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High fat challenges with different fatty acids affect distinct atherogenic gene expression pathways in immune cells from lean and obese subjects
Esser, D. ; Dijk, S.J. van; Oosterink, E. ; Lopez, S. ; Muller, M.R. ; Afman, L.A. - \ 2015
Molecular Nutrition & Food Research 59 (2015)8. - ISSN 1613-4125 - p. 1563 - 1572.
triglyceride-rich lipoproteins - blood mononuclear-cells - men - atherosclerosis - inflammation - activation - receptors - adherence - profiles - alpha
Scope - Early perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells toward a high MUFA or saturated fatty acids (SFA) challenge between subjects with different cardiovascular disease risk profiles and to identify fatty acid specific gene-expression pathways. Methods and results -In a cross-over study, 17 lean and 15 obese men (50–70 years) received two 95 g fat shakes, high in SFAs or MUFAs. Peripheral blood mononuclear cell gene-expression profiles were assessed fasted and 4-h postprandially. Comparisons were made between groups and shakes. During fasting, 294 genes were significantly differently expressed between lean and obese. The challenge increased differences to 607 genes after SFA and 2516 genes after MUFA. In both groups, SFA decreased expression of cholesterol biosynthesis and uptake genes and increased cholesterol efflux genes. MUFA increased inflammatory genes and PPAR-a targets involved in ß-oxidation. Conclusion - Based upon gene-expression changes, we conclude that an HF challenge magnifies differences in health, especially after MUFA. Our findings also demonstrate how SFAs and MUFAs exert distinct effects on lipid handling pathways in immune cells.
Nutritional aspects of metabolic inflammation in relation to health-insights from transcriptomic biomarkers in PBMC of fatty acids and polyphenols
Afman, L.A. ; Milenkovic, D. ; Roche, H. - \ 2014
Molecular Nutrition & Food Research 58 (2014)8. - ISSN 1613-4125 - p. 1708 - 1720.
blood mononuclear-cells - gene-expression profiles - fish-oil supplementation - improves insulin sensitivity - randomized controlled-trial - coronary-artery-disease - adipose-tissue - postmenopausal women - nlrp3 inflammasome - in-vivo
Recent research has highlighted potential important interaction between metabolism and inflammation, within the context of metabolic health and nutrition, with a view to preventing diet-related disease. In addition to this, there is a paucity of evidence in relation to accurate biomarkers that are capable of reflecting this important biological interplay or relationship between metabolism and inflammation, particularly in relation to diet and health. Therefore the objective of this review is to highlight the potential role of transcriptomic approaches as a tool to capture the mechanistic basis of metabolic inflammation. Within this context, this review has focused on the potential of peripheral blood mononuclear cells transcriptomic biomarkers, because they are an accessible tissue that may reflect metabolism and subacute chronic inflammation. Also these pathways are often dysregulated in the common diet-related diseases obesity, type 2 diabetes, and cardiovascular disease, thus may be used as markers of systemic health. The review focuses on fatty acids and polyphenols, two classes of nutrients/nonnutrient food components that modulate metabolism/inflammation, which we have used as an example of a proof-of-concept with a view to understanding the extent to which transcriptomic biomarkers are related to nutritional status and/or sensitive to dietary interventions. We show that both nutritional components modulate inflammatory markers at the transcriptomic level with the capability of profiling pro- and anti-inflammatory mechanisms in a bidirectional fashion; to this end transcriptomic biomarkers may have potential within the context of metabolic inflammation. This transcriptomic biomarker approach may be a sensitive indicator of nutritional status and metabolic health.
Nutrigenomics of Body Weight Regulation: A Rationale for Careful Dissection of Individual Contributors
Keijer, J. ; Hoevenaars, F.P.M. ; Nieuwenhuizen, A.G. ; Schothorst, E.M. van - \ 2014
Nutrients 6 (2014)10. - ISSN 2072-6643 - p. 4531 - 4551.
blood mononuclear-cells - diet-induced obesity - high-fat diet - adipose-tissue - metabolic-rate - adaptive thermogenesis - food-intake - nutrition transition - energy-requirements - mass-spectrometry
Body weight stability may imply active regulation towards a certain physiological condition, a body weight setpoint. This interpretation is ill at odds with the world-wide increase in overweight and obesity. Until now, a body weight setpoint has remained elusive and the setpoint theory did not provide practical clues for body weight reduction interventions. For this an alternative theoretical model is necessary, which is available as the settling point model. The settling point model postulates that there is little active regulation towards a predefined body weight, but that body weight settles based on the resultant of a number of contributors, represented by the individual’s genetic predisposition, in interaction with environmental and socioeconomic factors, such as diet and lifestyle. This review refines the settling point model and argues that by taking body weight regulation from a settling point perspective, the road will be opened to careful dissection of the various contributors to establishment of body weight and its regulation. This is both necessary and useful. Nutrigenomic technologies may help to delineate contributors to body weight settling. Understanding how and to which extent the different contributors influence body weight will allow the design of weight loss and weight maintenance interventions, which hopefully are more successful than those that are currently available.
Transcriptome-based functional classifiers for direct immunotoxicity
Shao, J. ; Berger, L.F. ; Hendriksen, P.J.M. ; Peijnenburg, A.A.C.M. ; Loveren, H. van; Volger, O.L. - \ 2014
Archives of Toxicology 88 (2014)3. - ISSN 0340-5761 - p. 673 - 689.
blood mononuclear-cells - gene-expression - cyclin g2 - in-vitro - t-cells - jurkat - toxicogenomics - bioactivation - activation - exposure
Current screening methods for direct immunotoxic chemicals are mainly based on general toxicity studies with rodents. The present study aimed to identify transcriptome- based functional classifiers that can eventually be exploited for the development of in vitro screening assays for direct immunotoxicity. To this end, a toxicogenomics approach was applied in which gene expression changes in human Jurkat lymphoblastic T cells were investigated in response to a wide range of compounds, including direct immunotoxicants, immunosuppressive drugs, and non-immunotoxic control chemicals. On the basis of DNA microarray data previously obtained by the exposure of Jurkat cells to 31 test compounds (Shao et al. in Toxicol Sci 135(2):328–346, 2013), we identified a set of 93 genes, of which 80 were significantly regulated (|numerical ratio| C1.62) by at least three compounds and the other 13 genes were significantly regulated by either one single compound or compound class. A total of 28 most differentially regulated genes were selected for qRT-PCR verification using a training set of 44 compounds consisting of the above-mentioned 31 compounds (23 immunotoxic and 8 non-immunotoxic) and 13 additional immunotoxicants. Good correlation between the results of microarray and qRT-PCR (Pearson’s correlation, R C 0.69) was found for 27 out of the 28 genes. Redundancy analysis of these 27 potential classifiers led to a final set of 25 genes. To assess the performance of these genes, Jurkat cells were exposed to 20 additional compounds (external verification set) followed by qRT-PCR. The classifier set of 25 genes gave a good performance in the external verification: accuracy 85 %, true positive rate (sensitivity) 88 %, and true negative rate (specificity) 67 %. Furthermore, on the basis of the gene ontology annotation of the 25 classifier genes, the immunotoxicants examined in this study could be categorized into distinct functional subclasses. In conclusion, we have identified and validated classifier genes that can be used for the development of an in vitro assay for the identification and initial characterization of hazards for direct immunotoxicity of chemicals and drugs. This assay promises to complement animal-free toxicity testing approaches within the field of direct immunotoxicity.
Toxicogenomics-Based Identification of Mechanisms for Direct Immunitoxicity
Shao, J. ; Katika, M.R. ; Schmeits, P.C. ; Hendriksen, P.J.M. ; Loveren, H. van; Peijnenburg, A.A.C.M. ; Volger, O.L. - \ 2013
Toxicological sciences 135 (2013)2. - ISSN 1096-6080 - p. 328 - 346.
unfolded protein response - nf-kappa-b - endoplasmic-reticulum stress - blood mononuclear-cells - liver-x-receptor - proliferator-activated receptor - gene-expression profiles - in-vitro - ochratoxin-a - human-lymphocytes
Compounds with direct immunotoxic properties, including metals, mycotoxins, agricultural pesticides, and industrial chemicals, form potential human health risks due to exposure through food, drinking water, and the environment. Insights into the mechanisms of action are currently lacking for the majority of these direct immunotoxicants. Therefore, the present work aimed to gain insights into the molecular mechanisms underlying direct immunotoxicity. To this end, we assessed in vitro the effects of 31 test compounds on the transcriptome of the human Jurkat T-cell line. These compounds included direct immunotoxicants, immunosuppressive drugs with different mode of actions, and nonimmunotoxic control chemicals. Pathway analysis of the microarray data allowed us to identify canonical pathways and Gene Ontology processes that were transcriptionally regulated in common by immunotoxicants (1) with structural similarities, such as tributyltin chloride and tributyltin oxide that activated the retinoic acid/X receptor signaling pathway and (2) without structural similarities, such as As2O3, dibutyltin chloride, diazinon, MeHg, ochratoxin A (OTA), S9-treated OTA, S9-treated cyclophosphamide, and S9-treated benzo[a]pyrene, which activated unfolded protein response, and FTY720, lindane, and propanil, which activated the cholesterol biosynthesis pathway. In addition, processes uniquely affected by individual immunotoxicants were identified, such as the induction of Notch receptor signaling and the downregulation of acute-phase response genes by OTA. These findings were validated by quantitative real-time PCR analysis of genes involved in these processes. Our study indicated that diverse modes of action are involved in direct immunotoxicity and that a set of pathways or genes, rather than one single gene, can be used to screen compounds for direct immunotoxicity.
Immune Modulation by Different Types of ß2¿1-Fructans Is Toll-Like Receptor Dependent
Vogt, L. ; Ramasamy, U. ; Meyer, D. ; Pullens, G. ; Venema, K. ; Faas, M.M. ; Schols, H.A. ; Vos, P. de - \ 2013
PLoS ONE 8 (2013)7. - ISSN 1932-6203 - 12 p.
chain fatty-acids - nf-kappa-b - blood mononuclear-cells - dendritic cells - lactobacillus-rhamnosus - bifidobacterium-lactis - signal-transduction - innate immunity - dietary fiber - inulin
Introduction ß2¿1-fructans are dietary fibers. Main objectives of this study were 1) to demonstrate direct signalling of ß2¿1-fructans on immune cells, 2) to study whether this is mediated by the pattern recognition receptors Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain-containing proteins (NODs), and 3) to relate the observed effects to the chain length differences in ß2¿1-fructans. Methods Four different ß2¿1-fructan formulations were characterised for their chain length profile. Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with ß2¿1-fructans, and production of IL-1Ra, IL-1ß, IL-6, IL-10, IL-12p70, and TNF-a was analysed. Reporter cells for TLRs and NODs were incubated with ß2¿1-fructans and analysed for NF-¿B/AP-1 activation. Results Cytokine production in human PBMCs was dose- and chain length-dependent. Strikingly, short chain enriched ß2¿1-fructans induced a regulatory cytokine balance compared to long chain enriched ß2¿1-fructans as measured by IL-10/IL-12 ratios. Activation of reporter cells showed that signalling was highly dependent on TLRs and their adapter, myeloid differentiation primary response protein 88 (MyD88). In human embryonic kidney reporter cells, TLR2 was prominently activated, while TLR4, 5, 7, 8, and NOD2 were mildly activated. Conclusions ß2¿1-fructans possess direct signalling capacity on human immune cells. By activating primarily TLR2, and to a lesser extent TLR4, 5, 7, 8, and NOD2, ß2¿1-fructan stimulation results in NF-¿B/AP-1 activation. Chain length of ß2¿1-fructans is important for the induced activation pattern and IL-10/IL-12 ratios.
A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies
Calder, P.C. ; Ahluwalia, N. ; Albers, R. ; Bosco, N. ; Bourdet-Sicard, R. ; Haller, D. ; Holgate, S.T. ; Jönsson, L.S. ; Latulippe, M.E. ; Marcos, A. ; Moreines, J. ; M'Rini, C. ; Müller, M.R. ; Pawelec, G. ; Neerven, R.J.J. van; Watzl, B. ; Zhao, J. - \ 2013
The British journal of nutrition 109 (2013)S1. - ISSN 0007-1145 - p. S1 - S34.
c-reactive protein - necrosis-factor-alpha - low-grade inflammation - coronary-artery-disease - blood mononuclear-cells - ischemic-heart-disease - plasma il-6 levels - obstructive pulmonary-disease - endoplasmic-reticulum stress - systemic-lupus-erythematosus
To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.
Challenges in translational research on probiotic lactobacilli: from in vitro assays to clinical trials
Meijerink, M. ; Mercenier, A.M.E. ; Wells, J. - \ 2013
Beneficial Microbes 4 (2013)1. - ISSN 1876-2883 - p. 83 - 100.
placebo-controlled trial - lactic-acid bacteria - regulatory t-cells - blood mononuclear-cells - intestinal epithelial-cells - irritable-bowel-syndrome - influenza-virus infection - randomized controlled-trial - tight junction proteins - host-microbiota dialog
Beneficial effects of certain probiotic strains have been established in the treatment and prevention of various immune and intestinal disorders in humans, including allergic diseases, chronic inflammatory diseases and diarrhoea. The proposed mechanisms underlying the immunomodulatory effects of probiotics in humans are not understood in precise detail but include enhancement of intestinal barrier function, altered epithelial signalling, competition with pathogens and effects on immune cells and immunity depending on the probiotic strain. The publication of controversial or inconclusive probiotic studies in humans highlights the need for a better understanding of the mechanisms and improved strain selection criteria. This review focuses on the immunomodulatory properties of lactobacilli and bifidobacteria in vitro and in vivo, current knowledge concerning the mechanisms in vivo and challenges in translational research on probiotics. A better understanding of the molecular mechanisms of probiotics, the effect of probiotic mixtures versus single strains, the effect of formulation of probiotics and the fate of ingested probiotics should help to clarify the value of immune assays as selection criteria for probiotics.
The Impact of Lactobacillus plantarum WCFS1 Teichoic Acid D-Alanylation on the Generation of Effector and Regulatory T-cells in Healthy Mice
Smelt, M.J. ; Haan, B.J. de; Bron, P.A. ; Swam, I. van; Meijerink, M. ; Wells, J. ; Kleerebezem, M. ; Faas, M.M. ; Vos, P. de - \ 2013
PLoS ONE 8 (2013)4. - ISSN 1932-6203 - 14 p.
placebo-controlled trial - inflammatory-bowel-disease - blood mononuclear-cells - tlr signaling pathways - lipoteichoic acid - double-blind - dendritic cells - ulcerative-colitis - maintaining remission - acidophilus deficient
To date it remains unclear how probiotics affect the immune system. Bacterial envelope components may play an essential role, as these are the first to establish bacterial-host cell interactions. Teichoic acids (TAs), and especially lipoteichoic acids, are the most pro-inflammatory components of the gram-positive bacterial envelope. This effect is dependent on D-alanyl substitution of the TA backbone and interactions with TLR2 on host cells. Although the pro-inflammatory properties of TAs have been established in vitro, it remains unclear how TAs affect immunomodulation in vivo. In this study, we investigated the role of TA D-alanylation on L. plantarum–induced intestinal and systemic immunomodulation in vivo. For this, we compared the effect of L. plantarum WCFS1 and its TA D-Alanylation negative derivative (dltX-D) on the distribution of dendritic cell and T cell populations and responses in healthy mice. We demonstrated that the majority of the L. plantaruminduced in vivo immunomodulatory effects were dependent on D-alanylation (D-Ala), as some L. plantarum WCFS1-induced immune changes were not observed in the dltX-D-treated group and some were only observed after treatment with dltX-D. Strikingly, not only pro-inflammatory immune responses were abolished in the absence of D-Ala substitution, but also antiinflammatory responses, such as the L. plantarum-induced generation of regulatory T cells in the spleen. With this study we provide insight in host-microbe interactions, by demonstrating the involvement of D-alanylation of TAs on the bacterial membrane in intestinal and systemic immunomodulation in healthy mice.
Human nutrigenomics of gene regulation by dietary fatty acids
Afman, L.A. ; Muller, M.R. - \ 2012
Progress in Lipid Research 51 (2012)1. - ISSN 0163-7827 - p. 63 - 70.
inflammation-related genes - activated receptor-alpha - blood mononuclear-cells - fish-oil supplementation - nonobese pima-indians - necrosis-factor-alpha - insulin-resistance - peripheral-blood - adipose-tissue - expression profiles
Nutrigenomics employs high-throughput genomics technologies to unravel how nutrients modulate gene and protein expression and ultimately influence cellular and organism metabolism. The most often-applied genomics technique so far is transcriptomics, which allows quantifying genome-wide changes in gene expression of thousands of genes at the same time in one sample. The performance of gene expression quantification requires sufficient high-quality homogenous cellular material, therefore research in healthy volunteers is restricted to biopsies from easy accessible tissues such as subcutaneous adipose tissue, skeletal muscle and intestinal biopsies or even more easily accessible cells such as peripheral blood mononuclear cells from blood. There is now significant evidence that fatty acids, in particular unsaturated fatty acids, exert many of their effects through modulation of gene transcription by regulating the activity of numerous transcription factors, including nuclear receptors such as peroxisome proliferator activated receptors, liver X receptor and sterol regulatory binding proteins. This review evaluates the human nutrigenomics studies performed on dietary fat since the initiation of nutrigenomics research around 10 years ago. Although the number of studies is still limited, all studies clearly suggest that changes in dietary fatty acids intake and composition can have a significant impact on cellular adaptive response capacity by gene transcription changes in humans. This adds important knowledge to our understanding of the strong effects that various fatty acids can have on numerous metabolic and inflammatory pathways, signaling routes and homeostatic control in the cell and ultimately on whole body health. It is important to use and integrate nutrigenomics in all future nutrition studies to build up the necessary framework for evidence-based nutrition in near future.
L. plantarum, L. salivarius, and L. lactis Attenuate Th2 Responses and Increase Treg Frequencies in Healthy Mice in a Strain Dependent Manner
Smelt, M.J. ; Haan, B.J. de; Bron, P.A. ; Swam, I. van; Meijerink, M. ; Wells, J. ; Faas, M.M. ; Vos, P. de - \ 2012
PLoS ONE 7 (2012)10. - ISSN 1932-6203
inflammatory-bowel-disease - lactobacillus-casei shirota - influenza-virus infection - placebo-controlled trial - complete genome sequence - blood mononuclear-cells - dendritic cells - double-blind - immune-system - acid bacteria
Many studies on probiotics are aimed at restoring immune homeostasis in patients to prevent disease recurrence or reduce immune-mediated pathology. Of equal interest is the use of probiotics in sub-clinical situations, which are characterized by reduced immune function or low-grade inflammation, with an increased risk of infection or disease as a consequence. Most mechanistic studies focus on the use of probiotics in experimental disease models, which may not be informative for these sub-clinical conditions. To gain better understanding of the effects in the healthy situation, we investigated the immunomodulatory effects of two Lactobacillus probiotic strains, i.e. L. plantarum WCFS1 and L. salivarius UCC118, and a non-probiotic lactococcus strain, i.e. L. lactis MG1363, in healthy mice. We studied the effect of these bacteria on the systemic adaptive immune system after 5 days of administration. Only L. plantarum induced an increase in regulatory CD103+ DC and regulatory T cell frequencies in the spleen. However, all three bacterial strains, including L. lactis, reduced specific splenic T helper cell cytokine responses after ex vivo restimulation. The effect on IFN-¿, IL5, IL10, and IL17 production by CD4+ and CD8+ T cells was dependent on the strain administered. A shared observation was that all three bacterial strains reduced T helper 2 cell frequencies. We demonstrate that systemic immunomodulation is not only observed after treatment with probiotic organisms, but also after treatment with non-probiotic bacteria. Our data demonstrate that in healthy mice, lactobacilli can balance T cell immunity in favor of a more regulatory status, via both regulatory T cell dependent and independent mechanisms in a strain dependent manner.
Immunomodulatory effects of potential probiotics in a mouse peanut sensitization model
Meijerink, M. ; Wells, J. ; Taverne, N. ; Zeeuw Brouwer, M.L. de; Hilhorst, B. ; Venema, K. ; Bilsen, J. van - \ 2012
FEMS Immunology and Medical Microbiology 65 (2012)3. - ISSN 0928-8244 - p. 488 - 496.
lactic-acid bacteria - placebo-controlled trial - regulatory t-cells - blood mononuclear-cells - atopic-dermatitis - dendritic cells - food allergy - lactobacillus-rhamnosus - cytokine production - responses
Peanut allergy accounts for the majority of severe food-related allergic reactions and there is a need for new prevention and treatment strategies. Probiotics may be considered for treatment on the basis of their immunomodulating properties. Cytokine profiles of probiotic strains were determined by in vitro co-culture with human PBMCs. Three strains were selected to investigate their prophylactic potential in a peanut sensitization model by analysing peanut-specific antibodies, mast cell degranulation and ex vivo cytokine production by splenocytes. The probiotic strains induced highly variable cytokine profiles in PBMCs. L. salivarius HMI001, L. casei Shirota (LCS) and L. plantarum WCFS1 were selected for further investigation owing to their distinct cytokine patterns. Prophylactic treatment with both HMI001 and LCS attenuated the Th2 phenotype (reduced mast cell responses and ex vivo IL-4 and/or IL-5 production). In contrast, WCFS1 augmented the Th2 phenotype (increased mast cell and antibody responses and ex vivo IL-4 production). In vitro PBMC screening was useful in selecting strains with anti-inflammatory and Th1 skewing properties. In case of HMI001 (high IL-10/IL-12 ratio) and LCS (high interferon- and IL-12), partial protection was seen in a mouse peanut allergy model. Strikingly, certain strains may worsen the allergic reaction as shown in the case of WCFS1.
Beneficial immunostimulatory effect of short-term Chlorella supplementation: enhancement of natural Killer cell activity and early inflammatory response (Randomized, double-blinded, placebo-controlled trial)
Kwak, J.H. ; Baek, S.H. ; Woo, Y. ; Han, J.K. ; Lee, L. van - \ 2012
Nutrition Journal 11 (2012)1. - ISSN 1475-2891
hot-water extract - accelerates dioxin excretion - blood mononuclear-cells - unicellular green-algae - listeria-monocytogenes - ifn-gamma - interferon-gamma - macrophage activation - independent mechanism - escherichia-coli
Background - In vitro and animal studies have demonstrated that Chlorella is a potent biological response modifier on immunity. However, there were no direct evidences for the effect of Chlorella supplementation on immune/inflammation response in healthy humans. Methods - This study was designed for an 8-week randomized, double-blinded, placebo-controlled trial: 5g of Chlorella (n=23) or Placebo (n=28) as form of tablets. Mainly, cytotoxic activities of Natural killer (NK) cells and serum concentrations of interferon-¿, interleukin-1ß and interleukin-12 were measured. Results - After the 8-week, serum concentrations of interferon-¿ (p
Responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes: a randomized trial
Dijk, S.J. van; Mensink, M.R. ; Esser, D. ; Feskens, E.J.M. ; Muller, M.R. ; Afman, L.A. - \ 2012
PLoS ONE 7 (2012)7. - ISSN 1932-6203
gene-expression profiles - blood mononuclear-cells - postprandial lipemia - nonfasting triglycerides - insulin sensitivity - visceral adiposity - glucose-tolerance - rich lipoproteins - healthy-subjects - men
Background The ability of subjects to respond to nutritional challenges can reflect the flexibility of their biological system. Nutritional challenge tests could be used as an indicator of health status but more knowledge on metabolic and immune responses of different subjects to nutritional challenges is needed. The aim of this study was to compare the responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes. Methodology/Principal Findings In a cross-over design 42 men (age 50–70 y) consumed three high-fat shakes containing saturated fat (SFA), monounsaturated fat (MUFA) or n-3 polyunsaturated (PUFA). Men were selected on BMI and health status (lean, obese or obese diabetic) and phenotyped with MRI for adipose tissue distribution. Before and 2 and 4 h after shake consumption blood was drawn for measurement of expression of metabolic and inflammation-related genes in peripheral blood mononuclear cells (PBMCs), plasma triglycerides (TAG), glucose, insulin, cytokines and ex vivo PBMC immune response capacity. The MUFA and n-3 PUFA challenge, compared to the SFA challenge, induced higher changes in expression of inflammation genes MCP1 and IL1ß in PBMCs. Obese and obese diabetic subjects had different PBMC gene expression and metabolic responses to high-fat challenges compared to lean subjects. The MUFA challenge induced the most pronounced TAG response, mainly in obese and obese diabetic subjects. Conclusion/Significance The PBMC gene expression response and metabolic response to high-fat challenges were affected by fat type and metabolic risk phenotype. Based on our results we suggest using a MUFA challenge to reveal differences in response capacity of subjects
Low-frequency electromagnetic fields do not alter responses of inflammatory genes and proteins in human monocytes and immune cell lines
Bouwens, M. ; Kleijn, S. de; Cuppen, J.J.M. ; Savelkoul, H.F.J. ; Verburg-van Kemenade, B.M.L. - \ 2012
Bioelectromagnetics 33 (2012)3. - ISSN 0197-8462 - p. 226 - 237.
blood mononuclear-cells - nf-kappa-b - magnetic-fields - human-lymphocytes - expression - macrophages - induction - exposure - cytokines - stimulation
The effects of low frequency electromagnetic fields (LF EMF) on human health are the subject of on-going research and serious public concern. These fields potentially elicit small effects that have been proposed to have consequences, either positive or negative, for biological systems. To reveal potentially weak but biologically relevant effects, we chose to extensively examine exposure of immune cells to two different signals, namely a complex multiple waveform field, and a 50¿Hz sine wave. These immune cells are highly responsive and, in vivo, modulation of cytokine expression responses can result in systemic health effects. Using time course experiments, we determined kinetics of cytokine and other inflammation-related genes in a human monocytic leukemia cell line, THP-1, and primary monocytes and macrophages. Moreover, cytokine protein levels in THP-1 monocytes were determined. Exposure to either of the two signals did not result in a significant effect on gene and protein expression in the studied immune cells. Also, additional experiments using non-immune cells showed no effects of the signals on cytokine gene expression. We therefore conclude that these LF EMF exposure conditions are not expected to significantly modulate innate immune signaling. Bioelectromagnetics.
Immunomodulatory mechanisms of lactobacilli
Wells, J. - \ 2011
Microbial Cell Factories 10 (2011)supl. 1. - ISSN 1475-2859
intestinal epithelial-cells - placebo-controlled trial - lactic-acid bacteria - blood mononuclear-cells - toll-like receptors - randomized controlled-trial - inflammatory-bowel-disease - tight junction proteins - necrosis-factor-alpha - in-vivo
Over the past decade it has become clear that lactobacilli and other probiotic and commensal organisms can interact with mucosal immune cells or epithelial cells lining the mucosa to modulate specific functions of the mucosal immune system. The most well understood signalling mechanisms involve the innate pattern recognition receptors such as Toll-like receptors, nucleotide oligomerization domain-like receptors and C-type lectin receptors. Binding of microbe-associated molecular patterns with these receptors can activate antigen presenting cells and modulate their function through the expression of surface receptors, secreted cytokines and chemokines. In vitro the cytokine response of human peripheral blood mononuclear cells and dendritic cells to lactobacilli can be strikingly different depending on both the bacterial species and the strain. Several factors have been identified in lactobacilli that influence the immune response in vitro and in vivo including cell surface carbohydrates, enzymes modifying the structure of lipoteichoic acids and metabolites. In mice mechanistic studies point to a role for the homeostatic control of inducible T regulatory cells in the mucosal tissues as one possible immunomodulatory mechanism. Increasing evidence also suggests that induction of epithelial signalling by intestinal lactobacilli can modulate barrier functions, defensin production and regulate inflammatory signalling. Other probiotic mechanisms include modulation of the T cell effector subsets, enhancement of humoral immunity and interactions with the epithelial-associated dendritic cells and macrophages. A major challenge for the future will be to gain more knowledge about the interactions occurring between lactobacilli and the host in vivo and to understand the molecular basis of innate signalling in response to whole bacteria which trigger multiple signalling pathways.
Strain-specific immunomodulatory effects of Lactobacillus plantarum strains on birch-pollen-allergic subjects out of season
Snel, J. ; Vissers, Y.M. ; Smit, B.A. ; Jongen, J.M.J. ; Meulen, E.T. ; Zwijsen, R. - \ 2011
Clinical and Experimental Allergy 41 (2011)2. - ISSN 0954-7894 - p. 232 - 242.
japanese cedar pollinosis - placebo-controlled-trial - blood mononuclear-cells - double-blind - cytokine production - hygiene hypothesis - clinical-trials - atopic disease - casei shirota - mast-cells
Background Allergic diseases are increasing world-wide, and according to the hygiene hypothesis may be related to a decreased exposure to environmental bacteria. Probiotic bacteria are recognized for their immunomodulating properties, and may benefit allergy patients. In vitro studies reveal immunomodulatory effects that are strain dependent. Differential immunomodulatory in vitro capacities cannot be extrapolated directly to in vivo efficacy. Thus, in vitro screening should preferably be followed by a comparative analysis of the selected immunomodulatory strains in an in vivo setting. Objective We selected five Lactobacillus strains on their IL-10-inducing capacity, and evaluated the immunomodulatory properties in birch-pollen-allergic subjects outside the hayfever season, with a reduction of IL-13 as the primary outcome. Methods A double-blind, placebo-controlled parallel study was performed in which 62 subjects with a proven birch-pollen allergy consumed one of five different probiotic yoghurts containing four Lactobacillus plantarum strains and one Lactobacillus casei strain or a placebo yoghurt. Blood samples were collected at the start and after 4 weeks. Several immune parameters were determined in serum and peripheral blood mononuclear cell cultures (PBMC) derived from these subjects. Results A decrease in birch-pollen-specific IgE was found for four probiotic strains. L. casei Shirota reduced the number of CD16+/CD56+ cells in peripheral blood mononuclear cells. For strain L. plantarum CBS125632, the decrease in IgE coincided with significant decreases in IL-5 and IL-13 production by aCD3/aCD28-stimulated PBMC cultures. Conclusion and Clinical Relevance Subjects with seasonal allergy can be used to determine immunomodulatory responses outside the pollen season within a 4-week study period. L. plantarum CBS125632 decreased several immune markers related to allergy, and may have the potential to alleviate the severity of seasonal allergy symptoms
Lactobacillus strains differentially modulate cytokine production by hPBMC from pollen allergic patients
Vissers, Y.M. ; Snel, J. ; Zuurendonk, P.F. ; Kleerebezem, M. ; Wichers, H.J. ; Savelkoul, H.F.J. - \ 2011
FEMS Immunology and Medical Microbiology 61 (2011)1. - ISSN 0928-8244 - p. 28 - 40.
blood mononuclear-cells - lactic-acid bacteria - regulatory t-cells - tumor-necrosis-factor - in-vitro - probiotic bacteria - intestinal microbiota - food allergy - immunomodulatory properties - mucosal immunology
The objective of this study was to assess the potential immunomodulatory effect of six Lactobacillus strains on human peripheral blood mononuclear cells (hPBMC) isolated from allergic patients. hPBMC from patients allergic to birch pollen or grass pollen were cultured in vitro in the presence or absence of selective bacterial strains. Cultures were left unstimulated or stimulated with aCD3/aCD28 or Bet v 1. After 1, 4 and 8 days, cells and culture supernatants were harvested and the effect on cellular proliferation and the supernatant levels of several cytokines was assessed. All strains had the ability to repress IL-13 production but did show a differential effect on IFN-¿ induction. Both strains B223 and B1697 showed a lower IFN-¿, IL-12 and TNF-a induction as compared with the other tested strains. Strain B633 showed the best proliferation-suppressive properties in aCD3/aCD28-stimulated cells. Suppression of the T-helper type 2 (Th2) cytokine induction and induction of the Th1 cytokine production by specific strains might be beneficial for allergic patients having a disturbed Th1/Th2 immune balance. Furthermore, hPBMC of patients with seasonal allergy outside the pollen season can be used to determine the immunomodulatory activities of probiotic bacteria
Transcription profiles of LPS-stimulated THP-1 monocytes and macrophages: a tool to study inflammation modulating effects of food-derived compounds
Chanput, W. ; Mes, J.J. ; Vreeburg, R.A.M. ; Savelkoul, H.F.J. ; Wichers, H.J. - \ 2010
Food & Function 1 (2010)3. - ISSN 2042-6496 - p. 254 - 261.
nf-kappa-b - necrosis-factor-alpha - blood mononuclear-cells - nitric-oxide synthase - gene-expression - messenger-rna - signaling pathways - cytokine production - citrus pectin - tnf-alpha
An assay was developed to study inflammation-related immune responses of food compounds on monocytes and macrophages derived from THP-1 cell line. First strategy focused on the effects after stimulation with either lipopolysaccharide (LPS) or Concanavalin A (ConA). Gene expression kinetics of inflammation-related cytokines (IL-1ß, IL-6, IL-8, IL-10 and TNF-a), inflammation-related enzymes (iNOS and COX-2), and transcription factors (NF-¿B, AP-1 and SP-1) were analyzed using RT-PCR. Time dependent cytokine secretion was investigated to study the inflammation-related responses at protein level. LPS stimulation induced inflammation-related cytokine, COX-2 and NF-¿B genes of THP-1 monocytes and THP-1 macrophages with the maximum up-regulation at 3 and 6 h, respectively. These time points, were subsequently selected to investigate inflammation modulating activity of three well known immuno-modulating food-derived compounds; quercetin, citrus pectin and barley glucan. Co-stimulation of LPS with either quercetin, citrus pectin, or barley glucan in THP-1 monocytes and macrophages showed different immuno-modulatory activity of these compounds. Therefore, we propose that simultaneously exposing THP-1 cells to LPS and food compounds, combined with gene expression response analysis are a promising in vitro screening tool to select, in a limited time frame, food compounds for inflammation modulating effects.
A saturated fatty acid-rich diet induces an obesity-linked proinflammatory gene expression profile in adipose tissue of subjects at risk of metabolic syndrome
Dijk, S.J. van; Feskens, E.J.M. ; Bos, M.B. ; Hoelen, D.W. ; Heijligenberg, R. ; Bromhaar, M.G. ; Groot, C.P.G.M. de; Vries, J.H.M. de; Müller, M.R. ; Afman, L.A. - \ 2009
American Journal of Clinical Nutrition 90 (2009)6. - ISSN 0002-9165 - p. 1656 - 1664.
inflammation-related genes - activated receptor-alpha - blood mononuclear-cells - nonobese pima-indians - insulin-resistance - healthy-men - glucose-metabolism - weight-loss - plasma - accumulation
Background: Changes in dietary fat composition could lower the risk of developing metabolic syndrome. Adipose tissue is an interesting tissue in this respect because of its role in lipid metabolism and inflammation. Objective: Our objective was to investigate the effect of a saturated fatty acid (SFA)– and a monounsaturated fatty acid (MUFA)–rich diet on insulin sensitivity, serum lipids, and gene expression profiles of adipose tissue in subjects at risk of metabolic syndrome. Design: A parallel controlled-feeding trial was conducted in 20 abdominally overweight subjects. Subjects received an SFA diet or an MUFA diet for 8 wk. Plasma and subcutaneous adipose tissue samples were obtained, and insulin sensitivity was measured by using a hyperinsulinemic-euglycemic clamp. Adipose tissue samples underwent whole-genome microarray and histologic analysis. Plasma and adipose tissue fatty acid composition and concentrations of serum cholesterol and plasma cytokine were determined. Results: Consumption of the SFA diet resulted in increased expression of genes involved in inflammation processes in adipose tissue, without changes in morphology or insulin sensitivity. The MUFA diet led to a more antiinflammatory gene expression profile, which was accompanied by a decrease in serum LDL-cholesterol concentrations and an increase in plasma and adipose tissue oleic acid content. Conclusions: Consumption of an SFA diet resulted in a proinflammatory "obesity-linked" gene expression profile, whereas consumption of an MUFA diet caused a more antiinflammatory profile. This suggests that replacement of dietary SFA with MUFA could prevent adipose tissue inflammation and may reduce the risk of inflammation-related diseases such as metabolic syndrome. This trial was registered at clinicaltrials.gov as NCT00405197.