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In this study, the effects of dietary myo-inositol on the skin mucosal immunity and growth of taimen (Hucho taimen) fry were determined. Triplicate groups of 500 fish (initial weight 5.58 ± 0.15 g) were fed different diets containing graded levels of myo-inositol (28.75, 127.83, 343.83, 565.81, and 738.15 mg kg -1 ) until satiation for 56 days. Thereafter, the nonspecific skin mucus immune parameters, antioxidative capacity, and growth performance were measured. The skin mucus protein and the activities of alkaline phosphatase were significantly higher than those in the control group (P < 0.05). However, there were no significant differences in lysozyme activity among the treatments (P > 0.05). The antimicrobial activity and minimum inhibitory concentration of the skin mucus were increased significantly by myo-inositol supplementation (P < 0.05). The superoxide dismutase, catalase, and glutathione peroxidase activities were significantly elevated in the treatment groups (P < 0.05), whereas the malondialdehyde contents were significantly decreased (P < 0.05). Low-level myo-inositol (28.75 mg kg -1 ) led to a significantly lower weight gain, feed efficiency, condition factor, and survival rate compared with the other treatments (P < 0.05). In conclusion, dietary myo-inositol deficiency (28.75 mg kg -1 ) adversely affects the skin mucus immune parameters, antioxidative capacity, and growth performance of Hucho taimen fry.

Background: In food toxicology, there is growing interest in studying the impacts of foodborne nanoparticles (NPs, originating from food additives, food supplements or food packaging) on the intestinal microbiome due to the important and complex physiological roles of these microbial communities in host health. Biocidal activities, as described over recent years for most inorganic and metal NPs, could favour chronic changes in the composition and/or metabolic activities of commensal bacteria (namely, intestinal dysbiosis) with consequences on immune functions. Reciprocally, direct interactions of NPs with the immune system (e.g., inflammatory responses, adjuvant or immunosuppressive properties) may in turn have effects on the gut microbiota. Many chronic diseases in humans are associated with alterations along the microbiota-immune system axis, such as inflammatory bowel diseases (IBD) (Crohn's disease and ulcerative colitis), metabolic disorders (e.g., obesity) or colorectal cancer (CRC). This raises the question of whether chronic dietary exposure to inorganic NPs may be viewed as a risk factor facilitating disease onset and/or progression. Deciphering the variety of effects along the microbiota-immune axis may aid the understanding of how daily exposure to inorganic NPs through various foodstuffs may potentially disturb the intricate dialogue between gut commensals and immunity, hence increasing the vulnerability of the host. In animal studies, dose levels and durations of oral treatment are key factors for mimicking exposure conditions to which humans are or may be exposed through the diet on a daily basis, and are needed for hazard identification and risk assessment of foodborne NPs. This review summarizes relevant studies to support the development of predictive toxicological models that account for the gut microbiota-immune axis., Conclusions: The literature indicates that, in addition to evoking immune dysfunctions in the gut, inorganic NPs exhibit a moderate to extensive impact on intestinal microbiota composition and activity, highlighting a recurrent signature that favours colonization of the intestine by pathobionts at the expense of beneficial bacterial strains, as observed in IBD, CRC and obesity. Considering the long-term exposure via food, the effects of NPs on the gut microbiome should be considered in human health risk assessment, especially when a nanomaterial exhibits antimicrobial properties.

The aim of the present study was to determine the effect of zearalenone (ZEN), administered per os to gilts at doses equivalent to 50%, 100%, and 150% of no-observed-adverse-effect level (NOAEL) values for 14, 28, and 42 days during weaning, on changes in the parameters of the oxidoreductive balance, cytokine secretion, and basal metabolism in ileal Payer's patches. Immunoenzymatic ELISA tests and biochemical methods were used to measure the concentrations of interleukin 1α, interleukin 1β, interleukin 12/23p40, interleukin 2, interferon γ, interleukin 4, interleukin 6, interleukin 8, tumor necrosis factor α, interleukin 10, transforming growth factor β, malondialdehyde, sulfhydryl groups, fructose, glucose, and proline, as well as the activity of peroxidase, superoxide dismutase and catalase. The study demonstrated that ZEN doses corresponding to 50%, 100%, and 150% of NOAEL values, i.e., 5 µg, 10 µg, and 15 µg ZEN/kg BW, respectively, have proinflammatory properties, exacerbate oxidative stress responses, and disrupt basal metabolism in ileal Payer's patches in gilts.

The diverse bacterial communities that colonize the gastrointestinal tract play an essential role in maintaining immune homeostasis through the production of critical metabolites such as short-chain fatty acids (SCFAs) and this can be disrupted by antibiotic use. However, few studies have addressed the effects of specific antibiotics longitudinally on the microbiome and immunity. We evaluated the effects of four specific antibiotics: enrofloxacin, cephalexin, paromomycin, and clindamycin, in healthy female rhesus macaques. All antibiotics disrupted the microbiome, including reduced abundances of fermentative bacteria and increased abundances of potentially pathogenic bacteria, including Enterobacteriaceae in the stool, and decreased Helicobacteraceae in the colon. This was associated with decreased SCFAs, indicating altered bacterial metabolism. Importantly, antibiotic use also substantially altered local immune responses, including increased neutrophils and Th17 cells in the colon. Furthermore, we observed increased soluble CD14 in plasma, indicating microbial translocation. These data provide a longitudinal evaluation of antibiotic-induced changes to the composition and function of colonic bacterial communities associated with specific alterations in mucosal and systemic immunity.

The present study aimed to investigate the protective effect of cultured Cordyceps sinensis polysaccharides (CSP) on cyclophosphamide (Cy)-induced intestinal mucosal immunosuppression and microbial dysbiosis in mice. Results showed that CSP stimulated cytokines secretion (IL-12, IFN-γ, IL-4, IL-13, IL-6, IL-17, IL-10, TGF-β3, TNF-α, IL-2, IL-21) and transcription factors production (T-bet, GATA-3, RORγt, Foxp3). TLRs (TLR-2, TLR-4, TLR-6) and NF-κB pathway key proteins (p-IκB-α, NF-κB p65) were also upregulated after CSP administration. Moreover, CSP recovered SCFAs levels which decreased by Cy treatment. Furthermore, 16S rRNA sequencing of fecal samples was performed. α-diversity and β-diversity analysis revealed CSP improved microbial community diversity and modulated the overall structure of gut microbiota. Taxonomic composition analysis found that CSP increased the abundance of probiotics (Lactobacillus, Bifidobacterium, Bacteroides) and decreased pathogenic bacteria (Clostridium, Flexispira). These findings suggested the potential of CSP as a prebiotics to reduce side effects of Cy on intestinal mucosal immunity and gut microbiota., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The protection of Lactobacillus plantarum JM113 against deoxynivalenol (DON)-induced apoptosis and intestinal inflammation on the jejunum of broiler chickens and the potential roles of gut microbiota were determined. A total of 144 one-day-old male broilers (Arbor Acres) were randomly divided into 3 treatment groups consisting of 6 replicates with 8 birds per replicate, including the CON (basal diet), the DON (basal diet + 10 mg/kg DON), and the DL (basal diet + 10 mg/kg DON + 1 × 10 9  CFU/kg L. plantarum JM113). The DON-diet decreased (P < 0.05) the mRNA expression of mucosal defense proteins and mechanistic target of rapamycin pathway genes. Meanwhile, DON challenge significantly increased Bcl-2-associated X gene/B-cell lymphoma 2 gene (Bcl-2) in the jejunum (P < 0.05) and demonstrated proapoptosis status. In contrast, the DL group showed normal immunity-related gene expression of jejunal mucosa and manifested a superior antiapoptosis status. Adding L. plantarum JM113 significantly raised (P < 0.05) propionic acid, n-butyric acid, and total short-chain fatty acids concentrations in cecal contents of birds fed with DON diet. In addition, DON exposure altered bacterial community structure and disturbed the abundance of several bacterial phyla, families, and genera, leading to dysbiosis. Supplementation with JM113 shifted the gut microbiota composition to that of the CON group. Finally, Spearman correlation analysis suggested that most positive correlations with the mRNA expression of immunity-related and apoptosis-regulatory gene were observed within the phylum Bacteroidetes, and most negative correlations with the indicators were observed within the phylum Firmicutes. The mRNA expression of Bcl-2, TLR2, mTOR, Raptor, and RPS6KB1 (P < 0.05), which are regarded as important cell proliferation and antiapoptosis parameters, were significantly negatively associated with the relative abundances of norank&#95;f&#95;&#95;Erysipelotrichaceae, Subdoligranulum, and Anaeroplasma, whereas they had a strong positive correlation with Ruminococcaceae&#95;UCG-004, Alistipes, and Ruminococcaceae&#95;NK4A214&#95;group. These results implied that L. plantarum JM113 supplementation could ameliorate DON-induced apoptosis and intestinal inflammation via manipulating the bacterial community composition and could be used as a potential candidate to attenuate intestinal impairments., (Copyright © 2019. Published by Elsevier Inc.)

The present study was designed to investigate the dietary effects of ginger extract (Zingiber officinale) on common carp (Cyprinus carpio). Three hundred and sixty fish weighing 10.9 ± 0.17 g were randomly divided into four experimental treatments in triplicates. Four experimental diets were designed containing different inclusion levels of ginger extract as 0% (control), 0.1%, 0.2%, and 0.4% named T1, T2, T3, and T4, respectively, and fish were fed 3% of body weight daily for 60 days. Feed conversion ratio, weight gain, and specific growth rate parameters were measured higher in the groups fed with ginger extract compared to the control, especially in T3 (P < 0.05). Also, fish treated with ginger extract showed lower carcass moisture and lipid, but higher protein contents compared to the control. The results showed significant increase in the number of erythrocytes and leucocytes, as well as the level of hematocrit and hemoglobin in fish fed with supplemented diets. In addition, significant enhancement was observed in cases of serum parameters, including total protein, albumin, globulin, lysozyme, superoxide dismutase, catalase, and total immunoglobulins in T3 and T4 compared to the control. The lowest serum cortisol level was noticed in T3. Furthermore, the T3 group showed the highest activities of skin mucus lysozyme, alkaline phosphatase, and protease (P < 0.05). In conclusion, the present results demonstrated that Zingiber officinale extract at a 0.2% level can effectively improve the growth and health status of Common Carp (Cyprinus carpio)., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The sinonasal mucosa has an essential role in defense mechanisms of the upper respiratory tract. The innate immune system presents the primary defense against noxious microorganisms followed by induction of the adaptive immune mechanisms as a consequence of the presence of pathogens. This well-known activation of adaptive immune system in response to presence of the antigen on mucosal surfaces is now broadly applicated in vaccinology research. Prevention of infectious diseases belongs to substantial challenges in maintaining the population health. Non-invasive, easily applicable mucosal vaccination purposes various research opportunities that could be usable in daily practice. However, the existence of multiple limitations such as rapid clearance of vaccine from nasal mucosa by means of mucociliary transport represents a great challenge in development of safe and efficient vaccines. Here we give an updated view on nasal functions with focus on nasal mucosal immunity and its potential application in vaccination in nearly future.

This study aimed to explore the effect of longan pulp polysaccharide (LP) on the systemic immunity and intestinal mucosal immunity of immunosuppressive mice. The synthesis process and secretion of intestinal secretory IgA (SIgA) were investigated. Results showed that LP increased the thymus index, spleen index, and serum IgA level in cyclophosphamide (CTX)-treated mice. SIgA secretion in the intestinal lumen was increased by LP as well. The underlying mechanism comes down to the facts as follow: LP increased intestinal cytokines expression and TGFβRII that is associated with pathways of IgA class switch recombination (CSR). By improving protein expression of mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) and integrin α4β7, LP was beneficial to gut homing of IgA+ plasma cells. LP increased IgA, polymeric immunoglobulin receptor (pIgR), and secretory component (SC) to fortify the SIgA secretion. This study suggested that moderate consumption of LP is helpful for improving systemic immunity and intestinal mucosal immunity via promotion of intestinal SIgA to strengthen the mucosal barrier.

This study evaluated the modulation of gut microbiota, immune responses, and gut morphometry in C57BL/6 mice, upon oral administration of S. maxima -derived modified pectin (SmP, 7.5 mg/mL) and pectin nanoparticles (SmPNPs; 7.5 mg/mL). Metagenomics analysis was conducted using fecal samples, and mice duodenum and jejunum were used for analyzing the immune response and gut morphometry, respectively. The results of metagenomics analysis revealed that the abundance of Bacteroidetes in the gut increased in response to both modified SmP and SmPNPs (75%) as compared with that in the control group (66%), while that of Firmicutes decreased in (20%) as compared with that in the control group (30%). The mRNA levels of mucin, antimicrobial peptide, and antiviral and gut permeability-related genes in the duodenum were significantly ( p < 0.05) upregulated (> 2-fold) upon modified SmP and SmPNPs feeding. Protein level of intestinal alkaline phosphatase was increased (1.9-fold) in the duodenum of modified SmPNPs feeding, evidenced by significantly increased goblet cell density (0.5 ± 0.03 cells/1000 µm 2 ) and villi height (352 ± 10 µm). Our results suggest that both modified SmP and SmPNPs have the potential to modulate gut microbial community, enhance the expression of immune related genes, and improve gut morphology., Competing Interests: The authors declare that they have no conflict of interest.

Nowadays, melatonin, previously considered only as a pharmaceutical product for rhythm regulation and sleep aiding, has shown its potential as a co-adjuvant treatment in intestinal diseases, however, its mechanism is still not very clear. A firm connection between melatonin at a physiologically relevant concentration and the gut microbiota and inflammation has recently established. Herein, we summarize their crosstalk and focus on four novelties. First, how melatonin is synthesized and degraded in the gut and exerts potentially diverse phenotypic effects through its diverse metabolites. Second, how melatonin mediates the activation and proliferation of intestinal mucosal immune cells with paracrine and autocrine properties. By modulating T/B cells, mast cells, macrophages and dendritic cells, melatonin immunomodulatory involved in regulating T-cell differentiation, intervening T/B cell interaction and attenuating the production of pro-inflammatory factors, achieving its antioxidant action via specific receptors. Third, how melatonin exerts antimicrobial action and modulates microbial components, such as lipopolysaccharide, amyloid-β peptides via nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or signal transducers and activators of transcription (STAT1) pathway to modulate intestinal immune function in immune-pineal axis. The last, how melatonin mediates the effect of intestinal bacterial activity signals on the body rhythm system through the NF-κB pathway and influences the mucosal epithelium oscillation via clock gene expression. These processes are achieved at mitochondrial and nuclear levels to control the host immune cell development. Considering unclear mechanisms and undiscovered actions of melatonin in gut-microbiome-immune axis, it's time to reveal them and provide new insight for the outlook of melatonin as a potential therapeutic target in the treatment and management of intestinal diseases., (© 2019 Wiley Periodicals, Inc.)

A lack of sunlight exposure, residence in the northern latitudes, and dietary vitamin D insufficiency are coprevalent with metabolic syndrome (MetS), Type 2 diabetes (T2D), and nonalcoholic fatty liver diseases (NAFLD), implying a potential causality and underlying mechanism. Whether vitamin D supplementation or treatment can improve these disorders is controversial, in part, because of the absence of large-scale trials. Experimental investigations, on the other hand, have uncovered novel biological functions of vitamin D in development, tumor suppression, and immune regulation, far beyond its original role as a vitamin that maintained calcium homeostasis. While the large intestine harbors massive numbers of microbes, the small intestine has a minimal quantity of bacteria, indicating the existence of a gating system located in the distal region of the small intestine that may restrain bacterial translocation to the small intestine. Vitamin D receptor (VDR) was found to be highly expressed at the distal region of small intestine, where the vitamin D signaling promotes innate immunity, including the expression of α-defensins by Paneth cells, and maintains the intestinal tight junctions. Thus, a new hypothesis is emerging, indicating that vitamin D deficiency may impair the intestinal innate immunity, including downregulation of Paneth cell defensins, leading to bacterial translocation, endotoxemia, systemic inflammation, insulin resistance, and hepatic steatosis. Here, we review the studies for vitamin D for innate immunity and metabolic homeostasis, and we outline the clinical trials of vitamin D for mitigating MetS, T2D, and NAFLD.

The study aimed to isolate host-associated probiotic (HAP) lactic acid bacteria from intestine of adult Caspian roach and compare the efficacy of HAP with a commercially available probiotic strain (Pediococcus acidilactici) on the growth and feed utilisation, digestive enzymes and systemic and mucosal immune system of roach fingerling. The HAP strain isolated from roach intestine was Enterococcus faecium strain CGMCC1.2136. The experiment was a simple completely randomized design and lasted for eight weeks. Two hundred and seventy fish with an average weight of 12 g randomly distributed into nine tanks. The trial consisted of three treatments with three respective replications. During the experimental period, fish received basal diet without any bacterial supplementation (as the control group), basal diet enriched with 10 8  CFU g -1 HAP or 10 7  CFU g -1 CP. At the end of the experiment, serum immune parameters of those fish fed HAP including alkaline phosphatase activity, total protein content, total immunoglobulin level, lysozyme activity and complement activity (ACH50) were significantly higher that other experimental groups (P < 0.05). Similarly, dietary supplementation of HAP resulted in better mucosal immune parameters in comparison to control group and commercial probiotic administration (P < 0.05). Intestinal heterotrophic bacteria and autochthonous LAB counts of those fish fed HAP were significantly higher than other experimental groups at the end of the experiment as well as 15 days seizing probiotic administrations (P < 0.05). Fish fed with HAP containing diet presented significantly higher amylase, lipase and protease activity in comparison to the CP fed fish and the control group (P < 0.05). Growth indices of those fish fed HAP were significantly higher than other treatments (P < 0.05). The highest carcass protein and ash content along with the lowest body moisture content belonged to those fish received HAP (P < 0.05). In conclusion, the use host-HAP resulted in better immune competence and growth performance and it seems aquaculture sector should probably focus on the development of probiotics isolated from the cultured species instead of using terrestrial probiotics with greatly different requirements and environmental conditions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Both konjac glucomannan (KGM) and inulin oligosaccharide have been shown to improve bowel function, but their effects on the mucosal barrier function and immunity are not fully understood. The aim of the present study was to determine the effects of a low-level supplementation of dietary fibres on the colonic mucosal barrier function, antioxidant enzyme defence and immunity. C57BL/6J mice (6 weeks of age, eight per group) were randomly assigned to consume one of the following diets: control or control diet supplemented with 2 % (w/w) of KGM, inulin oligosaccharide (degree polymerisation = 8) or KGM+inulin (1 %, w/w each (K+I)). Fresh faeces were collected on days 19-21. Mice were killed on day 22 after fasting. Segments of colon tissues were processed for histological procedure and stained for acidic mucins and tight junction protein marker zona occludin-1 (ZO-1). The remaining tissues were processed to determine the gene expression of mucin 2, tight junction proteins, antioxidant enzymes and cytokines. The plasma cytokines were measured. Results indicated that KGM, inulin and K+I significantly increased the mucosal layer thickness, mucin density (granule number/crypt) and gene expression of Muc2 as compared with the control. All fibre treatments increased the gene expressions of ZO-1, occludin, glutathione peroxidase, glutathione S-transferase π, catalase and IL-10. In addition, all fibre treatments increased faecal butyrate and probiotics, and plasma IL-10 concentrations. In conclusion, supplementation of low-level, 2 % (w/w), of K+I was sufficient to enhance the mucosal barrier function and anti-inflammatory status.

Infection with Brucella abortus causes contagious zoonosis, brucellosis, and leads to abortion in animals and chronic illness in humans. Chitosan nanoparticles (CNs), biocompatible and nontoxic polymers, acts as a mucosal adjuvant. In our previous study, B. abortus malate dehydrogenase (Mdh) was loaded in CNs, and it induced high production of pro-inflammatory cytokines in THP-1 cells and systemic IgA in BALB/C mice. In this study, the time-series gene expression analysis of nasal-associated lymphoid tissue (NALT) was performed to identify the mechanism by which Mdh affect the target site of nasal immunization. We showed that intranasal immunization of CNs-Mdh reduced cell viability of epithelial cells and muscle cells at first 1 h, then induced cellular movement of immune cells such as granulocytes, neutrophils and lymphocytes at 6h, and activated IL-6 signaling pathway at 12h within NALT. These activation of immune cells also promoted signaling pathway for high-mobility group box 1 protein (HMGB1), followed by the maturation of DCs required for mucosal immunity. The CNs also triggered the response to other organism and inflammatory response, showing it is immune-enhancing adjuvant. The ELISA showed that significant production of specific IgA was detected in the fecal excretions and genital secretions from the CNs-Mdh-immunized group after 2 weeks-post immunization. Collectively, these results suggest that B. abortus Mdh-loaded CNs triggers activation of HMGB1, IL-6 and DCs maturation signaling within NALT and induce production of systemic IgG and IgA., Competing Interests: The authors have declared that no competing interest exist.

Inflammation is a physiological process essential for maintaining homeostatic mechanisms in human, but however, exaggerated inflammatory responses are closely related to many chronic diseases. Cadmium (Cd) is a heavy metal with high toxicity when present in food, water and air has the potential of eliciting inflammatory reactions, with a major health risk to human. This review aimed to elucidate on the major routes of Cd exposure, the main organs affected by the exposure, the degree of toxicity as well as the roles of the toxic effects on the immune system which results to inflammatory responses. Immune modulation by Cd may cause serious adverse health effects in humans. Various studies have highlighted the ability of Cd as an environmental pollutant involved in the modulation of the innate, adaptive and mucosal immune responses in relations to the release of chemokine, gene expression, and susceptibility to microbial infections.

Vaccines are biological preparations that improve immunity to particular diseases and form an important innovation of 19th century research. It contains a protein that resembles a disease-causing microorganism and is often made from weak or killed forms of the microbe. Vaccines are agents that stimulate the body's immune system to recognize the antigen. Now, a new form of vaccine was introduced which will have the power to mask the risk side of conventional vaccines. This type of vaccine was produced from plants which are genetically modified. In the production of edible vaccines, the gene-encoding bacterial or viral disease-causing agent can be incorporated in plants without losing its immunogenic property. The main mechanism of action of edible vaccines is to activate the systemic and mucosal immunity responses against a foreign disease-causing organism. Edible vaccines can be produced by incorporating transgene in to the selected plant cell. At present edible vaccine are developed for veterinary and human use. But the main challenge faced by edible vaccine is its acceptance by the population so that it is necessary to make aware the society about its use and benefits. When compared to other traditional vaccines, edible vaccines are cost effective, efficient and safe. It promises a better prevention option from diseases.

The dietary effects of a native medicinal plant from Iran, common mallow (Malvae sylvestris), was evaluated on growth performance, innate immune parameters, mucosal immune parameters, and resistance of rainbow trout (Oncorhynchus mykiss) against Yersinia ruckeri. Therefore, 360 fish (initial weight 10.42 ± 0.09 g) were randomly distributed into 12 fiberglass tanks. Experimental diets supplemented with 0 (as control- C), 1% (M1), 3% (M2) and 5% (M3) levels of M. sylvestris flowers extract were fed to the fish based on 3% of body weight for 8 weeks. At the terminal sampling, growth performance, liver and digestive enzymes activities, blood and mucosal immune responses were determined. Results showed that M2 and M3 had greater final weight, weight gain, SGR, survival rate and lower FCR; higher levels of total protein, albumin, globulin, and lower cortisol levels in comparison to control; 5% extract also lowered cholesterol and glucose levels as well as Lactate Dehydrogenase (LDH) activity. We reported higher values of hematocrit, hemoglobin, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), White Blood Cell (WBC), Red Blood Cell (RBC) and lymphocytes for treated groups. Innate immune responses (Alternative complement activity (ACH50) in M2 and M3 group, total Immunoglobulin (Ig) and lysozyme in M3), mucosal immune parameters (ACH50, total Ig for M2 and M3 group and lysozyme in all treated groups) were enhanced. Activities of digestive enzymes (protease in all treated groups, amylase for 3 and 5%, while lipase only for 5%) and lower activity of liver ALT enzyme in individuals treated with highest dose was observed. Overall results indicated that the extract can positively affect growth performance and immune responses of rainbow trout., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The effective antigen (Ag) uptake by microfold cells (M-cells) is important for the induction of an efficient mucosal immune responses. Here, we show that 10-hydroxydecanoic acid (10-HDAA) from royal jelly (RJ) potentially supports M-cell differentiation and induces effective antigen-specific mucosal immune responses in cynomolgus macaques. 10-HDAA increases the expression level of receptor activator of nuclear factor-kappaB (NF-κB) (RANK) in Caco-2 cells, which suggests that 10-HDAA potentially prompts the differentiation of Caco-2 cells into M-cells and increased transcytosis efficiency. This idea is supported by the following observations. Intranasal administration of 10-HDAA increased the number of M-cells in the epithelium overlying nasopharynx-associated lymphoid tissue (NALT) in macaques. Oral administration of 10-HDAA increased the number of M-cells in the follicle-associated epithelium (FAE) covering Peyer's patches (PPs) and significantly increased the antigen-specific immunoglobulin A (IgA) level in macaques. These findings suggest that the exogenous honeybee-derived medium-chain fatty acid 10-HDAA may effectively enhance antigen-specific immune responses.

Medium-chain fatty acids (MCFAs) are the main form of Medium Chain Triglycerides (MCTs) utilized by monogastric animals. MCFAs can be directly absorbed and supply rapid energy to promote the renewal and repair of intestinal epithelial cells, maintain the integrity of intestinal mucosal barrier function, and reduce inflammation and stress. In our review, we pay more attention to the role of MCFAs on intestinal microbiota and mucosa immunity to explore MCFA's positive effect. It was found that MCFAs and their esterified forms can decrease pathogens while increasing probiotics. In addition, being recognized via specific receptors, MCFAs are capable of alleviating inflammation to a certain extent by regulating inflammation and immune-related pathways. MCFAs may also have a certain value to relieve intestinal allergy and inflammatory bowel disease (IBD). Unknown mechanism of various MCFA characteristics still causes dilemmas in the application, thus MCFAs are used generally in limited dosages and combined with short-chain organic acids (SOAs) to attain ideal results. We hope that further studies will provide guidance for the practical use of MCFAs in animal feed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Bovine respiratory disease (BRD) remains a major health problem despite extensive use of vaccines during the post-weaning period. Apparent vaccine failure is attributed, in part, to primary vaccination during the period of greatest risk for BRD, providing inadequate time for onset of protective immunity. The current study investigated whether intranasal (IN) vaccination of 3-6 week old calves with a modified-live viral (MLV) vaccine induced sufficient immune memory to prevent respiratory disease and accelerate onset of protective immunity 5 months later. Vaccine groups included naïve controls, a single IN vaccination at 3-6 weeks of age, primary IN vaccination at 6 months, and either an IN or subcutaneous (SC) booster vaccination at 6 months (n = 10/group). All calves were challenged with BHV-1 four days after vaccination at 6 months of age. Primary IN vaccination at 6 months did not significantly reduce clinical disease but significantly (P < 0.01) reduced virus shedding. A single IN vaccination at 3-6 weeks of age significantly (P < 0.05) reduced weight loss but did not reduce fever or virus shedding. Both IN and SC booster vaccinations, significantly (P < 0.01) reduced clinical disease but virus shedding was significantly (P < 0.001) reduced only by IN booster vaccination. Reduction in virus shedding was significantly (P < 0.01) greater following booster versus primary IN vaccination at 6 months. All vaccination regimes significantly (P < 0.01) reduced secondary bacterial pneumonia and altered interferon responses relative to naïve controls. Only IN booster vaccination significantly (P < 0.05) increased BHV-1 specific IgA in nasal secretions. These results confirm primary MLV IN vaccination at 3 to 6 weeks of age, when virus neutralizing maternal antibody was present, induced immune memory with a 5 month duration. This immune memory supported rapid onset of protective immunity four days after an IN booster vaccination., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study was aimed to assess the protective effects of γ-irradiated Astragalus polysaccharides (IAPS) on the development of small intestine and intestinal mucosal immunity of immunosuppressed broilers induced by cyclophosphamide (CPM). A total of 384 one-day-old broiler chicks with similar initial weight were randomly assigned into 6 groups: non-treated group (control), and CPM-treated groups fed either a basal diet or the diets containing 900 mg/kg APS, or 900, 600, 300 mg/kg IAPS, respectively. On days 16, 18, and 20, all broilers except for control group were intramuscularly injected with 0.5 mL CPM (40 mg/kg of BW). Broilers in the control group were intramuscularly injected with 0.5 mL sterilized saline (0.75%, wt/vol). This trial was lasted for 21 d. The results revealed that both APS and IAPS treatment elevated the duodenal IgA-producing cells number and the jejunal mRNA expression of interleukin-2 (IL-2), interleukin-10 (IL-10), and interferon γ of CPM-injected broilers (P < 0.05). The decreased jejunal villus height (VH), the ratio of VH to crypt depth (V/C), as well as the intestinal intraepithelial lymphocytes (IELs) and goblet cells number in CPM-injected broilers were elevated by dietary supplementation with 900 mg/kg APS or 900, 600 mg/kg IAPS (P < 0.05). The CPM-induced decrease in jejunum index, the duodenal VH and the jejunal IgA-producing cells number were only improved in the 900 mg/kg IAPS group (P < 0.05). Furthermore, the number of IELs and IgA-producing cells in duodenum, VH, V/C, the number of goblet cells, and mRNA expression of IL-2 and IL-10 in jejunum were higher in the 900 mg/kg IAPS group than those in the 900 mg/kg APS group (P < 0.05). In summary, IAPS possessed stronger immunomodulatory effect than APS at the same supplementation level. Therefore, gamma irradiation can be used as an alternative treatment to enhance the immunomodulatory activity of APS., (© 2019 Poultry Science Association Inc.)

The present study investigates the effect of dietary Ziziphus jujube fruit extract [ZJFE] on skin mucus non-specific immune parameters as well as mRNA levels of immune related gene in the skin of common carp fingerlings. An eight-week feeding trial was performed using different levels of dietary ZJFE (0, 0.25, 0.5 and 1%). At the end of the trial skin mucus immune parameters (total Ig, lysozyme and protease activity), cytokines genes (il1b, il8, il10 and tnf-alpha) expression in skin and growth performance were studied. The result showed highest and lowest skin mucus total Ig were observed in fish fed diet containing 0.5% ZJFE and control group, respectively (P < 0.05). There were no significant difference among treatments regarding skin mucus lysozyme activity (P >0.05). It should be noted that, feeding on 0.5 and 1% ZJFE significantly increased skin mucus protease activity (P <0.05). Likewise, gene expression studies in skin showed significant increase of il1b expression in fish fed 0.5% ZJFE compared other treatments (P <0.05). Also, il8 gene was noticeably up-regulated in 0.5 and 1% treatments compared to the control group (P <0.05). While there were no significant difference between 0.25% JFE treatment and control in case of relative il10 gene expression (P >0.05), feeding on diets containing 0.5% or 1% ZJFE significantly down-regulated il10 gene (P <0.05). Our study indicated that relative expression of tnf-alpha gene significantly increased in treated groups (P <0.05). Also, feeding on ZJFE supplemented diet improved growth performance parameters. Overall, this experiment demonstrated the potentially useful effects of ZJFE on skin mucosal immunity and performance of common carp fingerlings., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

An 8-week growth trial was conducted to investigate the effects of replacing dietary fishmeal with a plant protein blend on the growth performance, mucosal barrier integrity and the related regulation mechanism in Amur Sturgeon (Acipenser schrenckii) with initial weight of 87.48 g. Three isonitrogenous and isoenergetic diets were prepared. A basal diet containing 540 g/kg fishmeal (P0), whereas the other two diets were formulated by replacing 50% and 100% of FM with plant protein blend (soybean protein concentrate and cottonseed protein concentrate), and named as P50 and P100, respectively. Although essential amino acids, fatty acids, and available phosphorus had been balanced according to the nutrient requirement of sturgeon, compared with the fish of P0 and P50, the full plant protein diet (P100) significantly reduced growth performance and survival, and accompanied with serious spiral valve intestinal (SVI) damage. The increased tissue necrosis and failed responses in anti-oxidation, programming apoptosis, autophagy and cell proliferation system were regulated by inhibiting ERK1 phosphorylation, which indicated that SVI hypoimmunity and functional degradation were the main reasons for the high mortality and low utilization ability of plant protein in Amur sturgeon., (Copyright © 2019. Published by Elsevier Ltd.)

This study aims to determine the feasibility of using oligodeoxynucleotides with unmethylated cytosine-guanine dinucleotide sequences (CpG ODN) as an immunity protection strategy for a mouse model of acute respiratory distress syndrome (ARDS). This is a prospective laboratory animal investigation. Twenty-week-old BALB/c mice in Animal research laboratory were randomized into groups. An ARDS model was induced in mice using lipopolysaccharides (LPSs). CpG ODN was intranasally and transrectally immunized before or after the 3rd and 7th days of establishing the ARDS model. Mice were euthanized on Day 7 after the second immunization. Then, retroorbital bleeding was carried out and the chest was rapidly opened to collect the trachea and tissues from both lungs for testing. CpG ODN significantly improved the pathologic impairment in mice lung, especially after the intranasal administration of 50 μg. This resulted in the least severe lung tissue injury. Furthermore, interleukin-6 (IL-6) and IL-8 concentrations were lower, which was second to mice treated with the rectal administration of 20 µg CpG ODN. In contrast, the nasal and rectal administration of CpG ODN in BALB/c mice before LPS immunization did not appear to exhibit any significant protective effects. The intranasal administration of CpG ODN may be a potential treatment approach to ARDS. More studies are needed to further determine the protective mechanism of CpG ODN., (© 2019 Wiley Periodicals, Inc.)

The aims of this study were to investigate the antibacterial, immunostimulatory and antioxidant properties of different derivatives of Oliveria decumbens, in vitro and in vivo. The GC-MS spectrometry analysis showed γ-terpinene as the most frequent compound in essential oil, whereas carvacrol and thymol were the most common ones in aromatic water. Plant essential oil and hydroethanolic extract showed a positive in vitro bactericidal activity against Streptococcus iniae as evaluated by disc diffusion, minimum inhibitory concentration and minimum bactericidal concentration methods. Also, in vivo resistance against S. iniae and immune and antioxidant responses of Nile tilapia (Oreochromis niloticus) were assayed after 60 days treatment with O. decumbens derivatives. Plant hydroethanolic extract and essential oil and their 1:1 combination were added to diet at 0 (negative control), 0.01, 0.1 and 1% (w:w). The plant aromatic water at doses of 0.0312, 0.0625 and 0.1250% were also used as bath treatment. The results showed that aromatic water at lowest dose was more effective than other treatments in increment of fish resistance against S. iniae (7.14% mortality in comparison with 50% mortalities in control fish) and modulation of post-challenge respiratory burst activity. The bactericidal activity and biochemical contents of skin mucus did not change significantly among treatments. The levels of superoxide dismutase and catalase antioxidant enzymes activities in spleen tissue were significantly higher in treatments received extract, essential oils and their combination in comparison to other groups, while treatments did not affect peroxidase level. In conclusion, administration of different derivatives of Oliveria decumbens showed remarkable antibacterial activity against streptococcosis and enhanced antioxidant status and post-challenge immunity in Nile tilapia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Enterotoxin-based adjuvants including cholera toxin and heat-labile toxin (LT) are powerful manipulators of mucosal immunity; however, past clinical trials identified unacceptable neurological toxicity when LT or mutant AB 5 adjuvant proteins were added to intranasal vaccines. Here, we examined the isolated enzymatic A1 domain of LT (LTA1) for intranasal safety and efficacy in combination with influenza (flu) vaccination. LTA1-treated mice exhibited no neurotoxicity, as measured by olfactory system testing and H&E staining of nasal tissue in contrast with cholera toxin. In vaccination studies, intranasal LTA1 enhanced immune responses to inactivated virus antigen and subsequent protection against H1N1 flu challenge in mice (8-week or 24-months). In addition, lung H1N1 viral titers post-challenge correlated to serum antibody responses; however, enhanced protection was also observed in μMT mice lacking B-cells while activation and recruitment of CD4 T-cells into the lung was apparent. Thus, we report that LTA1 protein is a novel, safe and effective enterotoxin adjuvant that improves protection of an intranasal flu vaccination by a mechanism that does not appear to require B-cells.

In this study, an acidic polysaccharide from Codonopsis pilosula Nannf. var. modesta (Nannf.) L. T. Shen (WCP-I) and its main fragment, WCP-Ia, obtained after pectinase digestion, were structurally elucidated and found to consist of a rhamnogalacturonan I (RG-I) region containing both arabinogalactan type I (AG-I) and type II (AG-II) as sidechains. They both expressed immunomodulating activity against Peyer's patch cells. Endo-1,4-β-galactanase degradation gave a decrease of interleukine 6 (IL-6) production compared with native WCP-I and WCP-Ia, but exo-α-l-arabinofuranosidase digestion showed no changes in activity. This demonstrated that the stimulation activity partly disappeared with removal of β-d-(1→4)-galactan chains, proving that the AG-I side chain plays an important role in immunoregulation activity. WCP-Ia had a better promotion effect than WCP-I in vivo, shown through an increased spleen index, higher concentrations of IL-6, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) in serum, and a slight increment in the secretory immunoglobulin A (sIgA) and CD4 + /CD8 + T lymphocyte ratio. These results suggest that β-d-(1→4)-galactan-containing chains in WCP-I play an essential role in the expression of immunomodulating activity. Combining all the results in this and previous studies, the intestinal immune system might be the target site of WCP-Ia.

In preterm newborns the immaturity of the immune system is remarkable, with reduced innate and adaptive immune responses. Many bioactive compounds in breast milk, such as growth factors and adipokines, contribute to the immune system's maturation in early life. However, studies on the immunoregulatory activity in preterm neonates are practically nonexistent. The aim of the present study was to determine whether a nutritional supplementation in early life with leptin or epidermal growth factor (EGF) was able to promote the maturation of the systemic and intestinal immune system in preterm conditions. For this purpose, premature rats were daily supplemented by oral gavage with leptin or EGF. Term and Preterm groups receiving vehicle were used as controls. Preterm rats showed deficiencies compared to full-term ones, such as lower body weights, erythrocyte counts, plasma IgG and IgM concentrations and B cell percentages, and higher values of Th and Tc TCRαβ + cells in mesenteric lymph nodes, and intestinal permeability, among others. However, leptin and EGF supplementation were able to revert some of these deficiencies and to improve the premature immune system's development. These results suggest that leptin and EGF are involved in enhancing the maturation of the systemic and intestinal immune system in preterm conditions.

Limited protective effects of commercially available vaccines necessitate the development of novel pneumococcal vaccines. We recently reported a pneumococcal systemic vaccine containing two proteins, Pneumococcal surface protein A (PspA of family 1 and 2) and a bacterium-like particle-based pneumococcal mucosal vaccine containing PspA2 and PspA4 fragments, both eliciting broad protective immune responses. We had previously reported that subcutaneous (s.c.+s.c.+s.c.) immunization with the systemic vaccine induced more pronounced humoral serum IgG responses, while intranasal (i.n.+i.n.+i.n.) immunization with the mucosal vaccine elicited a more pronounced mucosal secretory IgA (sIgA) response. We hypothesized that a combinatorial administration of the two vaccines might elicit more pronounced and broader protective immune responses. Therefore, this study aimed to determine the efficacy of combinatorial prime-boost immunization using both systemic and mucosal vaccines for a pneumococcal infection. Combinatorial prime-boost immunization (s.c.+i.n. and i.n.+s.c.) induced not only IgG, but also mucosal sIgA production at high levels. Systemic priming and mucosal boosting immunization (s.c.+i.n.) provided markedly better protection than homologous prime-boost immunization (s.c.+s.c.+s.c. and i.n.+i.n.+i.n.). Moreover, it induced more robust Th1 and Th17 cell-mediated immune responses than mucosal priming and systemic boosting immunization (i.n.+s.c.). These results indicate that combinatorial prime-boost immunization potentially induces a robust systemic and mucosal immune response, making it an optimal alternative for maximum protection against lethal pneumococcal infections.

Most of current influenza virus vaccines fail to develop a strong immunity at lung mucosae (site of viral entry) due to sub-optimal vaccination protocols (e.g. inactivated virus administered by parenteral injections). Mucosal immunity could be improved by using locally-delivered vaccines containing appropriate adjuvants. Here we show, in a mouse model, that inclusion of silver nanoparticles (AgNPs) in virus-inactivated flu vaccine resulted in reduction of viral loads and prevention of excessive lung inflammation following influenza infection. Concomitantly, AgNPs enhanced specific IgA secreting plasma cells and antibodies titers, a hallmark of successful mucosal immunity. Moreover, vaccination in the presence of AgNPs but not with gold nanoparticles, protected mice from lethal flu. Compared with other commercial adjuvants (squalene/oil-based emulsion) or silver salts, AgNPs stimulated stronger antigen specific IgA production with lower toxicity by promoting bronchus-associated lymphoid tissue (BALT) neogenesis, and acted as a bona fide mucosal adjuvant., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The objective of this study was to explore the effects of starter feeding on caecal mucosal bacterial composition and the expression of genes involved in immune and tight junctions in pre-weaned lambs. Six pairs of new-born twin lambs were selected. From 10 days of age, one lamb of each pair received ewe's milk only (M group, n = 6), while the other one was fed ewe's milk plus starter feed (M + S group, n = 6). At 56 days of age, the lambs were sacrificed, and then cecum digesta was collected to measure pH values and concentrations of volatile fatty acid (VFA), and caecal mucosa were collected to determine the changes in bacterial communities and the mRNA expression of cytokines, toll-like receptors (TLRs) and tight junction proteins. The results showed the body weight and average daily gain were not significantly different between both groups. Starter feeding significantly (P < 0.05) increased the concentrations of propionate and butyrate; the proportions of acetate, propionate and butyrate to total concentrations of VFA; and decreased the ratio of acetate to propionate in caecal contents. Principal coordinate analysis showed that samples from the M + S group could be distinguished from those from the M group; starter feeding also increased the diversity of caecal mucosal bacteria. At the genus level, starter feeding significantly (FDR < 0.05) increased the relative abundance of Alistipes, Parabacteroides, Parasutterella and Butyricimonas, and caused a decreasing trend (FDR < 0.10) in the relative abundance of Campylobacter and Helicobacter. The real-time PCR results showed that starter feeding significantly (FDR < 0.05) decreased the relative mRNA expression level of IL-12, TNF-α and TLR4 and increased the relative mRNA expression level of claudin-4. These results indicate that starter feeding altered caecal mucosal bacterial communities and decreased the expression of inflammatory factors, which may be beneficial in alleviating the weaning stress of lambs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Medicinal plant has been applied as an alternative strategy for antibiotics and chemotherapeutics for controlling the outbreak of diseases in tilapia farming. In this study, five doses of Elephantopus scaber extract (ESE) were added to the basal diet at 0, 2.5, 5, 10, and 20 g kg -1 feed of Nile tilapia fingerlings (13.92 ± 0.06 g initial weight) in triplicate. After 4- and 8- weeks post-feeding, fish were sampled to determine the effects of the ESE supplemented on fish's growth performance, humoral, and skin mucus immune response. After 8 weeks post-feeding, a challenge test against Streptococcus agalactiae was carried out using 10 fish from each tank. Fish fed ESE showed significantly increased serum lysozyme (SL), serum peroxidase (SP), alternative complement (ACH50), phagocytosis (PI), and respiratory burst (RB) compared to the control group (P < 0.05). The skin mucus lysozyme (SMLA) and skin peroxidase (SMPA) were stimulated in fish fed ESE diets. Dietary inclusion of ESE significantly (P < 0.05) promoted final body weight (FW), weight gain (WG), and specific growth rate (SGR); while a reduction in feed conversion ratio (FCR) was observed in fish fed 5 g kg -1 ESE, after 8 weeks post-feeding. The challenge study indicated that the relative percent survival (RSP) was 38.10%, 76.19%, 66.67%, and 47.62% in Diet 2, Diet 3, Diet 4, and Diet 5, respectively. Among the supplemented groups, dietary of 5 g kg -1 ESE showed significantly higher RPS and the highest resistance to S. agalactiae in comparison with other groups. In conclusion, supplementation of ESE (5 g kg -1 ) enhanced the humoral and mucosal immunity, promoted growth performance, and improved disease resistance of Nile tilapia against Streptococcus agalactiae., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In physiological conditions, the gut is heavily infiltrated with various subsets of inflammatory cells, whose activity is tightly controlled by counter-regulatory mechanisms. Defects in such mechanisms can favour the development of chronic intestinal disorders, such as Crohn's disease (CD) and ulcerative colitis (UC), the principal forms of inflammatory bowel diseases (IBD) in humans, as well as systemic disorders. Over the last years, the frequency of intestinal and systemic immune-inflammatory disorders has increased in previously low incidence areas, likely due to the Westernization of lifestyles, including dietary habits. The Western diet is characterized by high consumption of proteins, saturated fats and sweets, as well as by a broad use of food additives (e.g., emulsifiers, bulking agents), which are used to preserve and enhance food quality. Accumulating evidence suggests that food additives can perturb gut homeostasis, thereby contributing to promote tissue-damaging inflammatory responses. For instance, mice given the emulsifiers carboxymethylcellulose and polysorbate 80 develop dysbiosis with overgrowth of mucus-degrading bacteria. Such an effect triggers colitis in animals deficient in either interleukin-10, a cytokine exerting anti-inflammatory and regulatory functions, or Toll-like receptor 5, a receptor recognizing the bacterial flagellin. Similarly, the polysaccharide maltodextrin induces endoplasmic reticulum stress in intestinal goblet cells, thereby impairing mucus release and increasing host susceptibility to colitis. In this review, we report and discuss the current knowledge about the impact of food additives on gut homeostasis and their potential contribution to the development of inflammatory disorders., Competing Interests: the authors declare no conflict of interest.

Lipololysaccharides (LPS) can disrupt the gut barrier. How dose LPS affects the immune performance of mesenteric lymph nodes? The results showed the hematological parameters significantly changed after LPS treatment. The length of intestinal villus was shortened and the depth of crypts was deepened, especially on the ileum. After LPS treatment 6 h, 12 h, the number of CD3 + T cells and CD4/CD8 in the mesenteric lymph nodes of ileum were reduced significantly; the levels of IFN-γ, TNF-ɑ and IL-2 were significantly decreased, and the levels of IL-6 and IL-10 were significantly increased in the ileum. The content of sIgA in the ileum was significantly decreased after LPS treatment 3 h, 6 h and was increased after LPS treatment 12 h. LPS through mesenteric lymph nodes, which induces the immune function reduced and the ileum injured obviously after treatment 6 h. Furthermore, the performance of intestinal immune performance was the lowest after LPS treatment 6 h., (Copyright © 2019. Published by Elsevier B.V.)

Astragalus polysaccharides (APS) are a traditional Chinese medicine with a therapeutic effect by enhancing immune function; however, the underlying functional mechanism is still unclear. The aim of the present study was to determine the effect of oral administration of APS on jejunum mucosal immunity in chickens vaccinated against Newcastle disease (ND). One-day-old Hy-Line male chickens were divided into five groups of 20 chicks each: three APS groups, one vaccinated control (VC) group and one non-vaccinated negative control (NC) group. On d 10, the APS groups were orally administered 0.5 mL of APS at doses of 1 mg/mL (APS L ), 2 mg/mL (APS M ) and 4 mg/mL (APS H ) daily for 4 consecutive days. The chicks in the control groups were administered 0.5 mL saline for those 4 days. All groups except NC were administered a ND virus (NDV) vaccine on day 14. The jejunum was removed from 4 randomly selected chickens of each group at 1, 7, 14 and 28 days after vaccination. The jejunal villus height (VH) and crypt depth (CD) were measured and the VH:CD ratio calculated. Immunohistochemistry was used to analyze the differences of IgA + cells in the jejunum. NDV specific secretory IgA (sIgA) levels in jejunal contents were detected using an indirect ELISA. At most time points, VH:CD ratios, number of IgA + cells, and sIgA levels were significantly higher in the APS groups than those in VC and NC groups, but there were little differences among the three doses of APS groups. These results indicate that oral administration of APS could enhance the intestinal mucosal immune function of chickens, and APS could be used as a vaccine enhancer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Mucosal immune activation, in the context of sexual transmission of HIV-1 infection, is crucial, as the increased presence of activated T cells enhance susceptibility to infection. In this regard, it has been proposed that immunomodulatory compounds capable of modulating immune activation, such as Vitamin D (VitD) may reduce HIV-1 transmission and might be used as a safe and cost-effective strategy for prevention. Considering this, we examined the in vitro effect of the treatment of peripheral blood mononuclear cells (PBMCs) with the active form of VitD, calcitriol, on cellular activation, function and susceptibility of CD4+ T cells to HIV-1 infection., Methods: We treated PBMCs from healthy HIV unexposed individuals (Co-HC) and frequently exposed, HIV-1 seronegative individuals (HESNs) from Colombia and from healthy non-exposed individuals from Canada (Ca-HC) with calcitriol and performed in vitro HIV-1 infection assays using X4- and R5-tropic HIV-1 strains respectively. In addition, we evaluated the activation and function of T cells and the expression of viral co-receptors, and select antiviral genes following calcitriol treatment., Results: Calcitriol reduced the frequency of infected CD4+ T cells and the number of viral particles per cell, for both, X4- and R5-tropic viruses tested in the Co-HC and the Ca-HC, respectively, but not in HESNs. Furthermore, in the Co-HC, calcitriol reduced the frequency of polyclonally activated T cells expressing the activation markers HLA-DR and CD38, and those HLA-DR+CD38-, whereas increased the subpopulation HLA-DR-CD38+. Calcitriol treatment also decreased production of granzyme, IL-2 and MIP-1β by T cells and increased the transcriptional expression of the inhibitor of NF-kB and the antiviral genes cathelicidin (CAMP) and APOBEC3G in PBMCs from Co-HC., Conclusion: Our in vitro findings suggest that VitD treatment could reduce HIV-1 transmission through a specific modulation of the activation levels and function of T cells, and the production of antiviral factors. In conclusion, VitD remains as an interesting potential strategy to prevent HIV-1 transmission that should be further explored., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Influenza is an infectious respiratory illness caused by the influenza virus. Though vaccines against influenza exist, they have limited efficacy. To additionally develop effective treatments, there is a need to study the mechanisms of host defenses from influenza viral infections. To date, the mechanism by which interleukin (IL)-33 modulates the antiviral immune response post-influenza infection is unclear. In this study, we demonstrate that exogenous IL-33 enhanced antiviral protection against influenza virus infection. Exogenous IL-33 induced the recruitment of dendritic cells, increased the secretion of pro-inflammatory cytokine IL-12, and promoted cytotoxic T-cell responses in the local microenvironment. Thus, our findings suggest a role of exogenous IL-33 in the antiviral immune response against influenza infection.

Present study evaluated the effects of curcumin, the principal curcuminoid of turmeric, on Cyprinus carpio growth, skin mucosal immune parameters, immune-related gene expression, and susceptibility to pathogen challenge. Diets containing four various concentrations of curcumin (g Kg -1 ): 0 g [basal diet], 5 g [T5], 10 g [T10], and 15 g [T15] were fed to the carp (average weight: 16.37 g) for 8 weeks. Growth parameters were analysed at 4 and 8 weeks post-feeding. Skin mucosal immune responses and expression were examined in 8 weeks post-feeding. Growth performance was significantly higher in T10 and T15, with final weight gain of 102.26 ± 2.31 g and specific growth rate of 3.24 ± 0.37, respectively. The lowest feed conversion ratio (2.35 ± 0.16) was recorded in T15 than in the control (P < 0.05). Among the skin mucosal immune parameters examined, lysozyme (36.8 ± 4.03 U mL -1 ), total immunoglobulin (6.74 ± 0.5 mg mL -1 ), protein level (18.7 ± 1.62 mg mL -1 ), alkaline phosphatase (96.37 ± 6.3 IU L -1 ), and protease activity (9.47 ± 0.82%) were significantly higher in T15, while the peroxidase activity was higher in T10 (10.24 ± 0.9 U mg -1 protein). Further, lysozyme, superoxide dismutase (SOD) and catalase (CAT) activities were measured in serum and found to be higher in T10 or T15 than in the control (P < 0.05). However, malondialdehyde level decreased significantly in T10 and T15. Furthermore, antioxidant genes (SOD, CAT, nuclear factor erythroid 2-related factor 2) and anti-inflammatory cytokine Interleukin-10 were upregulated in the head kidney, intestine, and hepatopancreas of fish in T10 and T15. Conversely, expression of pro-inflammatory cytokines (IL-1β, tumour necrosis factor-alpha), signalling molecule NF-κBp65 were down-regulated in the tested tissues of T10 and T15. Expression of Toll-like receptor 22 (TLR22) was down regulated in head-kidney and intestine of T15. Fish from T15 exhibited significantly higher relative post-challenge survival (69.70%) against Aeromonas hydrophila challenge. Results of the present study suggest that dietary supplements of curcumin at 15 g Kg -1 can significantly improve the growth performance, skin mucosal and serum antioxidant parameters, and strengthen the immunity of C. carpio. Therefore, curcumin represents a promising food additive for carps in aquaculture., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Taste receptors, first identified on the tongue, are best known for their role in guiding our dietary preferences. The expression of taste receptors for umami, sweet, and bitter have been demonstrated in tissues outside of the oral cavity, including in the airway, brain, gastrointestinal tract, and reproductive organs. The extra-oral taste receptor chemosensory pathways and the endogenous taste receptor ligands are generally unknown, but there is increasing data suggesting that taste receptors are involved in regulating some aspects of innate immunity, and may potentially control the composition of the nasal microbiome in healthy individuals or patients with upper respiratory diseases like chronic rhinosinusitis (CRS). For this reason, taste receptors may serve as potential therapeutic targets, providing alternatives to conventional antibiotics. This review focuses on the physiology of sweet (T1R) and bitter (T2R) taste receptors in the airway and their activation by secreted bacterial products. There is particular focus on T2R38 in sinonasal ciliated cells, as well as the sweet and bitter receptors found on specialized sinonasal solitary chemosensory cells. Additionally, this review explores the impact of genetic variations in these receptors on the differential susceptibility of patients to upper airway infections, such as CRS.

Globally, HIV/AIDS is a leading cause of morbidity worldwide among reproductive-aged cisgender women, highlighting the importance of understanding effects of contraceptives on HIV-1 risk. Some observational studies suggest there may be an increased risk of HIV-1 acquisition among women using the long-acting injectable progestin contraceptive, depo-medroxyprogesterone acetate. The potential mechanism of this susceptibility is unclear. There are few data on the role of the upper female reproductive tract in HIV-1 transmission, and the mechanisms of HIV-1 infection are likely to differ in the upper compared to the lower reproductive tract due to differences in tissue composition and variable effects of sex steroids on mucosal immune cell distribution and activity. In this study, we measured the susceptibility of mucosal immune cells from the upper female reproductive tract to HIV-1 entry using the virion-based HIV-1 fusion assay in samples from healthy female volunteers. We studied 37 infectious molecular clones for their ability to fuse to cells from endometrial biopsies in three participants and found that subtype (B or C) and origin of the virus (transmitted founder or chronic control) had little influence on HIV-1 fusion susceptibility. We studied the effect of contraceptives on HIV-1 susceptibility of immune cells from the cervix, endometrium and peripheral blood by comparing fusion susceptibility in four groups: users of the copper intrauterine device (IUD), levonorgestrel-containing oral contraceptive, levonorgestrel-containing IUD and unexposed controls (n = 58 participants). None of the contraceptives was associated with higher rates of HIV-1 entry into female reproductive tract cells compared to control samples from the mid-luteal phase., Competing Interests: SA is on the Board of Directors of One Heart World Wide, an NGO that does safe motherhood work in Nepal, is on the Advisory Board of Center for AIDS Research at University of California San Diego and has a research grant from the Society of Family Planning to study early initiation of postpartum contraception. BLS receives funding from the National Institutes of Health (NIAID R01 AI057020; NIDDK R01 DK108350; NCI P30 CA093373) and research contracts from Gilead Sciences. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The increasing cyanobacterial blooms have recently been considered a severe environmental problem. Microcystin-leucine arginine (MC-LR) is one of the secondary products of cyanobacteria metabolism and most harmful cyanotoxins found in water bodies. Studies show MC-LR negatively affects various human organs when exposed to it. The phenotype of the jejunal chronic toxicity induced by MC-LR has not been well described. The aim of this paper was to investigate the effects of MC-LR on the jejunal microstructure and expression level of inflammatory-related factors in jejunum. Mice were treated with different doses (1, 30, 60, 90 and 120 μg/L) of MC-LR for six months. The microstructure and mRNA expression levels of inflammation-related factors in jejunum were analyzed. Results showed that the microstructure of the jejunum was destroyed and expression levels of inflammation-related factors interleukin (IL)-1β, interleukin (IL)-8, tumor necrosis factor alpha, transforming growth factor-β1 and interleukin (IL)-10 were altered at different MC-LR concentrations. To the best of our knowledge, this is the first study that mice were exposed to a high dose of MC-LR for six months. Our data demonstrated MC-LR had the potential to cause intestinal toxicity by destroying the microstructure of the jejunum and inducing an inflammatory response in mice, which provided new insight into understanding the prevention and diagnosis of the intestinal diseases caused by MC-LR.

The generation of robust systemic and mucosal antibody and cell-mediated immune (CMI) responses that are protective, long-lasting, and can quickly be recalled upon subsequent re-exposure to the cognate antigen is the key to the development of effective vaccine candidates. These responses, whether they represent mechanistic or non-mechanistic immunological correlates of protection, usually entail the activation of T cell memory and effector subsets (T-CMI) and induction of long-lasting memory B cells. However, for ETEC and Shigella, the precise role of these key immune cells in primary and secondary (anamnestic) immune responses remains ill-defined. A workshop to address immune correlates for ETEC and Shigella, in general, and to elucidate the mechanistic role of T-cell subsets and B-cells, both systemically and in the mucosal microenvironment, in the development of durable protective immunity against ETEC and Shigella was held at the recent 2nd Vaccines against Shigella and ETEC (VASE) conference in June 2018. This report is a summary of the presentations and the discussion that ensued at the workshop., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: The long-term effect of immune tolerance has not been explored so far in atherosclerosis. In the present study, we assessed the effect of mucosal tolerance to a multi antigenic construct expressing three peptides from ApoB, HSP60, and outer membrane protein from Chlamydia pneumonia (AHC) for 30 weeks at every 6-week interval to understand the kinetics of immune modulation in disease progression. The safety profile of the molecule was also evaluated in mice., Methods: Apob tm2Sgy Ldlr tm1 Her/J mice (5-6 weeks) were orally dosed with multi antigenic construct (AHC) molecule on alternate days, followed by high-fat diet feeding to initiate atherosclerosis., Results: Treated animals showed an efficient reduction in plaque growth and lipid accumulation at 6 weeks (49%, p < 0.01) and 12 weeks (42.3%, p < 0.01) which decreased to 29% (p = 0.0001) at 18 weeks and at later time points. Macrophage accumulation was significantly lower at all time points (53% at 12 weeks to 27% at 30 weeks). Regulatory T cells increased in the spleen following treatment until 12 weeks (week 0 (2.57 ± 0.18 vs. 6.36 ± 0.03, p = 0.02), week 6 (4.52 ± 0.2 vs. 8.87 ± 0.32, p = 0.02), and week 12 (8.74 ± 0.37 vs. 15.4 ± 0.27, p = 0.02)) but showed a decline later. A similar trend was observed with tolerogenic dendritic cells. We observed an increase in antibody levels to low-density lipoprotein and oxidized LDL at later stages. AHC molecule was found to be safe in acute and repeated dose toxicity studies., Conclusions: Our results suggest that immune tolerance to AHC protein by oral administration is able to provide efficient atheroprotection up to 18 weeks and moderately at later stages. Apart from immune regulatory cells, protective antibodies may also have a role in controlling atherosclerosis.

At the interface of the environment and the nervous system, the olfactory mucosa (OM) is a privileged pathway for environmental toxicants and pathogens towards the central nervous system. The OM is known to produce antimicrobial and immunological components but the mechanisms of action of the immune system on the OM remain poorly explored. IL-17c is a potent mediator of respiratory epithelial innate immune responses, whose receptors are highly expressed in the OM of mice. We first characterized the presence of the IL-17c and its receptors in the OM. While IL-17c was weakly expressed in the control condition, it was strongly expressed in vivo after intranasal administration of polyinosinic-polycytidylic (Poly I:C), a Toll Like Receptor 3 agonist, mimicking a viral infection. Using calcium imaging and electrophysiological recordings, we found that IL-17c can effectively activate OM cells through the release of ATP. In the longer term, intranasal chronic instillations of IL-17c increased the cellular dynamics of the epithelium and promoted immune cells infiltrations. Finally, IL-17c decreased cell death induced by Poly(I:C) in an OM primary culture. The OM is thus a tissue highly responsive to immune mediators, proving its central role as a barrier against airway pathogens., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: Ulcerative colitis (UC) is an aetiologically refractory inflammatory disease, accompanied by dysfunction of the epithelial barrier and intestinal inflammation. Phosphodiesterase-4 (PDE4) serves as an intracellular proinflammatory enzyme, hydrolyzing and inactivating cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity in the intestine remains ill-defined. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in dextran sulfate sodium-induced murine UC., Experimental Approach: Intestinal inflammation and disease severity were evaluated by morphological, histopathological and biochemical assays, and in vivo imaging. Expression of inflammatory mediators, components of PDE4-mediated pathways in colon and macrophages were determined using quantitative real-time PCR, ELISA, Luminex assay, immunostaining, or western blotting, along with siRNA knockdown. Immune cells in mesenteric lymph nodes and colonic lamina propria were analysed by flow cytometry., Key Results: Apremilast attenuated clinical features of UC, suppressing microscopic colon damage, production of inflammatory mediators, oxidative stresses, and fibrosis. Apremilast also promoted epithelial barrier function and inhibited infiltration of immune cells into inflamed tissues, through decreasing expression of chemokines and chemokine receptors. Furthermore, in UC, PDE4A, PDE4B, and PDE4D were highly expressed in colon. Apremilast not only inhibited PDE4 isoform expression but also activated PKA-CREB and Epac-Rap1 pathways and subsequently suppressed MAPK, NF-κB, PI3K-mTOR, and JAK-STAT-SOCS3 activation., Conclusion and Implications: Inhibition of PDE4 by apremilast protected against UC, by interfering with mucosal immunity. These findings represent a promising strategy for regulating intestinal inflammation., (© 2019 The British Pharmacological Society.)

Cholera is a severe diarrheal disease caused by the bacterium Vibrio cholerae (V. cholerae) that results in 3-4 million cases globally with 100,000-150,000 deaths reported annually. Mostly confined to developing nations, current strategies to control the spread of cholera include the provision of safe drinking water and improved sanitation and hygiene, ideally in conjunction with oral vaccination. However, difficulties associated with the costs and logistics of these strategies have hampered their widespread implementation. Specific challenges pertaining to oral cholera vaccines (OCVs) include a lack of safe and effective adjuvants to further enhance gut immune responses, the complex and costly multicomponent vaccine manufacturing, limitations of conventional liquid formulation and the lack of an integrated delivery platform. Herein we describe the use of the orally active adjuvant α-Galactosylceramide (α-GalCer) to strongly enhance intestinal bacterium- and toxin-specific IgA responses to the OCV, Dukoral ® in C57BL/6 and BALB/c mice. We further demonstrate the mucosal immunogenicity of a novel multi-antigen, single-component whole-cell killed V. cholerae strain and the enhancement of its immunogenicity by adding α-GalCer. Finally, we report that combining these components and recombinant cholera toxin B subunit in the SmPill ® minisphere delivery system induced strong intestinal and systemic antigen-specific antibody responses.

Nasal immunization to prevent and treat diseases caused by infection through the respiratory tract cannot be actualized because of the lack of effective adjuvants. We have proven that compared with antigens loaded on CS or O-HTCC alone in nasal vaccination, antigens loaded on the nanoparticles of curdlan sulfate/O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (CS/O-HTCC) can induce stronger systemic and mucosal immune responses. In this study, we evaluated the immunostimulatory activity and mechanisms of CS/O-HTCC nanoparticles. The results showed that CS/O-HTCC nanoparticles can improve the activation of antigen-presenting cells, upregulate the production of inflammatory factors and cytokines, induce cross-presentation, and simultaneously activate type I interferon-related genes. CS/O-HTCC nanoparticles also activated the PI3K/AKT and MAPK pathways and significantly promoted IL-2 transcription to induce the proliferation of lymphocytes. The results revealed that CS/O-HTCC nanoparticles as a type of multifunctional adjuvant can improve multiple arms of immune responses., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Lactoferrin modulates mucosal immunity and targets mechanisms contributing to inflammation during human immunodeficiency virus disease. A randomized placebo-controlled crossover clinical trial of recombinant human (rh) lactoferrin was conducted among 54 human immunodeficiency virus-infected participants with viral suppression. Outcomes were tolerability, inflammatory, and immunologic measures, and the intestinal microbiome. The median age was 51 years, and the median CD4+ cell count was 651/µL. Adherence and adverse events did not differ between rh-lactoferrin and placebo. There was no significant effect on plasma interleukin-6 or D-dimer levels, nor on monocyte/T-cell activation, mucosal integrity, or intestinal microbiota diversity. Oral administration of rh-lactoferrin was safe but did not reduce inflammation and immune activation. Clinical Trials Registration: NCT01830595., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)