Repeated exposure of bronchial epithelial cells to particular matter increases allergen-induced cytokine release and permeability.

Long term particulate matter (PM) exposure has been associated with an increased incidence of respiratory diseases. Here, an in vitro model was developed to study how long term diesel exhaust particle (DEP) exposure might predispose to the development of allergic reactions. Airway epithelial (16HBE) cells were exposed to low concentrations of diesel exhaust particle (DEP) for 4 days after which they were challenged with house dust mite (HDM) extract (24 h). Compared to acute exposure (24 h), 4 days DEP exposure to 16HBE cells further reduced the transepithelial electrical resistance (TEER) and increased CXCL-8 release. DEP pre-exposure aggravated HDM-induced loss of TEER, increased tracer flux across the barrier and reduced CLDN-3 expression in these 16HBE cells. HDM-induced cytokine (IL-6, CCL-22, IL-10 and CXCL-8) release was significantly increased after DEP pre-exposure. In the current study an in vitro model with long term PM exposure was presented, which might be helpful for further understanding the interplay between long term PM exposure and allergic responses.

Human Milk Oligosaccharide 2'-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin.

Human milk oligosaccharides (HMOs) and their most abundant component, 2'-Fucosyllactose (2'-FL), are known to be immunomodulatory. Previously, it was shown that HMOs and 2'-FL bind to the C-type lectin receptor DC-SIGN. Here we show, using a ligand-receptor competition assay, that a whole mixture of HMOs from pooled human milk (HMOS) and 2'-FL inhibit the binding of the carbohydrate-binding receptor DC-SIGN to its prototypical ligands, fucose and the oligosaccharide Lewis-B, (Leb) in a dose-dependent way. Interestingly, such inhibition by HMOS and 2'-FL was not detected for another C-type lectin, langerin, which is evolutionarily similar to DC-SIGN. The cell-ligand competition assay using DC-SIGN expressing cells confirmed that 2'-FL inhibits the binding of DC-SIGN to Leb. Molecular dynamic (MD) simulations show that 2'-FL exists in a preorganized bioactive conformation before binding to DC-SIGN and this conformation is retained after binding to DC-SIGN. Leb has more flexible conformations and utilizes two binding modes, which operate one at a time via its two fucoses to bind to DC-SIGN. Our hypothesis is that 2'-FL may have a reduced entropic penalty due to its preorganized state, compared to Leb, and it has a lower binding enthalpy, suggesting a better binding to DC-SIGN. Thus, due to the better binding to DC-SIGN, 2'-FL may replace Leb from its binding pocket in DC-SIGN. The MD simulations also showed that 2'-FL does not bind to langerin. Our studies confirm 2'-FL as a specific ligand for DC-SIGN and suggest that 2'-FL can replace other DC-SIGN ligands from its binding pocket during the ligand-receptor interactions in possible immunomodulatory processes.

Lipoproteins attenuate TLR2 and TLR4 activation by bacteria and bacterial ligands with differences in affinity and kinetics.

BACKGROUND: The small intestine is a specialized compartment were close interactions take place between host, microbes, food antigens and dietary fatty acids. Dietary fats get absorbed by epithelial cells and processed into a range of lipoprotein particles after which they are basolaterally secreted and collected in the lymphatics. In contrast to the colon, the small intestine is covered only by a thin mucus coat that allows for intimate interactions between host-cells and microbes. Lipoproteins have long been recognized as protective factors in infectious diseases via the neutralization of bacterial toxins like lipopolysaccharides. Much less attention has been given to the potential role of lipoproteins as factors contributing to the maintenance of small intestinal immune homeostasis via modulating bacteria-induced immune responses. RESULTS: Lipoproteins VLDL, LDL and HDL were found to neutralize TLR responses towards specific TLR-ligands or a selection of gram-negative and gram-positive bacteria. Attenuation of TLR2 activity was acute and only slightly improved by longer pre-incubation times of ligands and lipoproteins with no differences between bacterial-lipopeptides or bacteria. In contrast, attenuation of TLR4 responses was only observed after extensive preincubation of lipoproteins and LPS. Preincubation of bacteria and lipoproteins led only to a modest attenuation of TLR4 activity. Moreover, compared to TLR2, TLR4 activity could only be attenuated by lipoproteins over a small ligand dose range. CONCLUSIONS: These results demonstrate the ability of lipoproteins VLDL, LDL and HDL to inhibit TLR responses towards bacterial-ligands and bacteria. Presence of lipoproteins was found to modulate the MAMP-induced cytokine release by primary human monocytes measured as changes in the release of IL-6, TNFα, GM-CSF and IFNγ. Using TLR2 and TLR4-reporter cells, lipoproteins were found to inhibit TLR responses with differences in affinity and kinetics. These data establish a role for lipoproteins as immunoregulatory molecules, attenuating TLR-responses and thereby positively contributing to mucosal homeostasis.

Dual role of Toll-like receptors in asthma and chronic obstructive pulmonary disease.

During the last decade, significant research has been focused on Toll-like receptors (TLRs) in the pathogenesis of airway diseases. TLRs are pattern recognition receptors that play pivotal roles in the detection of and response to pathogens. Because of the involvement of TLRs in innate and adaptive immunity, these receptors are currently being exploited as possible targets for drug development. Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which innate and adaptive immunity play an important role. To date, asthma is the most common chronic disease in children aged 5 years and older. COPD is prevalent amongst the elderly and is currently the fifth-leading cause of death worldwide with still-growing prevalence. Both of these inflammatory diseases result in shortness of breath, which is treated, often ineffectively, with bronchodilators and glucocorticosteroids. Symptomatic treatment approaches are similar for both diseases; however, the underlying immunological mechanisms differ greatly. There is a clear need for improved treatment specific for asthma and for COPD. This review provides an update on the role of TLRs in asthma and in COPD and discusses the merits and difficulties of targeting these proteins as novel treatment strategies for airway diseases. TLR agonist, TLR adjuvant, and TLR antagonist therapies could all be argued to be effective in airway disease management. Because of a possible dual role of TLRs in airway diseases with shared symptoms and risk factors but different immunological mechanisms, caution should be taken while designing pulmonary TLR-based therapies.

Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma.

BACKGROUND: Asthma is estimated to affect as many as 300 million people worldwide and its incidence and prevalence are rapidly increasing throughout the world, especially in children and within developing countries. Recently, there has been a growing interest in the use of potentially beneficial bacteria for allergic diseases. This study is aimed at exploring the therapeutic effects of long-term treatment with two different beneficial bacterial strains (Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1) and a glucocorticoid (budesonide), as a reference treatment, on inflammatory response in a murine model for chronic allergic asthma. METHODS: To mimic the chronic disease in asthmatic patients, we used the murine ovalbumin-induced asthma model combined with prolonged allergen exposure. Airway function; pulmonary airway inflammation; airway remodelling, mRNA expression of pattern recognition receptors, Th-specific cytokines and transcription factors in lung tissue; mast cell degranulation; in vitro T cell activation; and expression of Foxp3 in blood Th cells were examined. RESULTS: Lactobacillus rhamnosus reduced lung resistance to a similar extent as budesonide treatment in chronically asthmatic mice. Pulmonary airway inflammation, mast cell degranulation, T cell activation and airway remodelling were suppressed by all treatments. Beneficial bacteria and budesonide differentially modulated the expression of toll-like receptors (TLRs), nod-like receptors (NLRs), cytokines and T cell transcription factors. Bifidobacterium breve induced regulatory T cell responses in the airways by increasing Il10 and Foxp3 transcription in lung tissue as well as systemic by augmenting the mean fluorescence intensity of Foxp3 in blood CD4+ T cells. CONCLUSION: These findings show that Bifidobacterium breve M-16 V and Lactobacillus rhamnosus NutRes1 have strong anti-inflammatory properties that are comparable to budesonide and therefore may be beneficial in the treatment of chronic asthma.

A synbiotic mixture of Bifidobacterium breve M16-V, oligosaccharides and pectin, enhances Short Chain Fatty Acid production and improves lung health in a preclinical model for pulmonary neutrophilia.

Introduction: Pulmonary neutrophilia is a hallmark of numerous airway diseases including Chronic Obstructive Pulmonary Disease (COPD), Neutrophilic asthma, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS) and COVID-19. The aim of the current study was to investigate the effect of dietary interventions on lung health in context of pulmonary neutrophilia. Methods: Male BALB/cByJ mice received 7 intra-nasal doses of either a vehicle or lipopolysaccharides (LPS). To study the effect of nutritional interventions they received 16 intra-gastric doses of either a vehicle (PBS) or the following supplements (1) probiotic Bifidobacterium breve (B. breve) M16-V; (2) a prebiotic fiber mixture of short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides, and low-viscosity pectin in a 9:1:2 ratio (scGOS/lcFOS/lvPectin); and (3) A synbiotic combination B. breve M16-V and scGOS/lcFOS/lvPectin. Parameters for lung health included lung function, lung morphology and lung inflammation. Parameters for systemic immunomodulation included levels of fecal short chain fatty acids and regulatory T cells. Results: The synbiotic supplement protected against the LPS induced decline in lung function (35% improved lung resistance at baseline p = 0.0002 and 25% at peak challenge, p = 0.0002), provided a significant relief from pulmonary neutrophilia (40.7% less neutrophils, p < 0.01) and improved the pulmonary neutrophil-to-lymphocyte ratio (NLR) by 55.3% (p = 0.0033). Supplements did not impact lung morphology in this specific experiment. LPS applied to the upper airways induced less fecal SCFAs production compared to mice that received PBS. The production of acetic acid between day -5 and day 16 was increased in all unchallenged mice (PBS-PBS p = 0.0003; PBS-Pro p < 0.0001; PBS-Pre, p = 0.0045; PBS-Syn, p = 0.0005) which upon LPS challenge was only observed in mice that received the synbiotic mixture of B. breve M16-V and GOS:FOS:lvPectin (p = 0.0003). A moderate correlation was found for butyric acid and lung function parameters and a weak correlation was found between acetic acid, butyric acid and propionic acid concentrations and NLR. Conclusion: This study suggests bidirectional gut lung cross-talk in a mouse model for pulmonary neutrophilia. Neutrophilic lung inflammation coexisted with attenuated levels of fecal SCFA. The beneficial effects of the synbiotic mixture of B. breve M16-V and GOS:FOS:lvPectin on lung health associated with enhanced levels of SCFAs.

Dietary Intake of Yeast-Derived ß-Glucan and Rice-Derived Arabinoxylan Induces Dose-Dependent Innate Immune Priming in Mice.

Beta-glucans and arabinoxylans are known for their immunostimulatory properties. However, in vivo these have been documented almost exclusively following parenteral administration, underemphasizing oral intake. C57BL/6 mice are fed either a control diet or a diet supplemented with yeast-derived whole ß-glucan particle (yWGP) or with rice-derived arabinoxylan (rice bran-1) at a concentration of 1%, 2.5%, or 5% weight/weight (w/w) for 2 weeks. Thereafter, cells from blood, bone marrow, and spleen are collected for ex vivo stimulation with various microbial stimuli. Dietary intake of yWGP for 2 weeks at concentrations of 1% and 2.5% w/w increases ex vivo cytokine production in mouse blood and bone marrow, whereas 5% w/w yWGP shows no effect. In the spleen, cytokine production remains unaffected by yWGP. At a concentration of 1% w/w, rice bran-1 increases ex vivo cytokine production by whole blood, but 2.5% and 5% w/w cause inhibitory effects in bone marrow and spleen. This study demonstrates that dietary yWGP and rice bran-1 induce immune priming in mouse blood and bone marrow, with the strongest effects observed at 1% w/w. Future human trials should substantiate the efficacy of dietary ß-glucans and arabinoxylans to bolster host immunity, focusing on dose optimization.

Rice-derived arabinoxylan fibers are particle size-dependent inducers of trained immunity in a human macrophage-intestinal epithelial cell co-culture model.

Arabinoxylans have been identified for a wide range of purported health-promoting applications, primarily attributed to its immunomodulatory effects. Previously, we have reported the ability of arabinoxylans to induce non-specific memory in innate immune cells, commonly referred to as "trained innate immunity". In the present study, we investigated the effect of particle size on innate immune training and resilience in primary human macrophages as well as in a more physiologically relevant macrophage-intestinal epithelial cell co-culture model. We demonstrated that smaller (>45 & < 90 µm) compared to larger (>90 µm) particle size fractions of rice bran-derived arabinoxylan preparations have a higher enhancing effect on training and resilience in both models. Smaller particle size fractions elevated TNF-α production in primary macrophages and enhanced Dectin-1 receptor activation in reporter cell lines compared to larger particles. Responses were arabinoxylan source specific as only the rice-derived arabinoxylans showed these immune-supportive effects. This particle size-dependent induction of trained immunity was confirmed in the established co-culture model. These findings demonstrate the influence of particle size on the immunomodulatory potential of arabinoxylans, provide further insight into the structure-activity relationship, and offer new opportunities to optimize the immune-enhancing effects of these dietary fibers.

Gut microbiome studies in CKD: opportunities, pitfalls and therapeutic potential.

Interest in gut microbiome dysbiosis and its potential association with the development and progression of chronic kidney disease (CKD) has increased substantially in the past 6 years. In parallel, the microbiome field has matured considerably as the importance of host-related and environmental factors is increasingly recognized. Past research output in the context of CKD insufficiently considered the myriad confounding factors that are characteristic of the disease. Gut microbiota-derived metabolites remain an interesting therapeutic target to decrease uraemic (cardio)toxicity. However, future studies on the effect of dietary and biotic interventions will require harmonization of relevant readouts to enable an in-depth understanding of the underlying beneficial mechanisms. High-quality standards throughout the entire microbiome analysis workflow are also of utmost importance to obtain reliable and reproducible results. Importantly, investigating the relative composition and abundance of gut bacteria, and their potential association with plasma uraemic toxins levels is not sufficient. As in other fields, the time has come to move towards in-depth quantitative and functional exploration of the patient's gut microbiome by relying on confounder-controlled quantitative microbial profiling, shotgun metagenomics and in vitro simulations of microorganism-microorganism and host-microorganism interactions. This step is crucial to enable the rational selection and monitoring of dietary and biotic intervention strategies that can be deployed as a personalized intervention in CKD.

The Modulatory Effects of Fatty Acids on Cancer Progression.

Cancer is the second leading cause of death worldwide and the global cancer burden rises rapidly. The risk factors for cancer development can often be attributed to lifestyle factors, of which an unhealthy diet is a major contributor. Dietary fat is an important macronutrient and therefore a crucial part of a well-balanced and healthy diet, but it is still unclear which specific fatty acids contribute to a healthy and well-balanced diet in the context of cancer risk and prognosis. In this review, we describe epidemiological evidence on the associations between the intake of different classes of fatty acids and the risk of developing cancer, and we provide preclinical evidence on how specific fatty acids can act on tumor cells, thereby modulating tumor progression and metastasis. Moreover, the pro- and anti-inflammatory effects of each of the different groups of fatty acids will be discussed specifically in the context of inflammation-induced cancer progression and we will highlight challenges as well as opportunities for successful application of fatty acid tailored nutritional interventions in the clinic.

Whey-based diet containing medium chain triglycerides modulates the gut microbiota and protects the intestinal mucosa from chemotherapy while maintaining therapy efficacy.

Cytotoxicity (i.e. cell death) is the core mechanism by which chemotherapy induces its anti-cancer effects. Unfortunately, this same mechanism underpins the collateral damage it causes to healthy tissues. The gastrointestinal tract is highly susceptible to chemotherapy's cytotoxicity, resulting in ulcerative lesions (termed gastrointestinal mucositis, GI-M) that impair the functional capacity of the gut leading to diarrhea, anorexia, malnutrition and weight loss, which negatively impact physical/psychological wellbeing and treatment adherence. Preventing these side effects has proven challenging given the overlapping mechanisms that dictate chemotherapy efficacy and toxicity. Here, we report on a novel dietary intervention that, due to its localized gastrointestinal effects, is able to protect the intestinal mucosal from unwanted toxicity without impairing the anti-tumor effects of chemotherapy. The test diet (containing extensively hydrolyzed whey protein and medium chain triglycerides (MCTs)), was investigated in both tumor-naïve and tumor-bearing models to evaluate its effect on GI-M and chemo-efficacy, respectively. In both models, methotrexate was used as the representative chemotherapeutic agent and the diet was provided ad libitum for 14 days prior to treatment. GI-M was measured using the validated biomarker plasma citrulline, and chemo-efficacy defined by tumor burden (cm3/g body weight). The test diet significantly attenuated GI-M (P = 0.03), with associated reductions in diarrhea (P < 0.0001), weight loss (P < 0.05), daily activity (P < 0.02) and maintenance of body composition (P < 0.02). Moreover, the test diet showed significant impact on gut microbiota by increasing diversity and resilience, whilst also altering microbial composition and function (indicated by cecal short and brained chain fatty acids). The test diet did not impair the efficacy of methotrexate against mammary adenocarcinoma (tumor) cells. In line with the first model, the test diet minimized intestinal injury (P = 0.001) and diarrhea (P < 0.0001). These data support translational initiatives to determine the clinical feasibility, utility and efficacy of this diet to improve chemotherapy treatment outcomes.

Modulation of Toll-like receptor ligands and Candida albicans-induced cytokine responses by specific probiotics.

Probiotics have been proposed as modulators of gut inflammation, especially in inflammatory bowel disease (IBD). In order to be able to use them in these clinical conditions, their capacity to modulate immune responses towards other stimuli or microorganisms has to be thoroughly understood. In the present study, three different potentially probiotic strains, Bifidobacterium breve (NumRes 204), Lactobacillus rhamnosus (NumRes1) and Lactobacillus casei (DN-114 001), have been studied for their potential to modulate responses to stimulation with pure pattern-recognition receptor (PRR) ligands or to the gut commensal fungus Candida albicans. Cytokine production induced by PRR ligands or C. albicans was assessed in conditions of simultaneous stimulation or preincubation of primary immune cells with Bifidobacterium or Lactobacillus spp. Results indicate that simultaneous stimulation leads to potentiation of IL-1ß and IL-6 production, while the TNFα and IFN-γ production was inhibited. In settings of pre-incubation with these potentially probiotic strains, lower production of TNFα was observed in the presence of B. breve. Moreover, C. albicans-induced IL-17 production was decreased after pre-incubation with both Bifidobacterium or Lactobacillus probiotic strains. Whereas C. albicans induced cytokines are dampened by the tested probiotic strains, TNFα and IL-6 production by pure pattern-recognition receptor ligands are potentiated. Interestingly, an important role of Toll-like receptor 9 signalling that involves JNK kinase in the modulatory effects of these probiotic strains has been identified. In conclusion, specific probiotic strains exhibit cross-tolerance effects towards other inflammatory stimuli, especially C. albicans, which might have beneficial effects on gut inflammation.

Microbial-Derived Tryptophan Catabolites, Kidney Disease and Gut Inflammation.

Uremic metabolites, molecules either produced by the host or from the microbiota population existing in the gastrointestinal tract that gets excreted by the kidneys into urine, have significant effects on both health and disease. Tryptophan-derived catabolites are an important group of bacteria-produced metabolites with an extensive contribution to intestinal health and, eventually, chronic kidney disease (CKD) progression. The end-metabolite, indoxyl sulfate, is a key contributor to the exacerbation of CKD via the induction of an inflammatory state and oxidative stress affecting various organ systems. Contrastingly, other tryptophan catabolites positively contribute to maintaining intestinal homeostasis and preventing intestinal inflammation-activities signaled through nuclear receptors in particular-the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR). This review discusses the origins of these catabolites, their effect on organ systems, and how these can be manipulated therapeutically in the future as a strategy to treat CKD progression and gut inflammation management. Furthermore, the use of biotics (prebiotics, probiotics, synbiotics) as a means to increase the presence of beneficial short-chain fatty acids (SCFAs) to achieve intestinal homeostasis is discussed.

Dectin-1b activation by arabinoxylans induces trained immunity in human monocyte-derived macrophages.

Arabinoxylans of various structures and sources have shown to possess the ability to induce a range of immune responses in different cell types in vitro and in vivo. Although the underlying mechanisms remain to be fully established, several studies point towards the involvement of activation of pattern recognition receptors (PRRs). Activation of specific PRRs (i.e., Dectin-1 and CR3) has also been shown to play a key role in the induction of a non-specific memory response in innate immune cells, termed 'trained innate immunity'. In the current study, we assessed whether arabinoxylans are also able to induce trained innate immunity. To this end, a range of arabinoxylan preparations from different sources were tested for their physicochemical properties and their capacity to induce innate immune training and resilience. In human macrophages, rice and wheat-derived arabinoxylan preparations induced training and/or resilience effects, the extent depending on fiber particle size and solubility. Using a Dectin-1 antagonist or a CR3 antibody, it was demonstrated that arabinoxylan-induced trained immunity in macrophages is mainly dependent on Dectin-1b. These findings build on previous observations showing the immunomodulatory potential of arabinoxylans as biological response modifiers and open up promising avenues for their use as health promoting ingredients.

Probiotics, prebiotics, and synbiotics to prevent or combat air pollution consequences: The gut-lung axis.

Air pollution exposure is a public health emergency, which attributes globally to an estimated seven million deaths on a yearly basis We are all exposed to air pollutants, varying from ambient air pollution hanging over cities to dust inside the home. It is a mixture of airborne particulate matter and gases that can be subdivided into three categories based on particle diameter. The smallest category called PM0.1 is the most abundant. A fraction of the particles included in this category might enter the blood stream spreading to other parts of the body. As air pollutants can enter the body via the lungs and gut, growing evidence links its exposure to gastrointestinal and respiratory impairments and diseases, like asthma, rhinitis, respiratory tract infections, Crohn's disease, ulcerative colitis, and abdominal pain. It has become evident that there exists a crosstalk between the respiratory and gastrointestinal tracts, commonly referred to as the gut-lung axis. Via microbial secretions, metabolites, immune mediators and lipid profiles, these two separate organ systems can influence each other. Well-known immunomodulators and gut health stimulators are probiotics, prebiotics, together called synbiotics. They might combat air pollution-induced systemic inflammation and oxidative stress by optimizing the microbiota composition and microbial metabolites, thereby stimulating anti-inflammatory pathways and strengthening mucosal and epithelial barriers. Although clinical studies investigating the role of probiotics, prebiotics, and synbiotics in an air pollution setting are lacking, these interventions show promising health promoting effects by affecting the gastrointestinal- and respiratory tract. This review summarizes the current data on how air pollution can affect the gut-lung axis and might impact gut and lung health. It will further elaborate on the potential role of probiotics, prebiotics and synbiotics on the gut-lung axis, and gut and lung health.

Fatty Acids as a Tool to Boost Cancer Immunotherapy Efficacy.

Although immunotherapy represents one of the most potent therapeutic anti-cancer approaches, only a limited number of patients shows clinical benefit. Recent evidence suggests that patients' nutritional status plays a major role in immunotherapy outcome. Fatty acids are essential in a balanced diet and well-known to influence the immune response. Moreover, short-chain fatty acids (SCFAs) show beneficial effects in metabolic disorders as well as in cancer and polyunsaturated fatty acids (PUFAs) contribute to body weight and fat free mass preservation in cancer patients. In line with these data, several studies imply a role for SCFAs and PUFAs in boosting the outcome of immunotherapy. In this review, we specifically focus on mechanistic data showing that SCFAs modulate the immunogenicity of tumor cells and we discuss the direct effects of SCFAs and PUFAs on the immune system in the context of cancer. We provide preclinical and clinical evidence indicating that SCFAs and PUFAs may have the potential to boost immunotherapy efficacy. Finally, we describe the challenges and address opportunities for successful application of nutritional interventions focusing on SCFAs and PUFAs to increase the therapeutic potential of immunotherapeutic approaches for cancer.

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.

Continuous Exposure to Non-Soluble ß-Glucans Induces Trained Immunity in M-CSF-Differentiated Macrophages.

Beta-glucans enable functional reprogramming of innate immune cells, a process defined as "trained immunity", which results in enhanced host responsiveness against primary (training) and/or secondary infections (resilience). Trained immunity holds great promise for promoting immune responses in groups that are at risk (e.g. elderly and patients). In this study, we modified an existing in vitro model for trained immunity by actively inducing monocyte-to-macrophage differentiation using M-CSF and applying continuous exposure. This model reflects mucosal exposure to ß-glucans and was used to study the training effects of a variety of soluble or non-soluble ß-glucans derived from different sources including oat, mushrooms and yeast. In addition, trained immunity effects were related to pattern recognition receptor usage, to which end, we analyzed ß-glucan-mediated Dectin-1 activation. We demonstrated that ß-glucans, with different sources and solubilities, induced training and/or resilience effects. Notably, trained immunity significantly correlated with Dectin-1 receptor activation, yet Dectin-1 receptor activation did not perform as a sole predictor for ß-glucan-mediated trained immunity. The model, as validated in this study, adds on to the existing in vitro model by specifically investigating macrophage responses and can be applied to select non-digestible dietary polysaccharides and other components for their potential to induce trained immunity.

Prenatal and Postnatal Cigarette Smoke Exposure Is Associated With Increased Risk of Exacerbated Allergic Airway Immune Responses: A Preclinical Mouse Model.

Increased exposure to household air pollution and ambient air pollution has become one of the world's major environmental health threats. In developing and developed countries, environmental cigarette smoke (CS) exposure is one of the main sources of household air pollution (HAP). Moreover, results from different epidemiological and experimental studies indicate that there is a strong association between HAP, specifically CS exposure, and the development of allergic diseases that often persists into later life. Here, we investigated the impact of prenatal and postnatal CS exposure on offspring susceptibility to the development of allergic airway responses by using a preclinical mouse model. Pregnant BALB/c mice were exposed to either CS or air during pregnancy and lactation and in order to induce allergic asthma the offspring were sensitized and challenged with house dust mite (HDM). Decreased lung function parameters, like dynamic compliance and pleural pressure, were observed in PBS-treated offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. Maternal CS exposure significantly increased the HDM-induced airway eosinophilia and neutrophilia in the offspring. Prenatal and postnatal CS exposure increased the frequency of Th2 cells in the lungs of HDM-treated offspring compared to offspring born to air-exposed mothers. Offspring born to CS-exposed mothers showed increased levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid compared to offspring from air-exposed mothers. Ex-vivo restimulation of lung cells isolated from HDM-treated offspring born to CS-exposed mothers also resulted in increased IL-4 production. Finally, serum immunoglobulins levels of HDM-specific IgE and HDM-specific IgG1 were significantly increased upon a HDM challenge in offspring born to CS-exposed mothers compared to offspring from air-exposed mothers. In summary, our results reveal a biological plausibility for the epidemiological studies indicating that prenatal and postnatal CS exposure increases the susceptibility of offspring to allergic immune responses.

The Effects of Maternal Smoking on Pregnancy and Offspring: Possible Role for EGF?

Cigarette smoke exposure during pregnancy and lactation is associated with adverse pregnancy outcomes. Here, we investigated the effects of maternal smoke exposure on pregnancy and offspring immunity and explored whether, epidermal growth factor (EGF), an important growth-promoting factor in human colostrum and milk, might be a possible missing link in maternal smoke exposure and changes in infants' immune responses. Pregnant BALB/c mice were exposed to either cigarette smoke or air during gestation and lactation, and effects on pulmonary inflammation in dams and immune responses in offspring were examined. Maternal smoke exposure increased airway hyperresponsiveness and accumulation of inflammatory cells in the lungs of pregnant dams compared to non-pregnant dams. The E-cadherin protein expression was reduced in mammary glands of cigarette smoke-exposed pregnant dams. EGF levels were higher in mammary glands and serum of smoke-exposed pregnant dams compared to air-exposed pregnant dams. Offspring from cigarette smoke-exposed dams exhibited elevated levels of IL-17A, MCP-1, IL-22, and IL-13 in anti-CD3 stimulated spleen cell culture supernatants. EGF levels were also increased in serum of offspring from smoke-exposed dams. A positive correlation was observed between serum EGF levels and neutrophil numbers in bronchoalveolar lavage fluid of the dams. Interestingly, IL-17A, MCP-1, IL-22, IL13, and IFN-γ levels in anti-CD3 stimulated spleen cell culture supernatants of male pups also showed a positive correlation with EGF serum levels. In summary, our results reveal that maternal smoke exposure predisposes dams to exacerbated airway inflammation and offspring to exacerbated immune responses and both phenomena are associated with elevated EGF concentrations.