Maternal prebiotic supplementation during pregnancy and lactation modifies the microbiome and short chain fatty acid profile of both mother and infant.

BACKGROUND & AIMS: Improving maternal gut health in pregnancy and lactation is a potential strategy to improve immune and metabolic health in offspring and curtail the rising rates of inflammatory diseases linked to alterations in gut microbiota. Here, we investigate the effects of a maternal prebiotic supplement (galacto-oligosaccharides and fructo-oligosaccharides), ingested daily from <21 weeks' gestation to six months' post-partum, in a double-blinded, randomised placebo-controlled trial. METHODS: Stool samples were collected at multiple timepoints from 74 mother-infant pairs as part of a larger, double-blinded, randomised controlled allergy intervention trial. The participants were randomised to one of two groups; with one group receiving 14.2 g per day of prebiotic powder (galacto-oligosaccharides GOS and fructo-oligosaccharides FOS in ratio 9:1), and the other receiving a placebo powder consisting of 8.7 g per day of maltodextrin. The faecal microbiota of both mother and infants were assessed based on the analysis of bacterial 16S rRNA gene (V4 region) sequences, and short chain fatty acid (SCFA) concentrations in stool. RESULTS: Significant differences in the maternal microbiota profiles between baseline and either 28-weeks' or 36-weeks' gestation were found in the prebiotic supplemented women. Infant microbial beta-diversity also significantly differed between prebiotic and placebo groups at 12-months of age. Supplementation was associated with increased abundance of commensal Bifidobacteria in the maternal microbiota, and a reduction in the abundance of Negativicutes in both maternal and infant microbiota. There were also changes in SCFA concentrations with maternal prebiotics supplementation, including significant differences in acetic acid concentration between intervention and control groups from 20 to 28-weeks' gestation. CONCLUSION: Maternal prebiotic supplementation of 14.2 g per day GOS/FOS was found to favourably modify both the maternal and the developing infant gut microbiome. These results build on our understanding of the importance of maternal diet during pregnancy, and indicate that it is possible to intervene and modify the development of the infant microbiome by dietary modulation of the maternal gut microbiome.

Role of selenium in IgE mediated soybean allergy development.

Food allergy is a pathological immune reaction triggered by normal innocuous dietary proteins. Soybean is widely used in many food products and has long been recognized as a source of high-quality proteins. However, soybean is listed as one of the 8 most significant food allergens. The prevalence of soybean allergy is increasing worldwide and impacts the quality of life of patients. Currently, the only strategy to manage food allergy relies on strict avoidance of the offending food. Nutritional supplementation is a new prevention strategy which is currently under evaluation. Selenium (Se), as one of the essential micronutrients for humans and animals, carries out biological effects through its incorporation into selenoproteins. The use of interventions with micronutrients, like Se, might be an interesting new approach. In this review we describe the involvement of Se in a variety of processes, including maintaining immune homeostasis, preventing free radical damage, and modulating the gut microbiome, all of which may contribute to in both the prevention and treatment of food allergy. Se interventions could be an interesting new approach for future treatment strategies to manage soybean allergy, and food allergy in general, and could help to improve the quality of life for food allergic patients.

Study Protocol for a Randomised Controlled Trial Investigating the Effects of Maternal Prebiotic Fibre Dietary Supplementation from Mid-Pregnancy to Six Months' Post-Partum on Child Allergic Disease Outcomes.

Infant allergy is the most common early manifestation of an increasing propensity for inflammation and immune dysregulation in modern environments. Refined low-fibre diets are a major risk for inflammatory diseases through adverse effects on the composition and function of gut microbiota. This has focused attention on the potential of prebiotic dietary fibres to favourably change gut microbiota, for local and systemic anti-inflammatory effects. In pregnancy, the immunomodulatory effects of prebiotics may also have benefits for the developing fetal immune system, and provide a potential dietary strategy to reduce the risk of allergic disease. Here, we present the study protocol for a double-blinded, randomised controlled trial investigating the effects of maternal prebiotics supplementation on child allergic disease outcomes. Eligible pregnant women have infants with a first-degree relative with a history of medically diagnosed allergic disease. Consented women are randomised to consume either prebiotics (galacto-oligosaccharides and fructo-oligosaccharides) or placebo (maltodextrin) powder daily from 18-20 weeks' gestation to six months' post-partum. The target sample size is 652 women. The primary outcome is infant medically diagnosed eczema; secondary outcomes include allergen sensitisation, food allergies and recurrent wheeze. Breast milk, stool and blood samples are collected at multiple timepoints for further analysis.

Hypoallergenicity assessment of an extensively hydrolyzed whey-protein formula in cow's milk allergic infants.

BACKGROUND: Extensively hydrolyzed formulas are recommended for the dietary management of infants with cow's milk allergy (CMA). OBJECTIVES: Hypoallergenicity, growth, and gastrointestinal (GI) tolerability of a new extensively hydrolyzed whey-protein formula (eHWF) in CMA children were assessed. METHODS: In this prospective, randomized, international, multi-center study (Trial NL3889), 34 children with confirmed CMA (74% IgE-mediated) underwent a double-blind, placebo-controlled food challenge (DBPCFC) with an eHWF developed with non-porcine enzymes, supplemented with prebiotic short-chain galacto- and long-chain fructo-oligosaccharides (0.8 g/L, ratio 9:1), arachidonic acid (0.35/100 g), and docosahexaenoic acid (0.35/100 g). If tolerant to the eHWF, children participated in a 7-day open food challenge with this eHWF. Anthropometrics and GI tolerability were assessed in an optional 16-weeks follow-up. RESULTS: Of the 34 children who started the DBPCFC with the eHWF, 25 subjects (19 boys, mean age: 61 weeks, 18 with IgE-mediated CMA) completed the DBPCFC and 7-day open challenge without major protocol deviations and tested negative at both challenges. One child experienced a late moderate eczematous allergic reaction in the optional follow-up period, indicating the need for close monitoring of subjects starting new formula. Weight and length gain followed the World Health Organization growth curves. Changes in frequency and consistency of stools upon test formula intake were transient. CONCLUSIONS: The newly developed eHWF is a suitable option in CMA treatment as all subjects tolerated the product. This result is in line with the international criteria for hypoallergenicity (American Academy of Pediatrics) that state that more than 90% of CMA children must tolerate the formula. Use of the formula is also associated with normal growth curves and GI tolerability. TRIAL REGISTRATION: Trial NL3889, https://www.trialregister.nl/trial/3889.

Exposure to the Amino Acids Histidine, Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model.

Evidence of the impact of nutrition on human brain development is compelling. Previous in vitro and in vivo results show that three specific amino acids, histidine, lysine, and threonine, synergistically inhibit mTOR activity and behavior. Therefore, the prenatal availability of these amino acids could be important for human neurodevelopment. However, methods to study the underlying mechanisms in a human model of neurodevelopment are limited. Here, we pioneer the use of human cerebral organoids to investigate the impact of amino acid supplementation on neurodevelopment. In this study, cerebral organoids were exposed to 10 mM and 50 mM of the amino acids threonine, histidine, and lysine. The impact was determined by measuring mTOR activity using Western blots, general cerebral organoid size, and gene expression by RNA sequencing. Exposure to threonine, histidine, and lysine led to decreased mTOR activity and markedly reduced organoid size, supporting findings in rodent studies. RNA sequencing identified comprehensive changes in gene expression, with enrichment in genes related to specific biological processes (among which are mTOR signaling and immune function) and to specific cell types, including proliferative precursor cells, microglia, and astrocytes. Altogether, cerebral organoids are responsive to nutritional exposure by increasing specific amino acid concentrations and reflect findings from previous rodent studies. Threonine, histidine, and lysine exposure impacts the early development of human cerebral organoids, illustrated by the inhibition of mTOR activity, reduced size, and altered gene expression.

Selenium-Enriched Soy Protein Has Antioxidant Potential via Modulation of the NRF2-HO1 Signaling Pathway.

Selenium (Se)-enriched proteins are an important dietary source of Se for humans; however, only a few Se-enriched proteins have been identified. In the present study, we tested for potential antioxidant activity by Se-enriched soy protein, both in vitro and in vivo. Se-enriched soy protein isolate (S-SPI) was shown to have a higher free radical scavenging ability compared to ordinary soy protein isolate (O-SPI). Furthermore, Caco-2 cell viability was improved by S-SPI at low doses, whereas O-SPI did not. In addition, S-SPI was shown to inhibit oxidative stress via modulation of the NRF2-HO1 signaling pathway, upregulating the expression of downstream antioxidant enzymes (GPx, SOD). To further study the antioxidant capacity of S-SPI, BALB/c female mice were given oral gavages with 0.8 mL of S-SPI or O-SPI (5 g/kg/d, 20 g/kg/d and 40 g/kg/d) or saline as control. Hepatic GPx and SOD activity increased with increasing S-SPI dosage, but not with O-SPI. Taken together, our results suggest that Se-enriched soy protein has a high antioxidant ability and may be used as a dietary supplement for people with oxidative dam-age-mediated diseases.

Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation.

Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance.

Selenium Modulates the Allergic Response to Whey Protein in a Mouse Model for Cow's Milk Allergy.

Cow's milk allergy is a common food allergy in infants, and is associated with an increased risk of developing other allergic diseases. Dietary selenium (Se), one of the essential micronutrients for humans and animals, is an important bioelement which can influence both innate and adaptive immune responses. However, the effects of Se on food allergy are still largely unknown. In the current study it was investigated whether dietary Se supplementation can inhibit whey-induced food allergy in an animal research model. Three-week-old female C3H/HeOuJ mice were intragastrically sensitized with whey protein and cholera toxin and randomly assigned to receive a control, low, medium or high Se diet. Acute allergic symptoms, allergen specific immunoglobulin (Ig) E levels and mast cell degranulation were determined upon whey challenge. Body temperature was significantly higher in mice that received the medium Se diet 60 min after the oral challenge with whey compared to the positive control group, which is indicative of impaired anaphylaxis. This was accompanied by reductions in antigen-specific immunoglobulins and reduced levels of mouse mast cell protease-1 (mMCP-1). This study demonstrates that oral Se supplementation may modulate allergic responses to whey by decreasing specific antibody responses and mMCP-1 release.

The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies.

Infectious diseases and infections remain a leading cause of death in low-income countries and a major risk to vulnerable groups, such as infants and the elderly. The immune system plays a crucial role in the susceptibility, persistence, and clearance of these infections. With 70-80% of immune cells being present in the gut, there is an intricate interplay between the intestinal microbiota, the intestinal epithelial layer, and the local mucosal immune system. In addition to the local mucosal immune responses in the gut, it is increasingly recognized that the gut microbiome also affects systemic immunity. Clinicians are more and more using the increased knowledge about these complex interactions between the immune system, the gut microbiome, and human pathogens. The now well-recognized impact of nutrition on the composition of the gut microbiota and the immune system elucidates the role nutrition can play in improving health. This review describes the mechanisms involved in maintaining the intricate balance between the microbiota, gut health, the local immune response, and systemic immunity, linking this to infectious diseases throughout life, and highlights the impact of nutrition in infectious disease prevention and treatment.

Perinatal and Early-Life Nutrition, Epigenetics, and Allergy.

Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.

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

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.

Dietary Supplementation throughout Life with Non-Digestible Oligosaccharides and/or n-3 Poly-Unsaturated Fatty Acids in Healthy Mice Modulates the Gut-Immune System-Brain Axis.

The composition and activity of the intestinal microbial community structures can be beneficially modulated by nutritional components such as non-digestible oligosaccharides and omega-3 poly-unsaturated fatty acids (n-3 PUFAs). These components affect immune function, brain development and behaviour. We investigated the additive effect of a dietary combination of scGOS:lcFOS and n-3 PUFAs on caecal content microbial community structures and development of the immune system, brain and behaviour from day of birth to early adulthood in healthy mice. Male BALB/cByJ mice received a control or enriched diet with a combination of scGOS:lcFOS (9:1) and 6% tuna oil (n-3 PUFAs) or individually scGOS:lcFOS (9:1) or 6% tuna oil (n-3 PUFAs). Behaviour, caecal content microbiota composition, short-chain fatty acid levels, brain monoamine levels, enterochromaffin cells and immune parameters in the mesenteric lymph nodes (MLN) and spleen were assessed. Caecal content microbial community structures displayed differences between the control and dietary groups, and between the dietary groups. Compared to control diet, the scGOS:lcFOS and combination diets increased caecal saccharolytic fermentation activity. The diets enhanced the number of enterochromaffin cells. The combination diet had no effects on the immune cells. Although the dietary effect on behaviour was limited, serotonin and serotonin metabolite levels in the amygdala were increased in the combination diet group. The combination and individual interventions affected caecal content microbial profiles, but had limited effects on behaviour and the immune system. No apparent additive effect was observed when scGOS:lcFOS and n-3 PUFAs were combined. The results suggest that scGOS:lcFOS and n-3 PUFAs together create a balance-the best of both in a healthy host.

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

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.

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

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.

A free amino acid-based diet partially prevents symptoms of cow's milk allergy in mice after oral sensitization with whey.

BACKGROUND: Amino acid-based formulas (AAFs) are used for the dietary management of cow's milk allergy (CMA). Whether AAFs have the potential to prevent the development and/or symptoms of CMA is not known. OBJECTIVE: The present study evaluated the preventive effects of an amino acid (AA)-based diet on allergic sensitization and symptoms of CMA in mice and aimed to provide insight into the underlying mechanism. METHODS: C3H/HeOuJ mice were sensitized with whey protein or with phosphate-buffered saline as sham-sensitized control. Starting 2 weeks before sensitization, mice were fed with either a protein-based diet or an AA-based diet with an AA composition based on that of the AAF Neocate, a commercially available AAF prescribed for the dietary management of CMA. Upon challenge, allergic symptoms, mast cell degranulation, whey-specific immunoglobulin levels, and FoxP3+ cell counts in jejunum sections were assessed. RESULTS: Compared to mice fed with the protein-based diet, AA-fed mice had significantly lower acute allergic skin responses. Moreover, the AA-based diet prevented the whey-induced symptoms of anaphylaxis and drop in body temperature. Whereas the AA-based diet had no effect on the levels of serum IgE and mucosal mast cell protease-1 (mMCP-1), AA-fed mice had significantly lower serum IgG2a levels and tended to have lower IgG1 levels (P = .076). In addition, the AA-based diet prevented the whey-induced decrease in FoxP3+ cells. In sham-sensitized mice, no differences between the two diets were observed in any of the tested parameters. CONCLUSION: This study demonstrates that an AA-based diet can at least partially prevent allergic symptoms of CMA in mice. Differences in FoxP3+ cell counts and serum levels of IgG2a and IgG1 may suggest enhanced anti-inflammatory and tolerizing capacities in AA-fed mice. This, combined with the absence of effects in sham-sensitized mice indicates that AAFs for the prevention of food allergies may be an interesting concept that warrants further research.

Fructo-Oligosaccharides Modify Human DC Maturation and Peanut-Induced Autologous T-Cell Response of Allergic Patients In Vitro.

Background: Dendritic cells (DCs) play an important role in antigen presentation, and are an interesting target for immune-modulation in allergies. Short- and long-chain fructo-oligosaccharides (scFOS/lcFOS, FF) have immunomodulatory capacities, and may influence the outcome of DC antigen presentation. Objective: This study investigated the effect of FF during DC maturation and allergen presentation using cells of peanut-allergic patients in an autologous DC-T cell assay. Methods: CD14+ and CD4+ T cells were isolated from peanut-allergic patients. CD14+ monocytes were differentiated into immature DCs (imDCs), and matured (matDCs) in the presence or absence of crude peanut-extract (CPE) and/or FF, and co-cultured in an autologous DC-T cell assay. T cell polarization, proliferation and cytokine production were measured. Results: Expression of maturation surface molecule markers on matDCs was not affected by CPE and/or FF. By contrast, the IL-10 secretion by matDCs increased compared to imDCs, upon exposure to CPE and FF compared to CPE alone. Also the IP-10 secretion increased in CPE/FF-matDCs compared to imDC. CPE-matDCs enhanced IL-13 release in the DC-T-cell assay and Treg polarization in presence or absence of FF. CPE/FF-DCs tended to increase the Treg/Th1 and Treg/Th2 ratios compared to matDCs. The proliferation of both Treg and Th2 cells tended to increase when T cells were co-cultured with CPE-matDCs compared to matDCs, which became significant when CPE-matDCs were also exposed to FF and a same tendency was shown for Th1 proliferation. Conclusion: Only in the presence of FF, CPE-matDCs produced increased regulatory and Th1-related mediators. CPE-matDCs modified T cell polarization and proliferation, and additional exposure to FF tended to enhance Treg/Th2 and Treg/Th1 ratios instructed by CPE/FF-matDCs. However this effect was not strong enough to suppress CPE-matDCs induced IL-13 release by Th-cells. This indicates the ability of FF to modify DC maturation in the presence of an allergen supporting a more Treg/Th1 prone direction of the successive allergen specific Th2 cell response.

Pollen exposure weakens innate defense against respiratory viruses.

BACKGROUND: Hundreds of plant species release their pollen into the air every year during early spring. During that period, pollen allergic as well as non-allergic patients frequently present to doctors with severe respiratory tract infections. Our objective was therefore to assess whether pollen may interfere with antiviral immunity. METHODS: We combined data from real-life human exposure cohorts, a mouse model and human cell culture to test our hypothesis. RESULTS: Pollen significantly diminished interferon-λ and pro-inflammatory chemokine responses of airway epithelia to rhinovirus and viral mimics and decreased nuclear translocation of interferon regulatory factors. In mice infected with respiratory syncytial virus, co-exposure to pollen caused attenuated antiviral gene expression and increased pulmonary viral titers. In non-allergic human volunteers, nasal symptoms were positively correlated with airborne birch pollen abundance, and nasal birch pollen challenge led to downregulation of type I and -III interferons in nasal mucosa. In a large patient cohort, numbers of rhinoviruspositive cases were correlated with airborne birch pollen concentrations. CONCLUSION: The ability of pollen to suppress innate antiviral immunity, independent of allergy, suggests that high-risk population groups should avoid extensive outdoor activities when pollen and respiratory virus seasons coincide.

EPA and DHA have selective toxicity for PBMCs from multiple myeloma patients in a partly caspase-dependent manner.

Poly-unsaturated fatty acids (PUFAs) have been shown to have cytotoxic effects in both solid and non-solid tumors. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among the most studied PUFAs. The aim of the present study was to evaluate the cytotoxic effects of these two fatty acids (FAs) in the peripheral blood mononuclear cells (PBMCs) obtained from untreated patients (new cases) with confirmed symptomatic multiple myeloma (MM). Our results showed that EPA at the concentration of 100 µM and DHA at 50 and 100 µM induce potent apoptotic effects in the PBMCs of MM patients (P < 0.05) as evidenced by Annexin V and propidium iodide (PI) staining, while they have little or no effects on the PBMCs isolated from healthy donors (P > 0.05). The observed effects were concentration- and time-dependent and 72 h treatment with DHA at a concentration of 100 µM had the strongest effect (P < 0.01). CD138 + cells isolated from MM patients showed great sensitivity to EPA/DHA. EPA- and DHA-induced apoptosis was significantly inhibited by the pan-caspase inhibitor (Z-VAD-FMK), indicating that cell death was at least partly dependent on caspase activation. The results of the present study showed that EPA and DHA have selective toxicities for malignant human plasma cells from MM patients, but not for mononuclear cells of healthy donors. These results warrant further studies with larger study populations to investigate the usefulness of PUFAs as a promising adjunctive therapy in the treatment of MM.

Effect of raw milk consumption on perceived health, mood and immune functioning among US adults with a poor and normal health: A retrospective questionnaire based study.

INTRODUCTION: Raw milk consumption is controversially discussed, and people are looking for raw milk due to expected positive health impacts. The purpose of this consumer survey was to evaluate health conditions prior to and after consuming of raw milk (RM). METHODS: An on-line survey was distributed in Spring 2018 among existing consumers of raw milk. One-Item health score, 1-item immunity score, immune status (ISQ), mood, bowel and skin conditions were rated retrospectively based on validated questionnaires. Data from 327 participants (age 54 years) were included, of which 156 (48%) were allocated to the poor health group after they reported being immune depressed or suffering from a chronic disease. Others were allocated to the normal health group. Milk consumption pattern before and after changing of the milk diet were recorded. All health outcomes were evaluated according a linear mixed model in SPSS. RESULTS: Health, perceived immunity, bowel and mood scores increased post RM consumption with around 35% in the poor health group (P < 0.001), and around 9% in the normal health group (P < 0.001). Bowel and mood scores were overall lower in women than in men. Outcomes were independent of the origin of raw farm milk. CONCLUSIONS: This consumer survey suggests that positive health and mood changes are associated with the consumption of raw milk. Effects were strongest in people with a self-reported poor health status as well as in women.

Supplementation of diet with non-digestible oligosaccharides alters the intestinal microbiota, but not arthritis development, in IL-1 receptor antagonist deficient mice.

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.