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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Supplementation of diet with non-digestible oligosaccharides alters the intestinal microbiota, but not arthritis development, in IL-1 receptor antagonist deficient mice
Rogier, Rebecca ; Ederveen, Thomas H.A. ; Wopereis, Harm ; Hartog, Anita ; Boekhorst, Jos ; Hijum, Sacha A.F.T. Van; Knol, Jan ; Garssen, Johan ; Walgreen, Birgitte ; Helsen, Monique M. ; Kraan, Peter M. Van Der; Lent, Peter L.E.M. Van; De Loo, Fons A.J. Van; Abdollahi-Roodsaz, Shahla ; Koenders, Marije I. - \ 2019
PLoS ONE 14 (2019)7. - ISSN 1932-6203

The intestinal microbiome is perturbed in patients with new-onset and chronic autoimmune inflammatory arthritis. Recent studies in mouse models suggest that development and progression of autoimmune arthritis is highly affected by the intestinal microbiome. This makes modulation of the intestinal microbiota an interesting novel approach to suppress inflammatory arthritis. Prebiotics, defined as non-digestible carbohydrates that selectively stimulate the growth and activity of beneficial microorganisms, provide a relatively non-invasive approach to modulate the intestinal microbiota. The aim of this study was to assess the therapeutic potential of dietary supplementation with a prebiotic mixture of 90% short-chain galacto-oligosaccharides and 10% long-chain fructo-oligosaccharides (scGOS/lcFOS) in experimental arthritis in mice. We here show that dietary supplementation with scGOS/ lcFOS has a pronounced effect on the composition of the fecal microbiota. Interestingly, the genera Enterococcus and Clostridium were markedly decreased by scGOS/lcFOS dietary supplementation. In contrast, the family Lachnospiraceae and the genus Lactobacillus, both associated with healthy microbiota, increased in mice receiving scGOS/lcFOS diet. However, the scGOS/lcFOS induced alterations of the intestinal microbiota did not induce significant effects on the intestinal and systemic T helper cell subsets and were not sufficient to reproducibly suppress arthritis in mice. As expected, we did observe a significant increase in the bone mineral density in mice upon dietary supplementation with scGOS/lcFOS for 8 weeks. Altogether, this study suggests that dietary scGOS/lcFOS supplementation is able to promote presumably healthy gut microbiota and improve bone mineral density, but not inflammation, in arthritis-prone mice.

Long Chain Polyunsaturated Fatty Acids (LCPUFAs) in the Prevention of Food Allergy
Hoppenbrouwers, Tamara ; Cvejić Hogervorst, Jelena H. ; Garssen, Johan ; Wichers, Harry J. ; Willemsen, Linette E.M. - \ 2019
Frontiers in Immunology 10 (2019). - ISSN 1664-3224 - 1 p.
anti-inflammatory - food allergy - immune response - LCPUFA - PUFA

N-3 long chain polyunsaturated fatty acids (LCPUFAs) are considered to possess protective properties for human health by impacting on immunological reactions. An "inflammation-suppressive" effect appears to be the common denominator of the beneficial effects of most of these dietary components which may protect against the development of chronic immune disorders such as (food) allergy. LCPUFAs, especially n-3 LCPUFAs, have been shown to interact with both the sensitization as well as the effector phase in food allergy in pre-clinical models. In this review, we explore the anti-allergic properties of LCPUFAs by providing an overview of clinical, in vivo and in vitro studies. Furthermore, we discuss the susceptibility of LCPUFAs to lipid oxidation and possible strategies to support the efficacy of LCPUFAs in reducing the allergy risk by using additional components with anti-oxidative and anti-inflammatory capacities such as the flavonoid quercetin. Finally, we propose new strategies to prevent (food) allergy using combinations of LCPUFAs and additional nutrients in diets or supplements, and postulate to investigate the use of LCPUFAs in allergic symptom relief.

Prebiotic oligosaccharides in early life alter gut microbiome development in male mice while supporting influenza vaccination responses
Elsen, L.W.J. van den; Tims, S. ; Jones, A.M. ; Stewart, A. ; Stahl, B. ; Garssen, J. ; Knol, J. ; Forbes-Blom, E.E. ; van’t Land, B. - \ 2019
Beneficial Microbes 10 (2019)3. - ISSN 1876-2883 - p. 279 - 291.
Antibody - Gender - HMOS - Microbiota - TIV

Beneficial modulation of the gut microbiota is an attractive therapeutic approach to improve the efficacy of vaccine-induced immunity. In this study, mice were supplemented with the prebiotic milk oligosaccharide 2’-fucosyllactose (2’FL) as well as a complex mixture of immune modulatory prebiotic short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) from different stages in early life. Adult mice were vaccinated with trivalent influenza vaccine (TIV) and both development of the gut microbiota and antibody-mediated vaccine responses were followed over time. Within the control group, female mice demonstrated a larger antibody response to TIV vaccination than male mice, which was accompanied by enhanced cytokine production by splenocytes and a higher percentage of plasma cells in skin draining lymph nodes. In addition, the prebiotic diet improved vaccine-specific antibody responses in male mice. Introduction of prebiotics into the diet modulated the gut microbiota composition and at the genus level several bacterial groups showed a significant interaction effect which potentially contributed to the immunological effects observed. This study provides insight in the effect of scGOS/lcFOS/2’FL in influenza vaccination antibody production.

Gut microbiota from infant with cow’s milk allergy promotes clinical and immune features of atopy in a murine model
Mauras, Aurélie ; Wopereis, Harm ; Yeop, Intan ; Esber, Nathalie ; Delannoy, Johanne ; Labellie, Chantal ; Reygner, Julie ; Kapel, Nathalie ; Slump, Rob ; Eijndthoven, Tiemen van; Rutten, Lieke ; Knol, Jan ; Garssen, Johan ; Harthoorn, Lucien F. ; Butel, Marie José ; Bajaj-Elliott, Mona ; Hartog, Anita ; Waligora-Dupriet, Anne Judith - \ 2019
Allergy 74 (2019)9. - ISSN 0105-4538 - p. 1790 - 1793.
Development and validation of bioengineered intestinal tubules for translational research aimed at safety and efficacy testing of drugs and nutrients
Jochems, Paulus G.M. ; Bergenhenegouwen, Jeroen van; Genderen, Anne Metje van; Eis, Sophie T. ; Wilod Versprille, Livia J.F. ; Wichers, Harry J. ; Jeurink, Prescilla V. ; Garssen, Johan ; Masereeuw, Rosalinde - \ 2019
Toxicology in Vitro 60 (2019). - ISSN 0887-2333 - p. 1 - 11.
Caco-2 - In vitro - Microfluidic and screening - Small intestine

Currently used intestinal cell models have limited translational value, therefore, development of novel in vitro intestinal models that recapitulate the human in vivo setting more closely are of interest. Here, an advanced intestinal model was developed by the incorporation of physiological parameters, such as extracellular matrix (ECM)elements and shear stress, to cultured Caco-2 cells in a 3-dimensional environment. Caco-2 cells grown on ECM-coated hollow fiber membranes (HFM)under physiological shear stress show an improved phenotype, as demonstrated by the presence of enterocytes, goblet, Paneth, enteroendocrine and stem cells. Additionally, this model showed signs of an improved morphology due to the appearance of villi-like structures. Similar to epithelial cells grown on Transwells™, the current model remains easy to use, cost efficient and allows apical and basolateral access. The bioengineered intestinal tubule was validated by exposure to Clostridium difficile toxin A, the leading cause of healthcare-associated diarrhea. The loss of the tight junction network was supported by an increase in inulin-FITC leakage and the number of goblet cells increased, in agreement with clinical findings. In addition to toxicity screening, the bioengineered intestinal tubules are considered useful for drug and nutrient safety and efficacy testing.

Supplementation of dietary non-digestible oligosaccharides from birth onwards improve social and reduce anxiety-like behaviour in male BALB/c mice
Szklany, Kirsten ; Wopereis, Harm ; Waard, Cindy de; Wageningen, Thecla van; An, Ran ; Limpt, Kees van; Knol, Jan ; Garssen, Johan ; Knippels, Leon M.J. ; Belzer, Clara ; Kraneveld, Aletta D. - \ 2019
Nutritional Neuroscience (2019). - ISSN 1028-415X
Behaviour - dietary supplementation from birth - early life - fructo-oligosaccharide - galacto-oligosaccharide - healthy mice - intestinal microbiota - prebiotics - SCFA - serotonergic system

Objective: The intestinal microbiota is acknowledged to be essential in brain development and behaviour. Their composition can be modulated by prebiotics such as short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharide (lcFOS). Several studies reported potential health benefit of prebiotics on behaviour. As the prebiotic mixture of scGOS and lcFOS is included in infant formula, we investigated the effects of dietary supplementation with this specific mixture from the day of birth onwards on behaviour and intestinal microbiota development in mice. Method: Healthy male BALB/cByJ mice received, from day of birth, a dietary supplement with or without 3% scGOS:lcFOS (9:1). Behavioural tests were performed pre-weaning, in adolescence, early adulthood and adulthood. We assessed faecal microbiota compositions over time, caecal short-chain fatty acids as well as brain mRNA expression of Htr1a, Htr1b and Tph2 and monoamine levels. Results: Compared to control fed mice, scGOS:lcFOS fed mice showed reduced anxiety-like and repetitive behaviour over time and improved social behaviour in adulthood. The serotonergic system in the prefrontal cortex (PFC) and somatosensory cortex (SSC) was affected by the scGOS:lcFOS. In the PFC, mRNA expression of brain-derived neurotrophic factor (Bdnf) was enhanced in scGOS:lcFOS fed mice. Although the bacterial diversity of the intestinal microbiota was unaffected by the scGOS:lcFOS diet, microbiota composition differed between the scGOS:lcFOS and the control fed mice over time. Moreover, an increased saccharolytic and decreased proteolytic fermentation activity were observed in caecum content. Discussion: Supplementing the diet with scGOS:lcFOS from the day of birth is associated with reduced anxiety-like and improved social behaviour during the developmental period and later in life, and modulates the composition and activity of the intestinal microbiota in healthy male BALB/c mice. These data provide further evidence of the potential impact of scGOS:lcFOS on behaviour at several developmental stages throughout life and strengthen the insights in the interplay between the developing intestine and brain.

Mice co-administrated with partially hydrolysed whey proteins and prebiotic fibre mixtures show allergen-specific tolerance and a modulated gut microbiota
Kleinjans, L. ; Veening-Griffioen, D.H. ; Wehkamp, T. ; Bergenhenegouwen, J. van; Knol, J. ; Garssen, J. ; Knippels, L.M.J. ; Belzer, C. ; Jeurink, P.V. - \ 2019
Beneficial Microbes 10 (2019)2. - ISSN 1876-2883 - p. 165 - 178.
cow’s milk allergy - microbiota - non-digestible oligosaccharides - preventive tolerance induction

Non-breastfed infants at-risk of allergy are recommended to use a hydrolysed formula before the age of 6 months. The addition of prebiotics to this formula may reduce the allergy development in these infants, but clinical evidence is still inconclusive. This study evaluates (1) whether the exposure duration to different prebiotics alongside a partially hydrolysed whey protein (pHP) influences its' effectiveness to prevent allergy development and (2) whether the gut microbiota plays a role in this process. Mice orally sensitised with whey and/or cholera toxin were orally treated for six days before sensitization with phosphate buffered saline, whey or pHP to potentially induce tolerance. Two groups received an oligosaccharide diet only from day -7 until -2 (GFshort and GFAshort) whereas two other groups received their diets from day -15 until 37 (GFlong and GFAlong). On day 35, mice underwent an intradermal whey challenge, and the acute allergic skin response, shock score, and body temperatures were measured. At day 37, mice received whey orally and serum mouse mast cell protease-1, SLPI and whey-specific antibodies were assessed. Faecal samples were taken at day -15, -8 and 34. Feeding mice pHP alone during tolerance induction did not reduce ear swelling. The tolerance inducing mechanisms seem to vary according to the oligosaccharide-composition. GFshort, GFlong, and GFAlong reduced the allergic skin response, whereas GFAshort was not potent enough. However, in the treatment groups, the dominant Lactobacillus species decreased, being replaced by Bacteroidales family S24-7 members. In addition, the relative abundance of Prevotella was significantly higher in the GFlong, GFAshort and GFAlong groups. Co-administration of oligosaccharides and pHP can induce immunological tolerance in mice, although tolerance induction was strongest in the animals that were fed oligosaccharides during the entire protocol. Some microbial changes coincided with tolerance induction, however, a specific mechanism could not be determined based on these data.

A specific synbiotic-containing amino acid-based formula in dietary management of cow's milk allergy : A randomized controlled trial
Fox, Adam T. ; Wopereis, Harm ; Ampting, Marleen T.J. van; Oude Nijhuis, Manon M. ; Butt, Assad M. ; Peroni, Diego G. ; Vandenplas, Yvan ; Candy, David C.A. ; Shah, Neil ; West, Christina E. ; Garssen, Johan ; Harthoorn, Lucien F. ; Knol, Jan ; Michaelis, Louise J. - \ 2019
Clinical and Translational Allergy 9 (2019)1. - ISSN 2045-7022
Bifidobacterium breve M-16V - Cow's milk allergy - Gut microbiota - Prebiotic - Probiotic - Symptoms

Background: Here we report follow-up data from a double-blind, randomized, controlled multicenter trial, which investigated fecal microbiota changes with a new amino acid-based formula (AAF) including synbiotics in infants with non-immunoglobulin E (IgE)-mediated cow's milk allergy (CMA). Methods: Subjects were randomized to receive test product (AAF including fructo-oligosaccharides and Bifidobacterium breve M-16V) or control product (AAF) for 8 weeks, after which infants could continue study product until 26 weeks. Fecal percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) were assessed at 0, 8, 12, and 26 weeks. Additional endpoints included stool markers of gut immune status, clinical symptoms, and safety assessments including adverse events and medication use. Results: The trial included 35 test subjects, 36 controls, and 51 in the healthy reference group. Study product was continued by 86% and 92% of test and control subjects between week 8-12, and by 71% and 80%, respectively until week 26. At week 26 median percentages of bifidobacteria were significantly higher in test than control [47.0% vs. 11.8% (p < 0.001)], whereas percentages of ER/CC were significantly lower [(13.7% vs. 23.6% (p = 0.003)]. Safety parameters were similar between groups. Interestingly use of dermatological medication and reported ear infections were lower in test versus control, p = 0.019 and 0.011, respectively. Baseline clinical symptoms and stool markers were mild (but persistent) and low, respectively. Symptoms reduced towards lowest score in both groups. Conclusion: Beneficial effects of this AAF including specific synbiotics on microbiota composition were observed over 26 weeks, and shown suitable for dietary management of infants with non-IgE-mediated CMA.

Plasma citrulline concentration, a marker for intestinal functionality, reflects exercise intensity in healthy young men
Kartaram, Shirley ; Mensink, Marco ; Teunis, Marc ; Schoen, Eric ; Witte, Gerrit ; Janssen Duijghuijsen, Lonneke ; Verschuren, Martie ; Mohrmann, Karin ; M'Rabet, Laura ; Knipping, Karen ; Wittink, Harriet ; Helvoort, Ardy van; Garssen, Johan ; Witkamp, Renger ; Pieters, Raymond ; Norren, Klaske van - \ 2019
Clinical Nutrition 38 (2019)5. - ISSN 0261-5614 - p. 2251 - 2258.
Citrulline - Exercise intensity - Glutamine - Intestinal fatty acid binding protein - Intestinal function

Background & aims: Plasma citrulline concentration is considered to be a marker for enterocyte metabolic mass and to reflect its reduction as may occur during intestinal dysfunction. Strenuous exercise can act as a stressor to induce small intestinal injury. Our previous studies suggest that this comprises the intestinal ability to produce citrulline from a glutamine-rich protein bolus. In this study we investigated the effects of different exercise intensities and hydration state on citrulline and iFABP levels following a post-exercise glutamine bolus in healthy young men. Methods: Fifteen healthy young men (20–35 yrs, VO2 max 56.9 ± 3.9 ml kg−1 min−1) performed in a randomly assigned cross-over design, a rest (protocol 1) and four cycle ergometer protocols. The volunteers cycled submaximal at different percentages of their individual pre-assessed maximum workload (Wmax): 70% Wmax in hydrated (protocol 2) and dehydrated state (protocol 3), 50% Wmax (protocol 4) and intermittent 85/55% Wmax in blocks of 2 min (protocol 5). Immediately after 1 h exercise or rest, subjects were given a glutamine bolus with added alanine as an iso-caloric internal standard (7.5 g of each amino acid). Blood samples were collected before, during and after rest or exercise, up to 24 h post onset of the experiment. Amino acids and urea were analysed as metabolic markers, creatine phosphokinase and iFABP as markers of muscle and intestinal damage, respectively. Data were analysed using a multilevel mixed linear statistical model. p values were corrected for multiple testing. Results: Citrulline levels already increased before glutamine supplementation during normal hydrated exercise, while this was not observed in the dehydrated and rest protocols. The low intensity exercise protocol (50% Wmax) showed the highest increase in citrulline levels both during exercise (43.83 μmol/L ± 2.63 (p < 0.001)) and after glutamine consumption (50.54 μmol/L ± 2.62) compared to the rest protocol (28.97 μmol/L ± 1.503 and 41.65 μmol/L ± 1.96, respectively, p < 0.05). However, following strenuous exercise at 70% Wmax in the dehydrated state, citrulline levels did not increase during exercise and less after the glutamine consumption when compared to the resting condition and hydrated protocols. In line with this, serum iFABP levels were the highest with the strenuous dehydrated protocol (1443.72 μmol/L ± 249.9, p < 0.001), followed by the high intensity exercise at 70% Wmax in the hydrated condition. Conclusions: Exercise induces an increase in plasma citrulline, irrespective of a glutamine bolus. The extent to which this occurs is dependent on exercise intensity and the hydration state of the subjects. The same holds true for both the post-exercise increase in citrulline levels following glutamine supplementation and serum iFABP levels. These data indicate that citrulline release during exercise and after an oral glutamine bolus might be dependent on the intestinal health state and therefore on intestinal functionality. Glutamine is known to play a major role in intestinal physiology and the maintenance of gut health and barrier function. Together, this suggests that in clinical practice, a glutamine bolus to increase citrulline levels after exercise might be preferable compared to supplementing citrulline itself. To our knowledge this is the first time that exercise workload-related effects on plasma citrulline are reported in relation to intestinal damage.

Sex differences in lipid metabolism are affected by presence of the gut microbiota
Baars, Annemarie ; Oosting, Annemarie ; Lohuis, Mirjam ; Koehorst, Martijn ; Aidy, Sahar El; Hugenholtz, Floor ; Smidt, Hauke ; Mischke, Mona ; Boekschoten, Mark V. ; Verkade, Henkjan J. ; Garssen, Johan ; Beek, Eline M. van der; Knol, Jan ; Vos, Paul de; Bergenhenegouwen, Jeroen van; Fransen, Floris - \ 2018
Scientific Reports 8 (2018)1. - ISSN 2045-2322

Physiological processes are differentially regulated between men and women. Sex and gut microbiota have each been demonstrated to regulate host metabolism, but it is unclear whether both factors are interdependent. Here, we determined to what extent sex-specific differences in lipid metabolism are modulated via the gut microbiota. While male and female Conv mice showed predominantly differential expression in gene sets related to lipid metabolism, GF mice showed differences in gene sets linked to gut health and inflammatory responses. This suggests that presence of the gut microbiota is important in sex-specific regulation of lipid metabolism. Further, we explored the role of bile acids as mediators in the cross-talk between the microbiome and host lipid metabolism. Females showed higher total and primary serum bile acids levels, independent of presence of microbiota. However, in presence of microbiota we observed higher secondary serum bile acid levels in females compared to males. Analysis of microbiota composition displayed sex-specific differences in Conv mice. Therefore, our data suggests that bile acids possibly play a role in the crosstalk between the microbiome and sex-specific regulation of lipid metabolism. In conclusion, our data shows that presence of the gut microbiota contributes to sex differences in lipid metabolism.

A synbiotic-containing amino-acid-based formula improves gut microbiota in non-IgE-mediated allergic infants
Candy, David C.A. ; Ampting, Marleen T.J. Van; Oude Nijhuis, Manon M. ; Wopereis, Harm ; Butt, Assad M. ; Peroni, Diego G. ; Vandenplas, Yvan ; Fox, Adam T. ; Shah, Neil ; West, Christina E. ; Garssen, Johan ; Harthoorn, Lucien F. ; Knol, Jan ; Michaelis, Louise J. - \ 2018
Pediatric Research 83 (2018)3. - ISSN 0031-3998 - p. 677 - 686.
BackgroundPrebiotics and probiotics (synbiotics) can modify gut microbiota and have potential in allergy management when combined with amino-acid-based formula (AAF) for infants with cow's milk allergy (CMA).MethodsThis multicenter, double-blind, randomized controlled trial investigated the effects of an AAF-including synbiotic blend on percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) in feces from infants with suspected non-IgE-mediated CMA. Feces from age-matched healthy breastfed infants were used as reference (healthy breastfed reference (HBR)) for primary outcomes. The CMA subjects were randomized and received test or control formula for 8 weeks. Test formula was a hypoallergenic, nutritionally complete AAF including a prebiotic blend of fructo-oligosaccharides and the probiotic strain Bifidobacterium breve M-16V. Control formula was AAF without synbiotics.ResultsA total of 35 (test) and 36 (control) subjects were randomized; HBR included 51 infants. At week 8, the median percentage of bifidobacteria was higher in the test group than in the control group (35.4% vs. 9.7%, respectively; P<0.001), whereas ER/CC was lower (9.5% vs. 24.2%, respectively; P<0.001). HBR levels of bifidobacteria and ER/CC were 55% and 6.5%, respectively.ConclusionAAF including specific synbiotics, which results in levels of bifidobacteria and ER/CC approximating levels in the HBR group, improves the fecal microbiota of infants with suspected non-IgE-mediated CMA.
Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis
Rogier, Rebecca ; Ederveen, Thomas H.A. ; Boekhorst, Jos ; Wopereis, Harm ; Scher, Jose U. ; Manasson, Julia ; Frambach, Sanne J.C.M. ; Knol, Jan ; Garssen, Johan ; Kraan, Peter M. van der; Koenders, Marije I. ; Berg, Wim B. van den; Hijum, Sacha A.F.T. van; Abdollahi-Roodsaz, Shahla - \ 2017
Microbiome 5 (2017)1. - ISSN 2049-2618 - p. 63 - 63.
Autoimmune arthritis - IL-1 receptor antagonist - Microbiota - T helper 17 cells - Toll-like receptors
BACKGROUND: Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist (Il1rn -/- mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn -/- mice.RESULTS: Using high-throughput 16S rRNA gene sequencing, we show that IL-1Ra critically maintains the diversity and regulates the composition of intestinal microbiota in mice. IL-1Ra deficiency reduced the intestinal microbial diversity and richness, and caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella. Notably, the aberrant intestinal microbiota in IL1rn -/- mice specifically potentiated IL-17 production by intestinal lamina propria (LP) lymphocytes and skewed the LP T cell balance in favor of T helper 17 (Th17) cells, an effect transferable to WT mice by fecal microbiota. Importantly, LP Th17 cell expansion and the development of spontaneous autoimmune arthritis in IL1rn -/- mice were attenuated under germ-free condition. Selective antibiotic treatment revealed that tobramycin-induced alterations of commensal intestinal microbiota, i.e., reduced Helicobacter, Flexispira, Clostridium, and Dehalobacterium, suppressed arthritis in IL1rn -/- mice. The arthritis phenotype in IL1rn -/- mice was previously shown to depend on Toll-like receptor 4 (TLR4). Using the ablation of both IL-1Ra and TLR4, we here show that the aberrations in the IL1rn -/- microbiota are partly TLR4-dependent. We further identify a role for TLR4 activation in the intestinal lamina propria production of IL-17 and cytokines involved in Th17 differentiation preceding the onset of arthritis.CONCLUSIONS: These findings identify a critical role for IL1Ra in maintaining the natural diversity and composition of intestinal microbiota, and suggest a role for TLR4 in mucosal Th17 cell induction associated with the development of autoimmune disease in mice.
Voeding en immuniteit: Kan voeding bijdragen aan het voorkomen van allergie, infectie en ontsteking?
Neerven, R.J.J. van; Albers, R. ; Wichers, H.J. ; Garssen, J. ; Savelkoul, H.F.J. - \ 2017
Nederlands Tijdschrift voor Allergie en Astma 17 (2017). - ISSN 1879-9434 - p. 21 - 28.
De rol van voeding voor een goed werkend immuunsysteem
wordt steeds duidelijker. Een goed gebalanceerde
voeding kan bijdragen aan het voorkomen
van ziekte in het vroege leven (allergie, infecties) en
het late leven (ontsteking, infecties).
Het belang van macro- en micronutriënten voor het
normaal functioneren van het immuunsysteem is
reeds lang bekend. We leren ook steeds meer over
nieuwe voedingsmiddelen en -componenten die
specifieke effecten op het immuunsysteem kunnen
hebben. Dit zijn onder andere probiotica, prebiotica
en voedingsvezels, componenten van (moeder) melk,
vetzuren (PUFA en SCFA), en antioxidantia.
Deze kunnen het immuunsysteem zowel rechtstreeks
beïnvloeden als indirect via effecten op
darmbacteriën en darmepitheel. Dit artikel probeert
een overzicht te geven van de huidige kennis op dit
gebied, met een focus op de mogelijke rol van voeding
in het voorkomen van allergie, infectie, en ontsteking.
Characterizing microbiota-independent effects of oligosaccharides on intestinal epithelial cells : insight into the role of structure and size: Structure–activity relationships of non-digestible oligosaccharides
Akbari, Peyman ; Fink-Gremmels, Johanna ; Willems, Rianne H.A.M. ; Difilippo, Elisabetta ; Schols, Henk A. ; Schoterman, Margriet H.C. ; Garssen, Johan ; Braber, Saskia - \ 2017
European Journal of Nutrition 56 (2017)5. - ISSN 1436-6207 - p. 1919 - 1930.
Caco-2 cells - CXCL8 - Degree of polymerization - Intestinal permeability - Non-digestible oligosaccharides - Tight junctions
Purpose: The direct effects of galacto-oligosaccharides (GOS), including Vivinal® GOS syrup (VGOS) and purified Vivinal® GOS (PGOS), on the epithelial integrity and corresponding interleukin-8 (IL-8/CXCL8) release were examined in a Caco-2 cell model for intestinal barrier dysfunction. To investigate structure–activity relationships, the effects of individual DP fractions of VGOS were evaluated. Moreover, the obtained results with GOS were compared with Caco-2 monolayers incubated with fructo-oligosaccharides (FOS) and inulin. Methods: Caco-2 monolayers were pretreated (24 h) with or without specific oligosaccharides or DP fractions of VGOS (DP2 to DP6) before being exposed for 12 or 24 h to the fungal toxin deoxynivalenol (DON). Transepithelial electrical resistance and lucifer yellow permeability were measured to investigate barrier integrity. A calcium switch assay was used to study the reassembly of tight junction proteins. Release of CXCL8, a typical marker for inflammation, was quantified by ELISA. Results: In comparison with PGOS, FOS and inulin, VGOS showed the most pronounced protective effect on the DON-induced impairment of the monolayer integrity, acceleration of the tight junction reassembly and the subsequent CXCL8 release. DP2 and DP3 in concentrations occurring in VGOS prevented the DON-induced epithelial barrier disruption, which could be related to their high prevalence in VGOS. However, no effects of the separate DP GOS fractions were observed on CXCL8 release. Conclusions: This comparative study demonstrates the direct, microbiota-independent effects of oligosaccharides on the intestinal barrier function and shows the differences between individual galacto- and fructo-oligosaccharides. This microbiota-independent effect of oligosaccharides depends on the oligosaccharide structure, DP length and concentration.
Embracing Complexity beyond Systems Medicine: A New Approach to Chronic Immune Disorders
Velde, Anje A. Te; Bezema, Tjitske ; Kampen, Antoine H.C. Van; Kraneveld, Aletta D. ; Hart, Bert A. 't; Middendorp, Henriët Van; Hack, Erik C. ; Montfrans, Joris M. Van; Belzer, Clara ; Jans-Beken, Lilian ; Pieters, Raymond H. ; Knipping, Karen ; Huber, Machteld ; Boots, Annemieke M.H. ; Garssen, Johan ; Radstake, Tim R. ; Evers, Andrea W.M. ; Prakken, Berent J. ; Joosten, Irma - \ 2016
Frontiers in Immunology 7 (2016). - ISSN 1664-3224
In order to combat chronic immune disorders (CIDs), it is an absolute necessity to understand the bigger picture, one that goes beyond insights at a one-disease, molecular, cellular, and static level. To unravel this bigger picture we advocate an integral, cross-disciplinary approach capable of embracing the complexity of the field. This paper discusses the current knowledge on common pathways in CIDs including general psychosocial and lifestyle factors associated with immune functioning. We demonstrate the lack of more in-depth psychosocial and lifestyle factors in current research cohorts and most importantly the need for an all-encompassing analysis of these factors. The second part of the paper discusses the challenges of understanding immune system dynamics and effectively integrating all key perspectives on immune functioning, including the patient’s perspective itself. This paper suggests the use of techniques from complex systems science in describing and simulating healthy or deviating behavior of the immune system in its biopsychosocial surroundings. The patient’s perspective data are suggested to be generated by using specific narrative techniques. We conclude that to gain more insight into the behavior of the whole system and to acquire new ways of combatting CIDs, we need to construct and apply new techniques in the field of computational and complexity science, to an even wider variety of dynamic data than used in today’s systems medicine.
Mushroom immunomodulation and germplasm: variation between and within mushroom species and perspectives for application.
Schots, A. ; Wilbers, R.H.P. ; Westerhof, L.B. ; Esch, Betty C.A.M. van; Garssen, Johan ; Sonnenberg, A.S.M. - \ 2016
In: Science and Cultivation of Edible Fungi. - International Society for Mushroom Science (ISMS) - ISBN 9789090297712 - p. 281 - 284.
The piglet as a model for studying dietary components in infant diets : effects of galacto-oligosaccharides on intestinal functions
Alizadeh, A. ; Akbari, P. ; Difilippo, E. ; Schols, H.A. ; Ulfman, L.H. ; Schoterman, M.H.C. ; Garssen, J. ; Fink-Gremmels, J. ; Braber, S. - \ 2016
The British journal of nutrition 115 (2016)4. - ISSN 0007-1145 - p. 605 - 618.
Galacto-oligosaccharides - Gut microbiota - Immunomodulation - Intestinal integrity - Neonatal piglet models

Prebiotic oligosaccharides, including galacto-oligosaccharides (GOS), are used in infant formula to mimic human milk oligosaccharides, which are known to have an important role in the development of the intestinal microbiota and the immune system in neonates. The maturation of the intestines in piglets closely resembles that of human neonates and infants. Hence, a neonatal piglet model was used to study the multi-faceted effect of dietary GOS in early life. Naturally farrowed piglets were separated from the mother sow 24–48 h postpartum and received a milk replacer with or without the addition of GOS for 3 or 26 d, whereafter several indicators of intestinal colonisation and maturation were measured. Dietary GOS was readily fermented in the colon, leading to a decreased pH, an increase in butyric acid in caecum digesta and an increase in lactobacilli and bifidobacteria numbers at day 26. Histomorphological changes were observed in the intestines of piglets fed a GOS diet for 3 or 26 d. In turn, differences in the intestinal disaccharidase activity were observed between control and GOS-fed piglets. The mRNA expression of various tight junction proteins was up-regulated in the intestines of piglet fed a GOS diet and was not accompanied by an increase in protein expression. GOS also increased defensin porcine β-defensin-2 in the colon and secretory IgA levels in saliva. In conclusion, by applying a neonatal piglet model, it could be demonstrated that a GOS-supplemented milk replacer promotes the balance of the developing intestinal microbiota, improves the intestinal architecture and seems to stimulate the intestinal defence mechanism.

Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis
Rogier, Rebecca ; Ederveen, Thomas H.A. ; Boekhorst, Jos ; Wopereis, H.J. ; Scher, Jose U. ; Manasson, Julia ; Knol, J. ; Garssen, Johan ; Kraan, Peter M. van der; Koenders, Marije I. ; Berg, Wim B. van den; Hijum, Sacha A.F.T. van; Abdollahi-Roodsaz, Shahla - \ 2014
PRJEB7447 - ERP007176
The aim of this study was to investigate the role of IL-1 receptor signalling and the involvement of Toll-like receptor (TLR) 2 and TLR4 in defining the intestinal microbiota and the associated mucosal and systemic immune response. Multiplex 454 pyrosequencing of V5 and V6 hyper-variable regions of fecal bacterial 16S rRNA was used to define intestinal microbial communities in BALB/c wild type (WT), IL-1Ra-/- and IL-1Ra/TLR double knock-out (DKO) mice.
Altered gut microbiota and activity in a murine model of autism spectrum disorders
Theije, C.G. de; Wopereis, H.J. ; Ramadan, M. ; Eijndthoven, T. van; Lambert, J. ; Knol, J. ; Garssen, J. ; Kraneveld, A.D. ; Oozeer, R. - \ 2014
Brain, Behavior, and Immunity 37 (2014). - ISSN 0889-1591 - p. 197 - 206.
valproic acid - intestinal microbiota - maternal separation - host interactions - propionic-acid - onset autism - children - brain - microflora - exposure
Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders with evidence of genetic predisposition. Intestinal disturbances are reported in ASD patients and compositional changes in gut microbiota are described. However, the role of microbiota in brain disorders is poorly documented. Here, we used a murine model of ASD to investigate the relation between gut microbiota and autism-like behaviour. Using next generation sequencing technology, microbiota composition was investigated in mice in utero exposed to valproic acid (VPA). Moreover, levels of short chain fatty acids (SCFA) and lactic acid in caecal content were determined. Our data demonstrate a transgenerational impact of in utero VPA exposure on gut microbiota in the offspring. Prenatal VPA exposure affected operational taxonomic units (OTUs) assigned to genera within the main phyla of Bacteroidetes and Firmicutes and the order of Desulfovibrionales, corroborating human ASD studies. In addition, OTUs assigned to genera of Alistipes, Enterorhabdus, Mollicutes and Erysipelotrichalis were especially associated with male VPA-exposed offspring. The microbial differences of VPA in utero-exposed males deviated from those observed in females and was (i) positively associated with increased levels of caecal butyrate as well as ileal neutrophil infiltration and (ii) inversely associated with intestinal levels of serotonin and social behaviour scores. These findings show that autism-like behaviour and its intestinal phenotype is associated with altered microbial colonization and activity in a murine model for ASD, with preponderance in male offspring. These results open new avenues in the scientific trajectory of managing neurodevelopmental disorders by gut microbiome modulation
Human milk: a source of more life than we imagine
Jeurink, P.V. ; Bergenhenegouwen, J. van; Jimenez, E. ; Knippels, L.M.J. ; Fernandez, L. ; Garssen, J. ; Knol, J. ; Rodriguez, J.M. ; Martin, R. - \ 2013
Beneficial Microbes 4 (2013)1. - ISSN 1876-2883 - p. 17 - 30.
lactic-acid bacteria - human breast-milk - fragment-length-polymorphism - human skin microbiome - healthy women - infectious mastitis - dendritic cells - infant gut - staphylococcus-epidermidis - intestinal microbiota
The presence of bacteria in human milk has been acknowledged since the seventies. For a long time, microbiological analysis of human milk was only performed in case of infections and therefore the presence of non-pathogenic bacteria was yet unknown. During the last decades, the use of more sophisticated culture-dependent and -independent techniques, and the steady development of the -omic approaches are opening up the new concept of the 'milk microbiome', a complex ecosystem with a greater diversity than previously anticipated. In this review, possible mechanisms by which bacteria can reach the mammary gland (contamination versus active migration) are discussed. In addition, the potential roles of human milk for both infant and maternal health are summarised. A better understanding of the link between the milk microbiome and health benefit, the potential factors influencing this relationship and whether or not it can be influenced by nutrition is required to open new avenues in the field of pregnancy and lactation.
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