A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice
Plas, Rogier L.C. ; Poland, Mieke ; Faber, Joyce ; Argilès, Josep ; Dijk, Miriam van; Laviano, Alessandro ; Meijerink, Jocelijn ; Witkamp, Renger F. ; Helvoort, Ardy van; Norren, Klaske van - \ 2019
International Journal of Molecular Sciences 20 (2019)20. - ISSN 1661-6596
cachexia - fish oil - hypercalcemia - leucine - PTHrP
BACKGROUND: Dietary supplementation with leucine and fish oil rich in omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has previously been shown to reduce cachexia-related outcomes in C26 tumour-bearing mice. To further explore associated processes and mechanisms we investigated changes in plasma Ca2+ levels, the involvement of parathyroid hormone related protein (PTHrP), and its possible interactions with cyclooxygenase 2 (COX-2). METHODS: CD2F1 mice were subcutaneously inoculated with C26 adenocarcinoma cells or sham treated and divided in: (1) controls, (2) tumour-bearing controls, and (3) tumour-bearing receiving experimental diets. After 20 days, body and organ masses and total plasma Ca2+ levels were determined. Furthermore, effects of DHA, EPA and leucine on production of PTHrP were studied in cultured C26 cells. RESULTS: The combination of leucine and fish oil reduced tumour-associated hypercalcemia. Plasma Ca2+ levels negatively correlated with carcass mass and multiple organ masses. DHA was able to reduce PTHrP production by C26 cells in vitro. Results indicate that this effect occurred independently of COX-2 inhibition. CONCLUSION: Our results suggest that cancer-related hypercalcemia may be ameliorated by a nutritional intervention rich in leucine and fish oil. The effect of fish oil possibly relates to a DHA-induced reduction of PTHrP excretion by the tumour.
N-Eicosapentaenoyl Dopamine, A Conjugate of Dopamine and Eicosapentaenoic Acid (EPA), Exerts Anti-inflammatory Properties in Mouse and Human Macrophages
Augimeri, Giuseppina ; Plastina, Pierluigi ; Gionfriddo, Giulia ; Rovito, Daniela ; Giordano, Cinzia ; Fazio, Alessia ; Barone, Ines ; Catalano, Stefania ; Andò, Sebastiano ; Bonofiglio, Daniela ; Meijerink, Jocelijn ; Witkamp, Renger - \ 2019
Nutrients 11 (2019)9. - ISSN 2072-6643
cyclooxygenase-2 - cytokines - endocannabinoid - inflammation - N-acyl dopamine - N-eicosapentaenoyl dopamine - polyunsaturated fatty acids (PUFAs)
A large body of evidence suggests that dietary n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), contribute to a reduced inflammatory tone thereby lowering the risk for several chronic and degenerative diseases. Different mechanisms have been proposed to explain these anti-inflammatory effects, including those involving endocannabinoids and endocannabinoid-like molecules. In this context, fatty acid amides (FAAs), conjugates of fatty acids with amines or amino acids, are an emerging class of compounds. Dopamine conjugates of DHA (N-docosahexaenoyl dopamine, DHDA) and EPA (N-eicosapentaenoyl dopamine, EPDA) have previously been shown to induce autophagy, apoptosis, and cell death in different tumor lines. Additionally, DHDA has displayed anti-inflammatory properties in vitro. Here, we tested the immune-modulatory properties of EPDA in mouse RAW 264.7 and human THP-1 macrophages stimulated with lipopolysaccharide (LPS). EPDA suppressed the production of monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in both cell lines, and nitric oxide (NO), and macrophage-inflammatory protein-3α (MIP3A) in RAW 264.7 macrophages. At a transcriptional level, EPDA attenuated cyclooxygenase-2 (COX-2) expression in both cell lines and that of MCP-1, IL-6, and interleukin-1β (IL-1β) in THP-1 macrophages. Although further research is needed to reveal whether EPDA is an endogenous metabolite, our data suggest that this EPA-derived conjugate possesses interesting immune-modulating properties.
Intestinal Permeability Measured by Urinary Sucrose Excretion Correlates with Serum Zonulin and Faecal Calprotectin Concentrations in UC Patients in Remission
Wegh, C.A.M. ; Roos, N.M. De; Hovenier, R. ; Meijerink, J. ; Besseling-Van Der Vaart, I. ; Hemert, S. Van; Witteman, B.J.M. - \ 2019
Journal of Nutrition and Metabolism 2019 (2019). - ISSN 2090-0724
Background and Aims. Ulcerative colitis (UC) is associated with an increased intestinal permeability, possibly through a dysbiosis of intestinal bacteria. We investigated which markers are most relevant to assess intestinal permeability in UC patients and whether probiotics had an effect on these markers. Methods. In this twelve-week placebo-controlled randomized double-blind study, twenty-five subjects with UC in remission received either placebo or a multispecies probiotics. Samples of blood, urine, and faeces were taken at baseline, week 6, and week 12 to assess intestinal permeability and inflammation. Diaries and Bristol stool scale were kept to record stool frequency and consistency. Quality of life was scored from 32-224 with the inflammatory bowel disease questionnaire (IBD-Q). Results. This group of UC patients, in clinical remission, did not show increased intestinal permeability at baseline of this study. During the study, no significant group or time effects were found for intestinal permeability measured by the 5-sugar absorption test, serum zonulin, and faecal zonulin. Likewise, the inflammatory markers C-reactive protein (CRP), calprotectin, and the cytokines IFNγ, TNFα, IL-6, and IL-10 were not significantly affected. Stool frequency and consistency were not significantly affected either. The IBD-Q score, 194 for the probiotics group and 195 for the placebo group, remained unaffected. Correlations were tested between all outcomes; urinary sucrose excretion was significantly correlated with serum zonulin (r = 0.62) and faecal calprotectin (r = 0.55). Faecal zonulin was not significantly correlated with any of the other markers. Conclusion. Serum zonulin may be a more relevant biomarker of intestinal permeability than faecal zonulin, due to its correlation with other biomarkers of intestinal permeability. UC patients in remission did not show an effect of the probiotic treatment or a change in gut permeability. This should not discourage further studies because effects might be present during active disease or shortly after a flare up.
Capsaicin analogues derived from n-3 polyunsaturated fatty acids (PUFAs) reduce inflammatory activity of macrophages and stimulate insulin secretion by β-cells in vitro
Cione, Erika ; Plastina, Pierluigi ; Pingitore, Attilio ; Perri, Mariarita ; Caroleo, Maria Cristina ; Fazio, Alessia ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2019
Nutrients 11 (2019)4. - ISSN 2072-6643
Diabetes - Fatty acid amides - Inflammation - Obesity - PUFA - Vanillylamide
In this study, two capsaicin analogues, N-eicosapentaenoyl vanillylamine (EPVA) and N-docosahexaenoyl vanillylamine (DHVA), were enzymatically synthesized from their corresponding n-3 long chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both dietary relevant components. The compounds significantly reduced the production of some lipopolysaccharide (LPS)-induced inflammatory mediators, including nitric oxide (NO), macrophage-inflammatory protein-3α (CCL20) and monocyte chemoattractant protein-1 (MCP-1 or CCL2), by RAW264.7 macrophages. Next to this, only EPVA increased insulin secretion by pancreatic INS-1 832/13 β-cells, while raising intracellular Ca 2+ and ATP concentrations. This suggests that the stimulation of insulin release occurs through an increase in the intracellular ATP/ADP ratio in the first phase, while is calcium-mediated in the second phase. Although it is not yet known whether EPVA is endogenously produced, its potential therapeutic value for diabetes treatment merits further investigation.
Participatieve monitoring in Lumbricus : Een brug tussen innovatie en implementatie
Breman, B.C. ; Kuindersma, W. ; Meijerink, Sander ; Ellen, Gerald Jan ; Wassink, W. ; Brugmans, Bart ; Bolt, F.J.E. van der - \ 2019
Water Governance (2019)1. - ISSN 2211-0224 - p. 46 - 49.
Nederland staat voor een aantal grote uitdagingen op het gebied van het waterbeheer, dat heeft de zomer van 2018 nog maar eens extra duidelijk gemaakt. Omdat het klimaat verandert krijgen we vaker te maken met extreme neerslag en langdurige perioden van droogte. Dit heeft direct consequenties voor onder andere de waterkwaliteit en de waterkwantiteit. Op de hoger gelegen zandgronden in Nederland zijn deze consequenties zo mogelijk nog groter omdat hier de mogelijkheden om water tijdelijk te bergen of van elders aan te voeren vaak veel beperkter zijn.
Identification of hydroxytyrosyl oleate, a derivative of hydroxytyrosol with anti-inflammatory properties, in olive oil by-products
Plastina, Pierluigi ; Benincasa, Cinzia ; Perri, Enzo ; Fazio, Alessia ; Augimeri, Giuseppina ; Poland, Mieke ; Witkamp, Renger ; Meijerink, Jocelijn - \ 2019
Food Chemistry 279 (2019). - ISSN 0308-8146 - p. 105 - 113.
COX-2 - Hydroxytyrosyl ester - Inflammation - Macrophages - NO - Olive mill waste water - Olive oil - PGE
Hydroxytyrosyl esters with short, medium and long acyl chains were evaluated for their ability to reduce nitric oxide (NO) production by lipopolysaccharide-stimulated RAW264.7 macrophages. Among the compounds tested, C18 esters, namely hydroxytyrosyl stearate (HtySte) and hydroxytyrosyl oleate (HtyOle), were found to decrease NO production in a concentration-dependent manner, while the other compounds, including the parent hydroxytyrosol, were ineffective in the tested concentration range (0.5–5 μM). Further study of the potential immune-modulating properties of HtyOle revealed a significant and concentration-dependent suppression of prostaglandin E2 production. At a transcriptional level, HtyOle inhibited the expression of inducible NO synthase, cyclooxygenase-2 and interleukin-1β. Moreover, HtyOle was identified for the first time in olive oil by-products by means of high performance liquid chromatography coupled with mass spectrometry. By contrast, HtyOle was not found in intact olives. Our results suggest that HtyOle is formed during oil processing and represents a significant form in which hydroxytyrosol occurs.
|Sla van de bovenste plank
Marcelis, Leo - \ 2018
Verticale landbouw: de term lijkt te passen in het rijtje megastal, legbatterij en andere uitwassen van het moderne agrarische bedrijf. Maar het tegendeel is waar. Technologie biedt hier juist kansen voor duurzame voedselproductie
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
Wageningen University. Promotor(en): R.F. Witkamp, co-promotor(en): J. Meijerink; J.-P. 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.