Publications by authors named "Johan Garssen"

342 Publications

TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target.

Front Pharmacol 2020 15;11:601685. Epub 2021 Jan 15.

Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.

By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of "inhibition" aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.
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http://dx.doi.org/10.3389/fphar.2020.601685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844586PMC
January 2021

Reply to J Zempleni.

Adv Nutr 2021 02;12(1):281

Department of Pediatrics and Pediatric Infectious Diseases, Institute of Child's Health, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.

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http://dx.doi.org/10.1093/advances/nmaa149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850015PMC
February 2021

Classification and specific primer design for accurate detection of SARS-CoV-2 using deep learning.

Sci Rep 2021 01 13;11(1):947. Epub 2021 Jan 13.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.

In this paper, deep learning is coupled with explainable artificial intelligence techniques for the discovery of representative genomic sequences in SARS-CoV-2. A convolutional neural network classifier is first trained on 553 sequences from the National Genomics Data Center repository, separating the genome of different virus strains from the Coronavirus family with 98.73% accuracy. The network's behavior is then analyzed, to discover sequences used by the model to identify SARS-CoV-2, ultimately uncovering sequences exclusive to it. The discovered sequences are validated on samples from the National Center for Biotechnology Information and Global Initiative on Sharing All Influenza Data repositories, and are proven to be able to separate SARS-CoV-2 from different virus strains with near-perfect accuracy. Next, one of the sequences is selected to generate a primer set, and tested against other state-of-the-art primer sets, obtaining competitive results. Finally, the primer is synthesized and tested on patient samples (n = 6 previously tested positive), delivering a sensitivity similar to routine diagnostic methods, and 100% specificity. The proposed methodology has a substantial added value over existing methods, as it is able to both automatically identify promising primer sets for a virus from a limited amount of data, and deliver effective results in a minimal amount of time. Considering the possibility of future pandemics, these characteristics are invaluable to promptly create specific detection methods for diagnostics.
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http://dx.doi.org/10.1038/s41598-020-80363-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806918PMC
January 2021

Butyrate and Propionate Restore the Cytokine and House Dust Mite Compromised Barrier Function of Human Bronchial Airway Epithelial Cells.

Int J Mol Sci 2020 Dec 23;22(1). Epub 2020 Dec 23.

Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands.

Barrier dysfunction of airway epithelium contributes to the development of allergies, airway hyper-responsiveness and immunological respiratory diseases. Short-chain fatty acids (SCFA) enhance and restore the barrier function of the intestinal epithelium. This study investigated whether acetate, propionate and butyrate enhance the integrity of bronchial epithelial cells. Differentiating human bronchial epithelial cells (16HBE) grown on transwells were exposed to butyrate, propionate and acetate while trans-epithelial electrical resistance was monitored over time. Restorative effects of SCFA were investigated by subsequent incubation of cells with IL-4, IL-13 or house dust mite extract and SCFA. SCFA effects on IL-4-induced cytokine production and the expression of zonula occludens-1 (ZO-1) and Mitogen-activated protein kinases (MAPK) signalling pathways were investigated by ELISA and Western blot assays. Propionate and butyrate enhanced the barrier function of differentiating 16HBE cells and induced complete recovery of the barrier function after exposure to the above-mentioned stimuli. Butyrate decreased IL-4-induced IL-6 production. IL-4 decreased ZO-1 protein expression and induced phosphorylation of extracellular signal-regulated protein kinases 1/2 (ERK1/2) and c-Jun N-terminal kinases (JNK) in 16HBE cells, both of which could be restored by SCFA. SCFA showed prophylactic and restorative effects on airway epithelial barrier function, which might be induced by increased ZO-1 expression.
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http://dx.doi.org/10.3390/ijms22010065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793466PMC
December 2020

The Gut-Brain Axis in Autism Spectrum Disorder: A Focus on the Metalloproteases ADAM10 and ADAM17.

Int J Mol Sci 2020 Dec 24;22(1). Epub 2020 Dec 24.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584CG Utrecht, The Netherlands.

Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut-brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut-brain axis.
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http://dx.doi.org/10.3390/ijms22010118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796333PMC
December 2020

A combined microphysiological-computational omics approach in dietary protein evaluation.

NPJ Sci Food 2020 Dec 17;4(1):22. Epub 2020 Dec 17.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

Food security is under increased pressure due to the ever-growing world population. To tackle this, alternative protein sources need to be evaluated for nutritional value, which requires information on digesta peptide composition in comparison to established protein sources and coupling to biological parameters. Here, a combined experimental and computational approach is presented, which compared seventeen protein sources with cow's whey protein concentrate (WPC) as the benchmark. In vitro digestion of proteins was followed by proteomics analysis and statistical model-based clustering. Information on digesta peptide composition resulted in 3 cluster groups, primarily driven by the peptide overlap with the benchmark protein WPC. Functional protein data was then incorporated in the computational model after evaluating the effects of eighteen protein digests on intestinal barrier integrity, viability, brush border enzyme activity, and immune parameters using a bioengineered intestine as microphysiological gut system. This resulted in 6 cluster groups. Biological clustering was driven by viability, brush border enzyme activity, and significant differences in immune parameters. Finally, a combination of proteomic and biological efficacy data resulted in 5 clusters groups, driven by a combination of digesta peptide composition and biological effects. The key finding of our holistic approach is that protein source (animal, plant or alternative derived) is not a driving force behind the delivery of bioactive peptides and their biological efficacy.
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http://dx.doi.org/10.1038/s41538-020-00082-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746769PMC
December 2020

Immunological Outcomes of Allergen-Specific Immunotherapy in Food Allergy.

Front Immunol 2020 3;11:568598. Epub 2020 Nov 3.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

IgE-mediated food allergies are caused by adverse immunologic responses to food proteins. Allergic reactions may present locally in different tissues such as skin, gastrointestinal and respiratory tract and may result is systemic life-threatening reactions. During the last decades, the prevalence of food allergies has significantly increased throughout the world, and considerable efforts have been made to develop curative therapies. Food allergen immunotherapy is a promising therapeutic approach for food allergies that is based on the administration of increasing doses of culprit food extracts, or purified, and sometime modified food allergens. Different routes of administration for food allergen immunotherapy including oral, sublingual, epicutaneous and subcutaneous regimens are being evaluated. Although a wealth of data from clinical food allergen immunotherapy trials has been obtained, a lack of consistency in assessed clinical and immunological outcome measures presents a major hurdle for evaluating these new treatments. Coordinated efforts are needed to establish standardized outcome measures to be applied in food allergy immunotherapy studies, allowing for better harmonization of data and setting the standards for the future research. Several immunological parameters have been measured in food allergen immunotherapy, including allergen-specific immunoglobulin levels, basophil activation, cytokines, and other soluble biomarkers, T cell and B cell responses and skin prick tests. In this review we discuss different immunological parameters and assess their applicability as potential outcome measures for food allergen immunotherapy that may be included in such a standardized set of outcome measures.
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http://dx.doi.org/10.3389/fimmu.2020.568598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670865PMC
November 2020

The Impact of Milk and Its Components on Epigenetic Programming of Immune Function in Early Life and Beyond: Implications for Allergy and Asthma.

Front Immunol 2020 21;11:2141. Epub 2020 Oct 21.

Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands.

Specific and adequate nutrition during pregnancy and early life is an important factor in avoiding non-communicable diseases such as obesity, type 2 diabetes, cardiovascular disease, cancers, and chronic allergic diseases. Although epidemiologic and experimental studies have shown that nutrition is important at all stages of life, it is especially important in prenatal and the first few years of life. During the last decade, there has been a growing interest in the potential role of epigenetic mechanisms in the increasing health problems associated with allergic disease. Epigenetics involves several mechanisms including DNA methylation, histone modifications, and microRNAs which can modify the expression of genes. In this study, we focus on the effects of maternal nutrition during pregnancy, the effects of the bioactive components in human and bovine milk, and the environmental factors that can affect early life (i.e., farming, milk processing, and bacterial exposure), and which contribute to the epigenetic mechanisms underlying the persistent programming of immune functions and allergic diseases. This knowledge will help to improve approaches to nutrition in early life and help prevent allergies in the future.
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http://dx.doi.org/10.3389/fimmu.2020.02141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641638PMC
October 2020

The Role of Alcohol Metabolism in the Pathology of Alcohol Hangover.

J Clin Med 2020 Oct 25;9(11). Epub 2020 Oct 25.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3584CG Utrecht, The Netherlands.

The limited number of available studies that examined the pathology of alcohol hangover focused on biomarkers of alcohol metabolism, oxidative stress and the inflammatory response to alcohol as potentially important determinants of hangover severity. The available literature on alcohol metabolism and oxidative stress is reviewed in this article. The current body of evidence suggests a direct relationship between blood ethanol concentration and hangover severity, whereas this association is not significant for acetaldehyde. The rate of alcohol metabolism seems to be an important determinant of hangover severity. That is, fast elimination of ethanol is associated with experiencing less severe hangovers. An explanation for this observation may be the fact that ethanol-in contrast to acetaldehyde-is capable of crossing the blood-brain barrier. With slower ethanol metabolism, more ethanol is able to reach the brain and elicit hangover symptoms. Hangover severity was also significantly associated with biomarkers of oxidative stress. More oxidative stress in the first hours after alcohol consumption was associated with less severe next-day hangovers (i.e., a significant negative correlation was found between hangover severity and malondialdehyde). On the contrary, more oxidative stress at a later stage after alcohol consumption was associated with having more severe next-day hangovers (i.e., a significant positive correlation was found between hangover severity and 8-isoprostane). In conclusion, assessment of biomarkers of alcohol metabolism suggests that fast elimination of ethanol is associated with experiencing less severe hangovers. More research is needed to further examine the complex interrelationship between alcohol metabolism, the role of acetaldehyde and oxidative stress and antioxidants, and the pathology of the alcohol hangover.
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http://dx.doi.org/10.3390/jcm9113421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692803PMC
October 2020

Decreased Histone Acetylation Levels at Th1 and Regulatory Loci after Induction of Food Allergy.

Nutrients 2020 Oct 19;12(10). Epub 2020 Oct 19.

Danone Nutricia Research, 3584 CT Utrecht, The Netherlands.

Immunoglobulin E (IgE)-mediated allergy against cow's milk protein fractions such as whey is one of the most common food-related allergic disorders of early childhood. Histone acetylation is an important epigenetic mechanism, shown to be involved in the pathogenesis of allergies. However, its role in food allergy remains unknown. IgE-mediated cow's milk allergy was successfully induced in a mouse model, as demonstrated by acute allergic symptoms, whey-specific IgE in serum, and the activation of mast cells upon a challenge with whey protein. The elicited allergic response coincided with reduced percentages of regulatory T (Treg) and T helper 17 (Th17) cells, matching decreased levels of H3 and/or H4 histone acetylation at pivotal Treg and Th17 loci, an epigenetic status favoring lower gene expression. In addition, histone acetylation levels at the crucial T helper 1 (Th1) loci were decreased, most probably preceding the expected reduction in Th1 cells after inducing an allergic response. No changes were observed for T helper 2 cells. However, increased histone acetylation levels, promoting gene expression, were observed at the signal transducer and activator of transcription 6 () gene, a proallergic B cell locus, which was in line with the presence of whey-specific IgE. In conclusion, the observed histone acetylation changes are pathobiologically in line with the successful induction of cow's milk allergy, to which they might have also contributed mechanistically.
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http://dx.doi.org/10.3390/nu12103193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603208PMC
October 2020

Kinetics of Physiological Responses as a Measure of Intensity and Hydration Status During Experimental Physical Stress in Human Volunteers.

Front Physiol 2020 4;11:1006. Epub 2020 Sep 4.

Research Group Innovative Testing in Life Sciences and Chemistry, University of Applied Sciences Utrecht, Utrecht, Netherlands.

Introduction: Strenuous physical stress induces a range of physiological responses, the extent depending, among others, on the nature and severity of the exercise, a person's training level and overall physical resilience. This principle can also be used in an experimental set-up by measuring time-dependent changes in biomarkers for physiological processes. In a previous report, we described the effects of workload delivered on a bicycle ergometer on intestinal functionality. As a follow-up, we here describe an analysis of the kinetics of various other biomarkers.

Aim: To analyse the time-dependent changes of 34 markers for different metabolic and immunological processes, comparing four different exercise protocols and a rest protocol.

Methods: After determining individual maximum workloads, 15 healthy male participants (20-35 years) started with a rest protocol and subsequently performed (in a cross-over design with 1-week wash-out) four exercise protocols of 1-h duration at different intensities: 70% W in a hydrated and a mildly dehydrated state, 50% W and intermittent 85/55% W in blocks of 2 min. Perceived exertion was monitored using the Borg' Rating of Perceived Exertion scale. Blood samples were collected both before and during exercise, and at various timepoints up to 24 h afterward. Data was analyzed using a multilevel mixed linear model with multiple test correction.

Results: Kinetic changes of various biomarkers were exercise-intensity-dependent. Biomarkers included parameters indicative of metabolic activity (e.g., creatinine, bicarbonate), immunological and hematological functionality (e.g., leukocytes, hemoglobin) and intestinal physiology (citrulline, intestinal fatty acid-binding protein, and zonulin). In general, responses to high intensity exercise of 70% W and intermittent exercise i.e., 55/85% W were more pronounced compared to exercise at 50% W .

Conclusion: High (70 and 55/85% W ) and moderate (50% W ) intensity exercise in a bicycle ergometer test produce different time-dependent changes in a broad range of parameters indicative of metabolic activity, immunological and hematological functionality and intestinal physiology. These parameters may be considered biomarkers of homeostatic resilience. Mild dehydration intensifies these time-related changes. Moderate intensity exercise of 50% W shows sufficient physiological and immunological responses and can be employed to test the health condition of less fit individuals.
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http://dx.doi.org/10.3389/fphys.2020.01006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498705PMC
September 2020

The efficacy of bortezomib in human multiple myeloma cells is enhanced by combination with omega-3 fatty acids DHA and EPA: Timing is essential.

Clin Nutr 2020 Sep 15. Epub 2020 Sep 15.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, 3508, TB, the Netherlands. Electronic address:

Background & Aims: Although bortezomib as one of the first line medicines that has greatly improved the overall survival of patients with multiple myeloma (MM), undesired drug resistance is frequently observed. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been shown to be able to enhance the efficacy of chemotherapeutic drugs in many cancer types. The aim of the present study was to further evaluate the anticancer activity of DHA and EPA in relation to bortezomib chemosensitivity in human MM cells. The potential involvement of NF-κB signaling pathway was studied.

Methods: MM cells were treated with DHA/EPA with or without bortezomib. Cell viability was estimated by WST-1 assay. Apoptotic cells were determined through flow cytometry using annexin V and propidium iodide (PI) staining. Protein expression and phosphorylation was investigated by western blotting.

Results: Cell type dependent anticancer potential of DHA and EPA was observed in the cell viability assay. DHA and EPA induced apoptosis in L363, OPM2, MM.1S and U266 cell lines through both mitochondrial and death receptor pathways. Treating MM cells with DHA and EPA significantly downregulated IκBα and upregulated phosphorylation of p65, indicating that they triggered NF-κB activation in MM cells. Treating cells with DHA or EPA prior to bortezomib enhanced the induced cell death. However, concomitant use of bortezomib in combination with either of DHA or EPA decreased the cell death induced by bortezomib, indicating that timing of coincubation is important for the effects on chemosensitivity.

Conclusions: The present study provides novel evidence for the anticancer effects of DHA and EPA, and highlights their rational utilization in combination with bortezomib to achieve improved therapeutic outcome for MM.
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http://dx.doi.org/10.1016/j.clnu.2020.09.009DOI Listing
September 2020

Allergy Modulation by N-3 Long Chain Polyunsaturated Fatty Acids and Fat Soluble Nutrients of the Mediterranean Diet.

Front Pharmacol 2020 21;11:1244. Epub 2020 Aug 21.

Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.

The Mediterranean diet, containing valuable nutrients such as n-3 long chain poly-unsaturated fatty acids (LCPUFAs) and other fat-soluble micronutrients, is known for its health promoting and anti-inflammatory effects. Its valuable elements might help in the battle against the rising prevalence of non-communicable diseases (NCD), including the development of allergic diseases and other (chronic) inflammatory diseases. The fat fraction of the Mediterranean diet contains bioactive fatty acids but can also serve as a matrix to dissolve and increase the uptake of fat-soluble vitamins and phytochemicals, such as luteolin, quercetin, resveratrol and lycopene with known immunomodulatory and anti-inflammatory capacities. Especially n-3 LCPUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from marine oils can target specific receptors or signaling cascades, act as eicosanoid precursors and/or alter membrane fluidity and lipid raft formation, hereby exhibiting anti-inflammatory properties. Beyond n-3 LCPUFAs, fat-soluble vitamins A, D, E, and K1/2 have the potential to affect pro-inflammatory signaling cascades by interacting with receptors or activating/inhibiting signaling proteins or phosphorylation in immune cells (DCs, T-cells, mast cells) involved in allergic sensitization or the elicitation/effector phase of allergic reactions. Moreover, fat-soluble plant-derived phytochemicals can manipulate signaling cascades, mostly by interacting with other receptors or signaling proteins compared to those modified by fat-soluble vitamins, suggesting potential additive or synergistic actions by applying a combination of these nutrients which are all part of the regular Mediterranean diet. Research concerning the effects of phytochemicals such as polyphenols has been hampered due to their poor bio-availability. However, their solubility and uptake are improved by applying them within the dietary fat matrix. Alternatively, they can be prepared for targeted delivery by means of pharmaceutical approaches such as encapsulation within liposomes or even unique nanoparticles. This review illuminates the molecular mechanisms of action and possible immunomodulatory effects of n-3 LCPUFAs and fat-soluble micronutrients from the Mediterranean diet in allergic disease development and allergic inflammation. This will enable us to further appreciate how to make use of the beneficial effects of n-3 LCPUFAs, fat-soluble vitamins and a selection of phytochemicals as active biological components in allergy prevention and/or symptom reduction.
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http://dx.doi.org/10.3389/fphar.2020.01244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472571PMC
August 2020

Correction to: Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549).

BMC Pulm Med 2020 Sep 22;20(1):250. Epub 2020 Sep 22.

Cell and Molecular Biology Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12890-020-01244-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507606PMC
September 2020

Novel Dietary Proteins Selectively Affect Intestinal Health In Vitro after -Secreted Toxin A Exposure.

Nutrients 2020 Sep 11;12(9). Epub 2020 Sep 11.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.

Bacterial gastroenteritis forms a burden on a global scale, both socially and economically. The Gram-positive bacterium is an inducer of gastrointestinal bacterial infections, often triggered following disruption of the microbiota by broad-spectrum antibiotics to treat other conditions. The clinical manifestatiaons, e.g., diarrhea, are driven by its toxins secretion, toxin A (TcdA) and toxin B (TcdB). Current therapies are focused on discontinuing patient medication, including antibiotics. However, relapse rates upon therapy are high (20-25%). Here, eighteen dietary proteins were evaluated for their capacity to restore gut health upon -derived TcdA exposure. We used bioengineered intestinal tubules to assess proteins for their beneficial effects by examining the epithelial barrier, cell viability, brush-border enzyme activity, IL-6 secretion, IL-8 secretion and nitric oxide (NO) levels upon TcdA challenge. TcdA effectively disrupted the epithelial barrier, increased mitochondrial activity, but did not affect alkaline phosphatase activity, IL-6, IL-8 and NO levels. Intervention with dietary proteins did not show a protective effect on epithelial barrier integrity or mitochondrial activity. However, bovine plasma and potato protein increased alkaline phosphatase activity, egg-white protein increased IL-6 and IL-8 release and wheat, lesser mealworm and yeast protein increased NO levels after TcdA exposure. Hence, dietary proteins can influence parameters involved in intestinal physiology and immune activation suggesting that supplementation with specific dietary proteins may be of benefit during infections.
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http://dx.doi.org/10.3390/nu12092782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551268PMC
September 2020

Clinical Use of Antigens as Novel Immunotherapies for Autoimmune Disorders.

Front Immunol 2020 13;11:1821. Epub 2020 Aug 13.

Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Beta Sciences, Utrecht University, Utrecht, Netherlands.

The hygiene hypothesis states that improved hygiene and the resulting disappearance of once endemic diseases is at the origin of the enormous increase in immune related disorders such as autoimmune diseases seen in the industrialized world. Helminths, such as , are thought to provide protection against the development of autoimmune diseases by regulating the host's immune response. This modulation primarily involves induction of regulatory immune responses, such as generation of tolerogenic dendritic cells and alternatively activated macrophages. This points toward the potential of employing helminths or their products/metabolites as therapeutics for autoimmune diseases that are characterized by an excessive inflammatory state, such as multiple sclerosis (MS), type I diabetes (T1D) and inflammatory bowel disease (IBD). In this review, we examine the known mechanisms of immune modulation by , explore preclinical and clinical studies that investigated the use of an array helminthic products in these diseases, and propose that helminthic therapy opens opportunities in the treatment of chronic inflammatory disorders.
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http://dx.doi.org/10.3389/fimmu.2020.01821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438586PMC
August 2020

Perspective: The Role of Human Breast-Milk Extracellular Vesicles in Child Health and Disease.

Adv Nutr 2021 02;12(1):59-70

Department of Pediatrics and Pediatric Infectious Diseases, Institute of Child's Health, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.

Human breast milk (HM) contains multiple bioactive substances determining its impact on children's health. Extracellular vesicles (EVs) are a heterogeneous group of secreted nanoparticles that are present in HM and may be partially responsible for its beneficial effects. The precise roles and content of EVs in HM remain largely unknown. To examine this, we performed a short narrative review on the literature focusing on HM EVs to contextualize the available data, followed by a scoping review of MEDLINE and Embase databases. We identified 424 nonduplicate citations with 19 original studies included. In this perspective, we summarize the evidence around HM EVs, highlight some theoretical considerations based on existing evidence, and provide an overview of some challenges associated with the complexity and heterogeneity of EV research. We consider how the existing data from HM studies conform to the minimal information for studies of EVs (MISEV) guidelines. Across the studies a variety of research methods were utilized involving both bench-based and translational methods, and a range of different EV contents were examined including RNA, proteins, and glycopeptides. We observed a variety of health outcomes in these studies, including allergy and atopy, necrotizing enterocolitis, and HIV. While some promising results have been demonstrated, the heterogeneity in outcomes of interest, methodological limitations, and relatively small number of studies in the field make comparison between studies or further translational work problematic. To date, no studies have examined normative values of HM EVs in a large, diverse population or with respect to potentially important influencing factors such as timing (hind- vs. foremilk), stage (colostrum vs. mature milk), and infant age (preterm vs. term), which makes extrapolation from bench or "basic" research impossible. Future research should focus on addressing the current inadequacies in the literature and utilize MISEV guidelines to inform study design.
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http://dx.doi.org/10.1093/advances/nmaa094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849950PMC
February 2021

Dietary Vitamin D Supplementation Is Ineffective in Preventing Murine Cow's Milk Allergy, Irrespective of the Presence of Nondigestible Oligosaccharides.

Int Arch Allergy Immunol 2020 19;181(12):908-918. Epub 2020 Aug 19.

Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands,

Introduction: Cow's milk allergy (CMA) is one of the most common food allergies especially early in life. A mixture of nondigestible short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides, and pectin-derived acidic-oligosaccharides (GFA) may reduce allergy development and allergic symptoms in murine CMA. Recently, vitamin D (VitD) has been suggested to have beneficial effects in reducing allergy as well.

Objective: In this study, the immune modulatory effect on allergy prevention using the combination of GFA and VitD was investigated.

Methods: Female C3H/HeOuJ mice were fed a control or GFA-containing diet with depleted, standard (1,000 IU/kg), or supplemented (5,000 IU/kg) VitD content for 2 weeks before and during whey sensitization (n = 10-15). Mice were sensitized 5 times intragastrically with PBS as a control, whey as cow's milk allergen, and/or cholera toxin as adjuvant on a weekly interval. One week after the last sensitization, mice were intradermally challenged in both ear pinnae and orally with whey, subsequently the acute allergic skin response and shock symptoms were measured. After 18 h, terminal blood samples, mesenteric lymph nodes, and spleens were collected. Whey-specific immunoglobulin (Ig) E and IgG1 levels were measured by means of ELISA. T cell subsets and dendritic cells (DCs) were studied using flow cytometry.

Results: Additional VitD supplementation did not lower the allergic symptoms compared to the standard VitD diet. CMA mice fed the GFA diet supplemented with VitD (GFA VitD+) significantly decreased the acute allergic skin response of whey sensitized mice when compared to the CMA mice fed VitD (VitD+) group (p < 0.05). The effect of GFA was not improved by extra VitD supplementation even though the CMA mice fed the GFA VitD+ diet had a significantly increased percentage of CD103+ DCs compared to the VitD+ group (p < 0.05). The VitD-deprived mice showed a high percentage of severe shock and many reached the humane endpoint; therefore, these groups were not further analyzed.

Conclusions: High-dose VitD supplementation in mice does not protect against CMA development in the presence or absence of GFA.
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http://dx.doi.org/10.1159/000509750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845446PMC
January 2021

Machine Learning-Based Ensemble Recursive Feature Selection of Circulating miRNAs for Cancer Tumor Classification.

Cancers (Basel) 2020 Jul 3;12(7). Epub 2020 Jul 3.

UMR 518 MIA-Paris, INRAE, Université Paris-Saclay, 75013 Paris, France.

Circulating microRNAs (miRNA) are small noncoding RNA molecules that can be detected in bodily fluids without the need for major invasive procedures on patients. miRNAs have shown great promise as biomarkers for tumors to both assess their presence and to predict their type and subtype. Recently, thanks to the availability of miRNAs datasets, machine learning techniques have been successfully applied to tumor classification. The results, however, are difficult to assess and interpret by medical experts because the algorithms exploit information from thousands of miRNAs. In this work, we propose a novel technique that aims at reducing the necessary information to the smallest possible set of circulating miRNAs. The dimensionality reduction achieved reflects a very important first step in a potential, clinically actionable, circulating miRNA-based precision medicine pipeline. While it is currently under discussion whether this first step can be taken, we demonstrate here that it is possible to perform classification tasks by exploiting a recursive feature elimination procedure that integrates a heterogeneous ensemble of high-quality, state-of-the-art classifiers on circulating miRNAs. Heterogeneous ensembles can compensate inherent biases of classifiers by using different classification algorithms. Selecting features then further eliminates biases emerging from using data from different studies or batches, yielding more robust and reliable outcomes. The proposed approach is first tested on a tumor classification problem in order to separate 10 different types of cancer, with samples collected over 10 different clinical trials, and later is assessed on a cancer subtype classification task, with the aim to distinguish triple negative breast cancer from other subtypes of breast cancer. Overall, the presented methodology proves to be effective and compares favorably to other state-of-the-art feature selection methods.
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http://dx.doi.org/10.3390/cancers12071785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407482PMC
July 2020

The Inflammatory Response to Alcohol Consumption and Its Role in the Pathology of Alcohol Hangover.

J Clin Med 2020 Jul 2;9(7). Epub 2020 Jul 2.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3584CG Utrecht, The Netherlands.

An increasing number of studies are focusing on the inflammatory response to alcohol as a potentially important determinant of hangover severity. In this article, data from two studies were re-evaluated to investigate the relationship between hangover severity and relevant biomarkers of alcohol metabolism, oxidative stress and the inflammatory response to alcohol. Hangover severity was significantly and positively correlated with blood concentrations of biomarkers of the inflammatory response to alcohol, in particular, Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP). At 4 h after alcohol consumption, blood ethanol concentration (but not acetaldehyde) was significantly and positively associated with elevated levels of IL-6, suggesting a direct inflammatory effect of ethanol. In addition, biomarkers of oxidative stress, i.e., malondialdehyde and 8-isoprostrane, were significantly correlated with hangover severity, suggesting that oxidative stress also contributes to the inflammatory response. The timing of the assessments suggests initial slow elimination of ethanol in the first hours after alcohol consumption. As a consequence, more ethanol is present in the second half of the night and the next morning, which will elicit more oxidative stress and a more profound inflammatory response. Together, these processes result in more severe hangovers.
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http://dx.doi.org/10.3390/jcm9072081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408936PMC
July 2020

The Association between Ethanol Elimination Rate and Hangover Severity.

Int J Environ Res Public Health 2020 06 17;17(12). Epub 2020 Jun 17.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3584CG Utrecht, The Netherlands.

Assessments in blood and saliva suggests that the amount of ethanol present in the first hours after alcohol consumption and into the following morning is associated with hangover severity. The current analysis determines how ethanol elimination rate is related to hangover severity reported throughout the day. = 8 subjects participated in two studies. The first was a naturalistic study comprising an evening of alcohol consumption. Hangover severity was assessed hourly from 10 a.m. to 4 p.m., using a 1-item hangover severity scale ranging from 0 (absent) to 10 (extreme). The second study comprised a highly controlled alcohol challenge to reach a breath alcohol concentration (BrAC) of 0.05%. Breathalyzer tests were conducted every 5 min until BrAC reached zero. The ethanol elimination rate, expressed in BrAC%/hour, was computed by dividing the peak BrAC (%) by the time to BrAC of zero (h). At 11:00, 13:00, and 14:00, there were significant negative partial correlations, controlling for estimated BrAC, between ethanol elimination rate and hangover severity. The findings suggest that drinkers with a faster ethanol elimination rate experience less severe hangovers. The observations should be confirmed in a larger sample of subjects who participate in a single study that assesses both hangover severity and ethanol elimination rate.
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http://dx.doi.org/10.3390/ijerph17124324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345465PMC
June 2020

Free Amino Acids in Human Milk: A Potential Role for Glutamine and Glutamate in the Protection Against Neonatal Allergies and Infections.

Front Immunol 2020 28;11:1007. Epub 2020 May 28.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.

Breastfeeding is indicated to support neonatal immune development and to protect against neonatal infections and allergies. Human milk composition is widely studied in relation to these unique abilities, which has led to the identification of various immunomodulating components in human milk, including various bioactive proteins. In addition to proteins, human milk contains free amino acids (FAAs), which have not been well-studied. Of those, the FAAs glutamate and glutamine are by far the most abundant. Levels of these FAAs in human milk sharply increase during the first months of lactation, in contrast to most other FAAs. These unique dynamics are globally consistent, suggesting that their levels in human milk are tightly regulated throughout lactation and, consequently, that they might have specific roles in the developing neonate. Interestingly, free glutamine and glutamate are reported to exhibit immunomodulating capacities, indicating that these FAAs could contribute to neonatal immune development and to the unique protective effects of breastfeeding. This review describes the current understanding of the FAA composition in human milk. Moreover, it provides an overview of the effects of free glutamine and glutamate on immune parameters relevant for allergic sensitization and infections in early life. The data reviewed provide rationale to study the role of free glutamine and glutamate in human milk in the protection against neonatal allergies and infections.
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http://dx.doi.org/10.3389/fimmu.2020.01007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270293PMC
May 2020

Perceived Immune Fitness, Individual Strength and Hangover Severity.

Int J Environ Res Public Health 2020 06 5;17(11). Epub 2020 Jun 5.

Institute for Risk Assessment Sciences (IRAS), Utrecht University, 3584CM Utrecht, The Netherlands.

Various factors may contribute to alcohol hangover severity. The purpose of the current investigation was to evaluate the possible impact of alcohol consumption patterns, perceived immune status, and baseline fatigue on hangover severity. A survey was completed by a convenience sample of = 199 Dutch students who reported on their latest past month's heavy drinking occasion, including subjective intoxication (perceived drunkenness) and next-day hangover severity, which were rated on single-item scales ranging from 0 (absent) to 10 (extreme). In addition, perceived (momentary) immune fitness was assessed, and the Checklist Individual Strength (CIS) was completed to assess baseline fatigue. The analysis revealed that instead of the amount of alcohol consumed or estimated blood alcohol concentration, it appeared that subjective intoxication (i.e., level of drunkenness) was the most important determinant of alcohol hangover severity. Especially in men, albeit modest, it was perceived that immune fitness also significantly contributed to the level of hangover severity experienced.
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http://dx.doi.org/10.3390/ijerph17114039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311961PMC
June 2020

Loss of allergy-protective capacity of raw cow's milk after heat treatment coincides with loss of immunologically active whey proteins.

Food Funct 2020 Jun;11(6):4982-4993

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands. and Danone Nutricia Research, Utrecht, The Netherlands.

The allergy-protective capacity of raw cow's milk was demonstrated to be abolished after heat treatment. The heat-sensitive whey protein fraction of raw milk is often implied to be the source of this allergy-protective effect, but a direct link between these proteins and the protection against allergic diseases is missing. This study therefore aimed at investigating the mechanistic relation between heat damage to whey proteins and allergy development. Raw cow's milk was heated for 30 min at 50, 60, 65, 70, 75, or 80 °C and the native whey protein profile of these differentially heated milk samples was determined using LC-MS/MS-based proteomics. Changes in the native protein profile were subsequently related to the capacity of these milk samples to prevent the development of ovalbumin-induced food allergy in a murine animal model. A substantial loss of native whey proteins, as well as extensive protein aggregation, was observed from 75 °C. However, whey proteins with immune-related functionalities already started to denature from 65 °C, which coincided with the temperature at which a loss of allergy protection was observed in the murine model. Complement C7, monocyte differentiation antigen CD14, and polymeric immunoglobulin receptor concentrations decreased significantly at this temperature, although several other immunologically active whey proteins also showed a decrease around 65 °C. The current study demonstrates that immunologically active whey proteins that denature around 65 °C are of importance for the allergy-protective capacity of raw cow's milk and thereby provides key knowledge for the development of microbiologically safe alternatives to raw cow's milk.
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http://dx.doi.org/10.1039/d0fo01175dDOI Listing
June 2020

Immunomodulation by Human Milk Oligosaccharides: The Potential Role in Prevention of Allergic Diseases.

Front Immunol 2020 7;11:801. Epub 2020 May 7.

Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.

The prevalence and incidence of allergic diseases is rising and these diseases have become the most common chronic diseases during childhood in Westernized countries. Early life forms a critical window predisposing for health or disease. Therefore, this can also be a window of opportunity for allergy prevention. Postnatally the gut needs to mature, and the microbiome is built which further drives the training of infant's immune system. Immunomodulatory components in breastmilk protect the infant in this crucial period by; providing nutrients that contain substrates for the microbiome, supporting intestinal barrier function, protecting against pathogenic infections, enhancing immune development and facilitating immune tolerance. The presence of a diverse human milk oligosaccharide (HMOS) mixture, containing several types of functional groups, points to engagement in several mechanisms related to immune and microbiome maturation in the infant's gastrointestinal tract. In recent years, several pathways impacted by HMOS have been elucidated, including their capacity to; fortify the microbiome composition, enhance production of short chain fatty acids, bind directly to pathogens and interact directly with the intestinal epithelium and immune cells. The exact mechanisms underlying the immune protective effects have not been fully elucidated yet. We hypothesize that HMOS may be involved in and can be utilized to provide protection from developing allergic diseases at a young age. In this review, we highlight several pathways involved in the immunomodulatory effects of HMOS and the potential role in prevention of allergic diseases. Recent studies have proposed possible mechanisms through which HMOS may contribute, either directly or indirectly, via microbiome modification, to induce oral tolerance. Future research should focus on the identification of specific pathways by which individual HMOS structures exert protective actions and thereby contribute to the capacity of the authentic HMOS mixture in early life allergy prevention.
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http://dx.doi.org/10.3389/fimmu.2020.00801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221186PMC
May 2020

Direct Inhibition of the Allergic Effector Response by Raw Cow's Milk-An Extensive In Vitro Assessment.

Cells 2020 05 19;9(5). Epub 2020 May 19.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands.

The mechanisms underlying the allergy-protective effects of raw cow's milk are poorly understood. The current focus is mainly on the modulation of T cell responses. In the present study, we investigated whether raw cow's milk can also directly inhibit mast cells, the key effector cells in IgE-mediated allergic responses. Primary murine bone marrow-derived mast cells (BMMC) and peritoneal mast cells (PMC), were incubated with raw milk, heated raw milk, or shop milk, prior to IgE-mediated activation. The effects on mast cell activation and underlying signaling events were assessed. Raw milk was furthermore fractionated based on molecular size and obtained fractions were tested for their capacity to reduce IgE-mediated mast cell activation. Coincubation of BMMC and PMC with raw milk prior to activation reduced β-hexosaminidase release and IL-6 and IL-13 production, while heated raw milk or shop milk had no effect. The reduced mast cell activation coincided with a reduced intracellular calcium influx. In addition, SYK and ERK phosphorylation levels, both downstream signaling events of the FcεRI, were lower in raw milk-treated BMMC compared to control BMMC, although differences did not reach full significance. Raw milk-treated BMMC furthermore retained membrane-bound IgE expression after allergen stimulation. Raw milk fractionation showed that the heat-sensitive raw milk components responsible for the reduced mast cell activation are likely to have a molecular weight of > 37 kDa. The present study demonstrates that raw cow's milk can also directly affect mast cell activation. These results extend the current knowledge on mechanisms via which raw cow's milk prevents allergic diseases, which is crucial for the development of new, microbiologically safe, nutritional strategies to reduce allergic diseases.
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http://dx.doi.org/10.3390/cells9051258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290799PMC
May 2020

Exposure of Intestinal Epithelial Cells to 2'-Fucosyllactose and CpG Enhances Galectin Release and Instructs Dendritic Cells to Drive Th1 and Regulatory-Type Immune Development.

Biomolecules 2020 05 19;10(5). Epub 2020 May 19.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 Utrecht, The Netherlands.

Intestinal epithelial cells (IEC) release immunomodulatory galectins upon exposure to CpG DNA (mimicking bacterial triggers) and short-chain galacto- and long-chain fructo-oligosaccharides (GF). This study aims to investigate the immunomodulatory properties of 2'-fucosyllactose (2'-FL), a non-digestible oligosaccharide (NDO) abundantly present in human milk, using a co-culture model developed to study the crosstalk between IEC and innate and adaptive immune cells. IECs, co-cultured with αCD3/CD28-activated peripheral blood mononuclear cells (PBMC), were apically exposed to NDOs and CpG, washed and co-cultured with immature monocyte-derived dendritic cells (moDC). Subsequently, moDC were co-cultured with naïve CD4+ T-cells. In the presence of CpG, both 2'-FL or GF-exposed IEC enhanced Th1-type IFNγ and regulatory IL-10 secretion of PBMCs, compared to CpG alone, while Th2-type IL-13 was reduced. Both NDOs increased IEC-derived galectin-3, -4, -9 and TGF-β1 of CpG-exposed IEC. Only galectin-9 correlated with all modified immune parameters and TGF-β1 secretion. MoDCs exposed to 2'-FL and CpG-conditioned IEC instructed IFNγ and IL-10 secretion by CD4+ T-cells, suggesting the development of a regulatory Th1 response. These results reveal that 2'-FL and GF could contribute to the mucosal immune development by supporting the effect of microbial CpG DNA associated with the modulation of epithelial galectin and TGF-β1 secretion.
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http://dx.doi.org/10.3390/biom10050784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278199PMC
May 2020

Specific Polyunsaturated Fatty Acids Can Modulate Human moDC2s and Subsequent Th2 Cytokine Release.

Front Immunol 2020 4;11:748. Epub 2020 May 4.

Food and Biobased Research, Wageningen University & Research, Wageningen, Netherlands.

Allergy is becoming a rapidly increasing problem worldwide, and models are frequently used to study the mechanisms behind the different types of allergic response. The dendritic cell (DC)-T-cell model can be used to study sensitization. However, lipopolysaccharide (LPS) is often used to maturate the DCs, but it gives rise to a DC1 phenotype, whereas Th2-driven inflammatory diseases such as allergy are characterized by the involvement of the DC2 phenotype. Our aim was to create a DC2-T-cell human model (human moDC2s) to study sensitization and validate the model using polyunsaturated fatty acids (PUFAs) that were previously shown to have immunomodulatory properties. We found that the generated DC2s expressed OX40L and drove naive T-cells into IL-13 production of CD4 effector T-cells. In line with findings, -3 long-chain (LC)PUFA docosahexaenoic acid (DHA) effectively decreased the DC2's surface expression of OX40L, as well as the IL-12p40 and IL-23 cytokine production by DC2s and subsequently lowered IL-13 production by DC2-induced effector T-cells. Similar cytokine production effects were found with eicosapentaenoic acid (EPA) and arachidonic acid (AA), whereas linoleic acid (LA) increased OX40L surface expression and subsequent T-cell-derived IL-13/IFNγ ratios, suggesting an increased risk of allergy development. Altogether, these data show that human moDC2s are able to induce Th2-type IL-13 secretion by T-cell differentiated in the presence of these DC2s and that this model can be differentially modulated by PUFAs. These results are in line with previous studies using PUFAs, indicating that this model may be of use to predict outcomes.
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http://dx.doi.org/10.3389/fimmu.2020.00748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212991PMC
May 2020

Beyond Heat Stress: Intestinal Integrity Disruption and Mechanism-Based Intervention Strategies.

Nutrients 2020 Mar 11;12(3). Epub 2020 Mar 11.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands.

The current climate changes have increased the prevalence and intensity of heat stress (HS) conditions. One of the initial consequences of HS is the impairment of the intestinal epithelial barrier integrity due to hyperthermia and hypoxia following blood repartition, which often results in a leaky gut followed by penetration and transfer of luminal antigens, endotoxins, and pathogenic bacteria. Under extreme conditions, HS may culminate in the onset of "heat stroke", a potential lethal condition if remaining untreated. HS-induced alterations of the gastrointestinal epithelium, which is associated with a leaky gut, are due to cellular oxidative stress, disruption of intestinal integrity, and increased production of pro-inflammatory cytokines. This review summarizes the possible resilience mechanisms based on in vitro and in vivo data and the potential interventions with a group of nutritional supplements, which may increase the resilience to HS-induced intestinal integrity disruption and maintain intestinal homeostasis.
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http://dx.doi.org/10.3390/nu12030734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146479PMC
March 2020

Strain-Specific Probiotic Properties of Bifidobacteria and Lactobacilli for the Prevention of Diarrhea Caused by Rotavirus in a Preclinical Model.

Nutrients 2020 Feb 15;12(2). Epub 2020 Feb 15.

Physiology Section, Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona (UB), 08028 Barcelona, Spain.

Probiotic supplementation with different lactobacilli and bifidobacterial strains has demonstrated beneficial effects in infectious diarrhea caused by rotavirus (RV) in young children. Preclinical models of RV infection might be a good strategy to screen for the efficacy of new probiotic strains or to test their comparative efficacy. Neonatal Lewis rats were supplemented with M-16V, NCFM, , or PS2 from days 2-14 of life. On day five, animals received RV SA-11 orally. Fecal samples were collected daily, weighed, and scored for the calculation of severity and incidence of diarrhea. In addition, fecal pH and fecal viral shedding were measured. Animals were sacrificed at the end of the study and their blood was obtained for the quantification of RV-specific immunoglobulins. RV infection was induced in ~90% of the animals. All probiotics caused a reduction of several clinical variables of severity and incidence of diarrhea, except PS2. NCFM, M-16V, and R0052 seemed to be very effective probiotic strains. In addition, all strains reduced the viral elimination one day post-inoculation. No differences were detected in the specific anti-RV humoral response. The present study highlights the strain-specific effects of probiotics and identifies promising probiotics for use in ameliorating and preventing RV-induced diarrhea in children, for example by including them in infant formulas.
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http://dx.doi.org/10.3390/nu12020498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071190PMC
February 2020