme diëten

The fatty acid composition of our daily diet is considered a major determinant of long-term health risk and the development of disease. Several lines of evidence point toward a state of chronic ‘low-grade’ inflammation as an overarching process that is modulated by fatty acids and their different metabolites. Diets rich in omega-3 polyunsaturated fatty acids (PUFAs), among which docosahexaenoic acid (22:6n-3; DHA) have been found to be associated with a reduction of inflammatory activity. However, the mechanisms underlying these immune-modulatory effects of n-3 PUFAs are only partly known. Earlier data from our group and from other labs have provided evidence for an as yet largely unexplored mechanism involving the formation of DHA-derived fatty acid amides. Fatty acid amides (FAAs) are a group of lipids formed from fatty acids and biogenic amines, which are widely occurring in nature. An increasing number of FAAs, including conjugates of fatty acids with neurotransmitters and mono-amines, have been detected as endogenous molecules in different cells and tissues. However, their bioactivities have remained largely unknown so far.

In the first experimental part (chapter 2 and 3) of this thesis, we explored the immune-modulatory profiles of two relatively unknown DHA-derived FAAs conjugates with dopamine and serotonin, respectively. In chapter 2, we enzymatically synthesised the dopamine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and demonstrated that DHDA significantly suppressed the production of several mediators involved in (neuro-)inflammation. We showed that these immune-modulatory effects involved the enzyme cyclooxygenase-2 (COX-2), as its gene-expression and (or) production of its metabolite PGE2 were down-regulated by DHDA in both activated macrophages as well as microglia. Additionally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in the cell types tested. In chapter 3, we investigated the effects of docosahexaenoyl serotonin (DHA-5-HT), the serotonin conjugate of DHA on inflammatory processes in human PBMCs. By comparing the immune-modulatory potencies of 6 serotonin-conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT), oleic acid (OA-5-HT), arachidonic acid (AA-5-HT), eicosapentaenoic acid (EPA-5-HT) and docosahexaenoic acid (DHA-5-HT), DHA-5-HT turned out to exert the strongest inhibitory effects on the production of IL-17 from ConA-stimulated human PBMCs. Furthermore, DHA-5-HT concentration-dependently inhibited the production of IL-17 and CCL-20, two important Th17 mediators involved in the pathogenesis of IBD. Also, we demonstrated the in vivo presence of N-acyl serotonins in human intestine. Taken together, we revealed the immune-modulatory effects of two n-3 PUFA-derived fatty acid amides with thus far largely unknown functions and showed that these compounds were far more potent than its parent compound DHA. These findings were shown not only for innate inflammatory processes in stimulated mouse macrophages, but were also found to be present in human PBMCs and likely involved the adaptive CD4+ Th17 response.

In order to study the effects of dietary omega-3 fatty acids on endocannabinoid tone in relation to obesity and metabolic health, a parallel-designed, randomized human study was conducted in the second part of the thesis. In this 12 weeks intervention hundred men and women with abdominal obesity were assigned to either a Western type energy restricted (ER) diet, a Targeted ER diet or a control group. The two ER diet groups were both subjected to energy restriction but their diets differed in nutrient composition. The traditional, more Western-style diet (Western ER diet) included both saturated as well as unsaturated fats, whereas the Targeted ER diet was amongst others enriched with monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs). This intervention resulted in significant weight loss and significant improvements of metabolic parameters in both energy restriction (ER) dietary intervention groups. In chapter 4, we revealed that the two weight loss regimes (ER-diets) with different fatty acid composition did not significantly affect fasting peripheral levels of AEA and 2-AG in both plasma and abdominal adipose tissues. By contrast, plasma DHEA was found to be significantly decreased in the Western ER group compared with the Targeted ER group. Additionally, circulating EC-related compounds DHEA, DHAGly, PEA and SEA were significantly decreased in the Western ER diet group after intervention. Furthermore, decreased levels of DHEA were positively associated with body weight reduction. In chapter 5, by performing a high calorie mixed meal test (MMT) before and after the intervention, we found that postprandial AEA and 2-AG levels were significantly reduced in the targeted ER group upon the intervention. By contrast, the DHA-derived compounds DHEA and DHAGly showed a significant increase in the Targeted ER group after 12 weeks of intervention. Additionally, all measured endocannabinoids and related compounds, with the exception of 2-AG, showed a similar characteristic time curve in response to the MMT, with EC levels reaching their highest concentration as early as 5 minutes after food intake (T=10min in experiment).

In conclusion, we showed here that two largely unknown amidated DHA conjugates are more potent mediators of inflammatory processes than their parent compound DHA. These findings support our previously proposed idea that DHA-derived FAAs play a role in the underlying mechanism of the beneficial health effects of DHA. We further uncovered that a combination of ER and n-3 PUFAs in the diet alters the postprandial endocannabinoid tone. Given the fact that the endocannabinoid system (ECS) plays an important role in both the central and peripheral regulation of food intake and energy homeostasis, these findings provide new insights in the potentially mechanisms involved in an over-activated endocannabinoid system during obesity.

N-Docosahexaenoyl Dopamine, an Endocannabinoid-like Conjugate of Dopamine and the n-3 Fatty Acid Docosahexaenoic Acid, Attenuates Lipopolysaccharide-Induced Activation of Microglia and Macrophages via COX-2
Wang, Ya ; Plastina, Pierluigi ; Vincken, Jean Paul ; Jansen, Renate ; Balvers, Michiel ; Klooster, Jean Paul ten; Gruppen, Harry ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2017
ACS Chemical Neuroscience 8 (2017)3. - ISSN 1948-7193 - p. 548 - 557.
cyclooxygenase-2 - Endocannabinoids - interleukin-6 - N-arachidonoyl dopamine - N-docosahexaenoyl dopamine - prostaglandin E

Several studies indicate that the n-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) contributes to an attenuated inflammatory status in the development of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. To explain these effects, different mechanisms are being proposed, including those involving endocannabinoids and related signaling molecules. Many of these compounds belong to the fatty acid amides, conjugates of fatty acids with biogenic amines. Conjugates of DHA with ethanolamine or serotonin have previously been shown to possess anti-inflammatory and potentially neuroprotective properties. Here, we synthesized another amine conjugate of DHA, N-docosahexaenoyl dopamine (DHDA), and tested its immune-modulatory properties in both RAW 264.7 macrophages and BV-2 microglial cells. N-Docosahexaenoyl dopamine significantly suppressed the production of nitric oxide (NO), the cytokine interleukin-6 (IL-6), and the chemokines macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1), whereas its parent compounds, dopamine and DHA, were ineffective. Further exploration of potential effects of DHDA on key inflammatory mediators revealed that cyclooxygenase-2 (COX-2) mRNA level and production of prostaglandin E2 (PGE2) were concentration-dependently inhibited in macrophages. In activated BV-2 cells, PGE2 production was also reduced, without changes in COX-2 mRNA levels. In addition, DHDA did not affect NF-kB activity in a reporter cell line. Finally, the immune-modulatory activities of DHDA were compared with those of N-arachidonoyl dopamine (NADA) and similar potencies were found in both cell types. Taken together, our data suggest that DHDA, a potentially endogenous endocannabinoid, may be an additional member of the group of immune-modulating n-3 fatty acid-derived lipid mediators.

Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function
Ottman, Noora ; Reunanen, Justus ; Meijerink, Marjolein ; Pietila, Taija E. ; Kainulainen, Veera ; Klievink, Judith ; Huuskonen, Laura ; Aalvink, Steven ; Skurnik, Mikael ; Boeren, Sjef ; Satokari, Reetta ; Mercenier, Annick ; Palva, Airi ; Smidt, Hauke ; Vos, Willem M. de; Belzer, Clara - \ 2017
PLoS One 12 (2017)3. - ISSN 1932-6203

Gut barrier function is key in maintaining a balanced response between the host and its microbiome. The microbiota can modulate changes in gut barrier as well as metabolic and inflammatory responses. This highly complex system involves numerous microbiota-derived factors. The gut symbiont Akkermansia muciniphila is positively correlated with a lean phenotype, reduced body weight gain, amelioration of metabolic responses and restoration of gut barrier function by modulation of mucus layer thickness. However, the molecular mechanisms behind its metabolic and immunological regulatory properties are unexplored. Herein, we identify a highly abundant outer membrane pili-like protein of A. muciniphila MucT that is directly involved in immune regulation and enhancement of trans-epithelial resistance. The purified Amuc 1100 protein and enrichments containing all its associated proteins induced production of specific cytokines through activation of Toll-like receptor (TLR) 2 and TLR4. This mainly leads to high levels of IL-10 similar to those induced by the other beneficial immune suppressive microorganisms such as Faecalibacterium prausnitzii A2-165 and Lactobacillus plantarum WCFS1. Together these results indicate that outer membrane protein composition and particularly the newly identified highly abundant pili-like protein Amuc-1100 of A. muciniphila are involved in host immunological homeostasis at the gut mucosa, and improvement of gut barrier function.

Effect of Endoscopic Gastroplication on the Genome-Wide Transcriptome in the Upper Gastrointestinal Tract
Wielen, Nikkie van der; Paulus, Givan ; Avesaat, Mark van; Masclee, Ad ; Meijerink, Jocelijn ; Bouvy, Nicole - \ 2017
Obesity Surgery 27 (2017)3. - ISSN 0960-8923 - p. 740 - 748.
Adiponectin - Duodenum - Gastric tissue - Gastroplication - Gene expression - HbA1c - Immunity - Inflammation - Transcriptome
Background: Bariatric surgery is an effective intervention strategy in obesity, resulting in sustained weight loss and a reduction of comorbidities. Gastroplication, using the articulating circular endoscopic stapler, was recently introduced as a transoral bariatric technique. This procedure reduces gastric volume and induced 34.9 % of excess weight loss in the first year (Paulus et al. Gastrointest Endosc. 81(2):312–20, 3). The aim of the present study was to gain insight in the long-term effects and underlying mechanisms of gastroplication by investigating differences in the genome-wide gastric and duodenal transcriptome before and 1 year after intervention. Methods: Ten morbidly obese patients (BMI 39.8 ± 0.9 kg/m2 (mean ± SEM)) underwent gastroplication. Previous to the procedure and after 1 year, blood samples were taken, and mucosal biopsies were collected from the fundus, antrum and duodenum. Gene expression was measured using microarray analysis. Plasma adiponectin, HbA1c, IL-1β, IL-6, IL-7, TNF-α, IFN-γ, MCP-1, IL-8, TGF-1 and CRP levels were determined. Results: Downregulation of inflammatory genes and gene sets was observed in the fundus and duodenum 1 year after surgery. Gene expression of ghrelin and its activating enzyme GOAT were downregulated in the upper gastrointestinal tract. Patients showed a reduction in plasma HbA1c levels (from 6.17 ± 0.51 to 5.32 ± 0.14 %, p = 0.004) and an increase of plasma adiponectin (from 16.87 ± 3.67 to 27.67 ± 5.92 μg/ml, p = 0.002). Conclusions: Individuals undergoing gastroplication displayed a downregulation of inflammatory tone in the stomach and duodenum, which coincided with improved HbA1c and adiponectin levels. The reduction of inflammatory tone in the upper gastrointestinal tract may be a consequence of an improved metabolic health status or alternatively caused by the procedure itself.
Docosahexaenoyl Serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate, has anti-inflammatory properties by attenuating IL23–IL17 signalling in macrophages
Poland, M.C.R. ; Klooster, Jean Paul ten; Wang, Zheng ; Pieters, Raymond ; Boekschoten, M.V. ; Witkamp, R.F. ; Meijerink, J. - \ 2016
Mus musculus - GSE87369 - PRJNA344499
Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signalling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signalling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4 + Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100–500 nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signalling pathway in the aetiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.
The noncaloric sweetener rebaudioside a stimulates glucagon-like peptide 1 release and increases enteroendocrine cell numbers in 2-dimensional mouse organoids derived from different locations of the intestine
Wielen, Nikkie van der; Klooster, Jean Paul ten; Muckenschnabl, Susanne ; Pieters, Raymond ; Hendriks, Henk F.J. ; Witkamp, Renger F. ; Meijerink, Jocelijn - \ 2016
The Journal of Nutrition 146 (2016)12. - ISSN 0022-3166 - p. 2429 - 2435.
Duodenum - GLP-1 - Glucagon-like peptide 1 - Gut hormone - Ileum - Jejunum - Minigut - Organoids - Peptide YY - Stevia

Background: Glucagon-like peptide 1 (GLP-1) contributes to satiety and plays a pivotal role in insulin secretion and glucose homeostasis. Similar to GLP-1, peptide YY (PYY) and cholecystokinin also influence food intake. The secretion of these hormones by enteroendocrine cells along the intestine is modulated by nutrients. Preparations from the Stevia rebaudiana plant, including rebaudioside A, are increasingly being used as noncaloric sweeteners. Objective: We investigated the effects of rebaudioside A on enteroendocrine cells by assessing both cell numbers as well as their secretory capacity in an organoid model. Methods: A 2-dimensional organoid model derived from duodenal, jejunal, and ileal crypts of a C57BL/6J mouse was developed and characterized with the use of gene expression and immunofluorescence. We stimulated these organoids with 10 mmol/L rebaudioside A for 1 h and measured their GLP-1, PYY, and cholecystokinin release. We also analyzed the effects of rebaudioside A on gene expression in enteroendocrine cells after an 18-h incubation. Results: The 2-dimensional organoids contained crypt cells and differentiated villus cells, including enterocytes and goblet and enteroendocrine cells. These enteroendocrine cells stained positive for GLP-1, PYY, and serotonin. The cultured 2-dimensional organoids maintained their location-specific gene expression patterns. Compared with the control, rebaudioside A induced GLP-1 secretion 1.7-fold in the duodenum (P <0.01), 2.2-fold in the jejunum (P <0.01), and 4.3-fold in the ileum (P <0.001). PYY release was increased by rebaudioside A 3-fold in the ileumcompared with the control (P <0.05). Long-term (18-h) stimulation with the sweetener induced the expression of the enteroendocrine-specific markers chromogranin A, glucagon, Pyy, and cholecystokinin 3.5- (P <0.001), 3.5- (P <0.001), 3.8- (P <0.05), and 6.5-fold (P <0.001), respectively. Conclusions: These results show novel ex vivo effects of rebaudioside A on enteroendocrine cells of the mouse small intestine and highlight potentially new applications for rebaudioside A in metabolic diseases.

Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23–IL-17 signaling in macrophages
Poland, Mieke ; Klooster, Jean Paul ten; Wang, Zheng ; Pieters, Raymond ; Boekschoten, Mark ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2016
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1861 (2016)12. - ISSN 1388-1981 - p. 2020 - 2028.
Acyl serotonines - DHA - DHA-5-HT - Endocannabinoids - Intestine - Nrf2

Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100–500 nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.

Immunomodulatory properties of oat and barley β-glucan populations on bone marrow derived dendritic cells
Rosch, Christiane ; Meijerink, Marjolein ; Delahaije, Roy J.B.M. ; Taverne, Nico ; Gruppen, Harry ; Wells, Jerry M. ; Schols, Henk A. - \ 2016
Journal of Functional Foods 26 (2016). - ISSN 1756-4646 - p. 279 - 289.
Dendritic cells - Homogenisation - Immunomodulation - Particulate - Solubility

Specific structures of oat and barley β(1,3)(1,4)-glucans induced different in vitro immunomodulatory effects in bone marrow derived dendritic cells (BMDC) from TLR2/4 knock out mice. All barley β-glucan fractions induced larger amounts of cytokines in BMDCs than their oat equivalents. The particulate fractions of both glucans induced high amounts of cytokines, especially after sample homogenisation. The small particulate barley β-glucans induced more cytokines than the equivalent oat fraction, hence there are more features influencing the immunomodulatory properties of β-glucans than only the particle size. The soluble glucan fraction and heated suspension induced only low amounts of cytokines, but were different for the two β-glucans, indicating that molecular specificity matters for immunomodulation. Immunomodulatory activity is influenced by the insolubility of β-glucans, to which characteristics as particle size, granule conformation and particulate homogeneity are related. Consequently, sample preparation influences the immunomodulatory activity of β-glucans.

Strain-specific features of extracellular polysaccharides and their impact on Lactobacillus plantarum-host interactions
Lee, I.C. ; Caggianiello, Graziano ; Swam, Iris I. van; Taverne, Nico ; Meijerink, Marjolein ; Bron, Peter A. ; Spano, Giuseppe ; Kleerebezem, Michiel - \ 2016
Applied and Environmental Microbiology 82 (2016)13. - ISSN 0099-2240 - p. 3959 - 3970.

Lactobacilli are found in diverse environments and are widely applied as probiotic, health-promoting food supplements. Polysaccharides are ubiquitously present on the cell surface of lactobacilli and are considered to contribute to the species- and strainspecific probiotic effects that are typically observed. Two Lactobacillus plantarum strains, SF2A35B and Lp90, have an obvious ropy phenotype, implying high extracellular polysaccharide (EPS) production levels. In this work, we set out to identify the genes involved in EPS production in these L. plantarum strains and to demonstrate their role in EPS production by gene deletion analysis. A model L. plantarum strain, WCFS1, and its previously constructed derivative that produced reduced levels of EPS were included as reference strains. The constructed EPS-reduced derivatives were analyzed for the abundance and sugar compositions of their EPS, revealing cps2-like gene clusters in SF2A35B and Lp90 responsible for major EPS production. Moreover, these mutant strains were tested for phenotypic characteristics that are of relevance for their capacity to interact with the host epithelium in the intestinal tract, including bacterial surface properties as well as survival under the stress conditions encountered in the gastrointestinal tract (acid and bile stress). In addition, the Toll-like receptor 2 (TLR2) signaling and immunomodulatory capacities of the EPS-negative derivatives and their respective wild-type strains were compared, revealing strain-specific impacts of EPS on the immunomodulatory properties. Taken together, these experiments illustrate the importance of EPS in L. plantarum strains as a strain-specific determinant in host interaction.

Nutrient-induced glucagon like peptide-1 release is modulated by serotonin
Ripken, Dina ; Wielen, Nikkie van der; Wortelboer, Heleen M. ; Meijerink, Jocelijn ; Witkamp, Renger F. ; Hendriks, Henk F.J. - \ 2016
Journal of Nutritional Biochemistry 32 (2016). - ISSN 0955-2863 - p. 142 - 150.
GLP-1 - Nutrients - Rebaudioside A - Serotonin - Small intestine

Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists.Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50 mM) and rebaudioside A (12.5 mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release.Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155 μM) further enhanced casein and safflower oil induced-serotonin release.Exposure of ileal tissue segments to serotonin (30 μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100 μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10 μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process.

Intestinal nutrient sensing : a gut feeling for food
Wielen, N. van der - \ 2016
University. Promotor(en): Renger Witkamp, co-promotor(en): Jocelijn Meijerink; Henk F.J. Hendriks. - Wageningen : Wageningen University - ISBN 9789462576995 - 200 p.
obesity - hormones - intestines - gastrointestinal hormones - pancreozymin - vasoactive intestinal peptide - sensing - in vivo experimentation - animal models - in vitro - gastric bypass - food - weight reduction - stevia rebaudiana - release - obesitas - hormonen - darmen - maagdarmhormonen - pancreozymine - vasoactief intestinaal peptide - aftasten - in vivo experimenten - diermodellen - buik bypass - voedsel - gewichtsvermindering - vrijgeven

The alarming increase in obesity rates creates an urgent need for effective prevention and treatment strategies. The most effective treatment for obesity today is bariatric surgery. Bariatric surgery comprises a number of different procedures having in common that they induce weight loss and alter gut hormone release. Gut hormones are well known for their effects on food intake behavior and their role in weight loss after bariatric surgery is undeniable. In addition, the therapeutic use of GLP-1 (Glucagon-Like Peptide-1) analogues including liraglutide in type II diabetes and obesity is on the rise. This underlines why gut hormones are considered promising targets for the development of new treatment strategies against obesity and its comorbidities.

The secretion of gut hormones, among which GLP-1, is influenced by nutrient ingestion. The interactions of dietary components or their breakdown products with receptors and transporters located on the enteroendocrine cells of the intestinal tract can induce their release, a process called intestinal nutrient sensing. In this thesis, we aimed to further elucidate intestinal nutrient sensing mechanisms on a cellular level. First, the regional expression of several gut nutrient sensing related genes along the intestinal tract was assessed in three commonly studied species, namely mouse, pig and man. Gene expression of receptors, transporters and peptides involved in nutrient sensing shows a distinctive distribution pattern along the small intestine, which is in the distal small intestine highly similar between the species. Subsequently, we sought to investigate if this expression was changed after a weight loss inducing bariatric procedure. By whole transcriptome analysis, we showed that upper gastrointestinal tissue expression of genes associated with nutrient sensing was hardly changed. In contrast, a considerable reduction in inflammatory pathways was observed.

Next, we sought to investigate the effects of the non-caloric sweetener rebaudioside A. This Stevia rebaudiana-derived compound was approved on the European market in 2011. As there is still some controversy about the effects of sweeteners in general on GLP-1 release, we investigated the effects of this specific sweetener. Because of the short half-life of GLP-1, the effect of nutrient stimulation was mainly studied in ex vivo and in vitro models in which local intestinal hormone release could be determined. A two dimensional gut model using intestinal organoids derived from murine intestinal crypts was developed to study location-specific hormone secretion. Rebaudioside A was found to induce GLP-1 and PYY release ex vivo from porcine intestinal tissue and in two dimensional organoids. This induction of the release was specific for the intestinal location, with the ileum being most potently stimulated by rebaudioside A. Moreover, prolonged exposure to rebaudioside A increased enteroendocrine cell numbers in two dimensional organoids. When studying the underlying mechanism in enteroendocrine STC-1 cells, we concluded that rebaudioside A-induced GLP-1 release was independent of the sweet taste receptor.

The studies presented in this thesis add to our understanding the role of receptors and other molecular structures that are likely to be involved in nutrient sensing and the modulation of gut hormone release. What we know now is that several factors play a role in gut hormone release. This includes not only the nature and dose of the active compound(s), but also the location and timing of its (their) interactions with receptors and other targets along the gastrointestinal tract. We have shown that rebaudioside A may be a potential compound to induce gut hormone release in vivo, especially when applied to the distal small intestine. Therefore, rebaudioside A may be a promising compound to influence food intake, possibly most potent when delivered in the ileum.

The agr Inhibitors Solonamide B and Analogues Alter Immune Responses to Staphylococccus aureus but Do Not Exhibit Adverse Effects on Immune Cell Functions
Baldry, Mara ; Kitir, Betöl ; Frøkir, Hanne ; Christensen, S.B. ; Taverne, Nico ; Meijerink, Marjolein ; Franzyk, Henrik ; Olsen, C.A. ; Wells, J.M. ; Ingmer, Hanne - \ 2016
PLoS One 11 (2016)1. - ISSN 1932-6203 - 17 p.

Staphylococcus aureus infections are becoming increasingly difficult to treat due to antibiotic resistance with the community-Associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300 being of particular concern. The inhibition of bacterial virulence has been proposed as an alternative approach to treat multi-drug resistant pathogens. One interesting anti-virulence target is the agr quorum-sensing system, which regulates virulence of CA-MRSA in response to agr-encoded autoinducing peptides. Agr regulation confines exotoxin production to the stationary growth phase with concomitant repression of surfaceexpressed adhesins. Solonamide B, a non-ribosomal depsipeptide of marine bacterial origin, was recently identified as a putative anti-virulence compound that markedly reduced expression of ?-hemolysin and phenol-solublemodulins. To further strengthen solonamide anti-virulence candidacy, we report the chemical synthesis of solonamide analogues, investigation of structure-function relationships, and assessment of their potential tomodulate immune cell functions. We found that structural differences between solonamide analogues confer significant differences in interference with agr, while immune cell activity and integrity is generally not affected. Furthermore, treatment of S. aureus with selected solonamides was found to only marginally influence the interaction with fibronectin and biofilm formation, thus addressing the concern that application of compounds inducing an agr-negative state may have adverse interactions with host factors in favor of host colonization.

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