Autism spectrum disorder (ASD) is a range of neurodevelopmental conditions that affect communication and social behavior. Besides social deficits, systemic inflammation, gastrointestinal immune-related problems and changes in the gut microbiota composition are characteristic for people with ASD. Animal models showed that these characteristics can induce ASD-associated behavior, suggesting an intimate relationship between the microbiota, gut, immune system and the brain in ASD. Multiple factors can contribute to the development of ASD, but mutations leading to enhanced activation of the mammalian target of rapamycin (mTOR) are reported frequently. Hyperactivation of mTOR leads to deficits in the communication between neurons in the brain and to immune impairments. Hence, mTOR might be a critical factor linking the gut-brain-immune axis in ASD. Pharmacological inhibition of mTOR is shown to improve ASD-associated behavior and immune functions, however, the clinical use is limited due to severe side reactions. Interestingly, studies have shown that mTOR activation can also be modified by nutritional stimuli, in particular by amino acids. Moreover, specific amino acids are demonstrated to inhibit inflammation, improve gut barrier function and to modify the microbiota composition. In this review we will discuss the gut-brain-immune axis in ASD and explore the potential of amino acids as a treatment option for ASD, either via modification of mTOR activity, the immune system or the gut microbiota composition.
The Mediterranean diet, containing valuable nutrients like n-3 long chain poly-unsaturated fatty acids (LCPUFAs) and other fat-soluble micronutrients, is known for its health promoting and anti-inflammatory effects. Its valuable elements might help in the battle against the rising prevalence of non-communicable diseases (NCD) including the development of allergic diseases and other (chronic)inflammatory diseases. The fat fraction of the Mediterranean diet contains bioactive fatty acids but can serve as a matrix to dissolve and increase the uptake of fat-soluble vitamins and phytochemicals like luteolin, quercetin, resveratrol and lycopene with known immunomodulatory and anti-inflammatory capacities as well. Especially n-3 LCPUFAs like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from marine oils can target specific receptors or signaling cascades, act as eicosanoid precursors and/or alter membrane fluidity and lipid raft formation hereby exhibiting anti-inflammatory properties. Beyond n-3 LCPUFAs, fat-soluble vitamins A, D, E and K1/2 have the potential to affect pro-inflammatory signaling cascades by interacting with receptors or activating/inhibiting signaling proteins or phosphorylation in immune cells (DCs, T-cells, mast cells) involved in allergic sensitization or the elicitation/effector phase of allergic reactions. Moreover, fat-soluble plant-derived phytochemicals can manipulate signaling cascades, mostly by interacting with other receptors or signaling proteins compared to those modified by fat-soluble vitamins, suggesting potential additive or synergistic actions by applying a combination of these nutrients which are all part of the regular Mediterranean diet. Research concerning the effects of phytochemicals such as polyphenols has been hampered due to their poor bio-availability. However, their solubility and uptake are improved by applying within the dietary fat matrix. Alternatively, they can be prepared for targeted delivery by means of pharmaceutical approaches like encapsulation within liposomes or even unique nanoparticles. This review illuminates the molecular mechanisms of action and possible immunomodulatory effects of n-3 LCPUFAs and fat-soluble micronutrients from the Mediterranean diet in allergic disease development and allergic inflammation. This will enable us to further appreciate how to make use of the beneficial effects of n-3 LCPUFAs, fat-soluble vitamins and a selection of phytochemicals as active biological components in allergy prevention and/or symptom reduction.
In the Netherlands, the number of chickens and pigs exceeds the number of human inhabitants by far. Therefore, combating infections in livestock is not only of economical importance, but also of great importance to public health. The innate immune system provides a first line defense against infectious pathogens, and its effector mechanisms rely on the recognition of features that are common to many pathogens. These features, known as pathogen-associated molecular patterns can be recognized by pattern recognition molecules at the site of infection, which is often an epithelial surface like the lung, skin or gastro-intestinal tract. Collectins, an important group of pattern recognition molecules, have been reported to be expressed in many epithelial surfaces. In the lung, Surfactant Protein-D (SP-D) contributes to the maintenance of a sterile respiratory system. Its role in the gastro-intestinal tract, which is dominated by the presence of micro-organisms, is less clear. Therefore, we investigated the interaction of porcine SP-D (pSP-D) with various Gram-negative bacteria isolated from the porcine intestine. It was shown that while pSP-D is capable of reducing growth rates of E. coli K12, the growth rates and survival of pathogenic bacterial strains isolated from the porcine intestine remained unaffected. Furthermore, pSP-D was shown to affect bacterial adhesion- and invasion- characteristics, leading to a significant increase in adhesion and invasion of bacteria into IPI-I2 cells. It is not yet clear what the mechanism behind these effects is, but it could reflect a scavenger function for pSP-D in the intestine. In the chicken, only two collectins had been described thus far. In this thesis, we report the discovery of three new chicken collectins, chicken Collectin 1-3 (cCL-1, -2,and -3) and one chicken lectin, chicken Lung Lectin (cLL). Results from this study support the assumption that cCL-1, -2 and -3, together with their respective mammalian homologues CL-L1, CL-K1 and CL-P1 represent three new unique classes within the collectin protein family. Because of its predominant expression in the chicken respiratory tract, the newly discovered chicken lectin was designated chicken Lung Lectin (cLL). To investigate whether these chicken (col)lectins are involved in avian innate immunity, their mRNA expression levels during bacterial and viral infections were investigated. Samples derived from three infection-models were analyzed, and the results showed that mRNA expression of chicken (col)lectins cCL-1, cCL-2, cSP-A and cLL can be affected by both bacterial and viral infections. We also investigated the structural and functional aspects of cLL. To this end, recombinant cLL was successfully produced in HEK-293 EBNA cells. Characterization of recombinant cLL revealed that this protein is capable of binding sugars, and, as predicted from its sequence, does so in a calcium-dependent manner. In addition, cLL showed anti-viral activity against avian IAV in our preliminary tests, and HAA-inhibition of a human isolate of IAV was shown. Further investigation into the function of the (col)lectins can provide insight how they are involved in innate defense against invading pathogens, and exploiting their properties and functions may provide an alternative strategy towards preventing infections in pigs and poultry.
Deoxynivalenol (DON), a highly prevalent contaminant of grain-based products, is known to induce reproductive- and immunotoxicities. Considering the importance of immune development in early life, the present study investigated the effects of perinatal DON exposure on allergy development and vaccine responsiveness in the offspring. Pregnant mice received control or DON-contaminated diets (12.5 mg/kg diet) during pregnancy and lactation. After weaning, female offspring were sensitized to ovalbumin (OVA) by oral administration of OVA with cholera toxin (CT). Male offspring were injected with Influvac vaccine. OVA-specific acute allergic skin response (ASR) in females and vaccine-specific delayed-type hypersensitivity (DTH) in males were measured upon intradermal antigen challenge. Immune cell populations in spleen and antigen-specific plasma immunoglobulins were analyzed. In female CT+OVA-sensitized offspring of DON-exposed mothers ASR and OVA-specific plasma immunoglobulins were significantly higher, compared to the female offspring of control mothers. In vaccinated male offspring of DON-exposed mothers DTH and vaccine-specific antibody levels were significantly lower, compared to the male offspring of control mothers. In both models a significant reduction in regulatory T cells, Tbet + Th1 cells and Th1-related cytokine production of the offspring of DON-exposed mothers was observed. In conclusion, early life dietary exposure to DON can adversely influence immune development in the offspring. Consequently, the immune system of the offspring may be skewed towards an imbalanced state, resulting in an increased allergic immune response to food allergens and a decreased immune response to vaccination against influenza virus in these models.
Deoxynivalenol, T-2 toxin, and zearalenone, major Fusarium mycotoxins, contaminate human food on a global level. Exposure to these mycotoxins during pregnancy can lead to abnormalities in neonatal development. Therefore, the aim of this study was to investigate the effects of Fusarium mycotoxins on human placental epithelial cells. As an in vitro model of placental barrier, BeWo cells were exposed to different concentrations of deoxynivalenol, zearalenone or T-2 toxin. Cytotoxicity, effects on barrier integrity, paracellular permeability along with mRNA and protein expression and localization of junctional proteins after exposure were evaluated. Induction of proinflammatory responses was determined by measuring cytokine production. Increasing mycotoxin concentrations affect BeWo cell viability, and T-2 toxin was more toxic compared to other mycotoxins. Deoxynivalenol and T-2 toxin caused significant barrier disruption, altered protein and mRNA expression of junctional proteins, and induced irregular cellular distribution. Although the effects of zearalenone on barrier integrity were less prominent, all tested mycotoxins were able to induce inflammation as measured by IL-6 release. Overall, Fusarium mycotoxins disrupt the barrier of BeWo cells by altering the expression and structure of junctional proteins and trigger proinflammatory responses. These changes in placental barrier may disturb the maternal-fetal interaction and adversely affect fetal development.
Deoxynivalenol (DON), a highly prevalent mycotoxin food contaminant, is known to have immunotoxic effects. In the current study, the potential of dietary interventions with specific mixtures of trans-galactosyl-oligosaccharides (TOS) to alleviate these effects were assessed in a murine influenza vaccination model. Vaccine-specific immune responses were measured in C57Bl/6JOlaHsd mice fed diets containing DON, TOS or a combination, starting 2 weeks before the first vaccination. The direct effects of TOS and its main oligosaccharide, 3′-galactosyl-lactose (3′-GL), on DON-induced damage were studied in Caco-2 cells, as an in vitro model of the intestinal epithelial barrier. Exposure to DON significantly reduced vaccine-specific immune responses and the percentages of Tbet+ Th1 cells and B cells in the spleen. DON significantly altered epithelial structure and integrity in the ileum and reduced the SCFA levels in the cecum. Adding TOS into DON-containing diets significantly improved vaccine-specific immune responses, restored the immune cell balance in the spleen and increased SCFA concentrations in the cecum. Incubating Caco-2 cells with TOS and 3′-GL in vitro further confirmed their protective effects against DON-induced barrier disruption, supporting immune modulation. Overall, dietary intervention with TOS can attenuate the adverse effects of DON on Th1-mediated immune responses and gut homeostasis. These beneficial properties might be linked to the high levels of 3′-GL in TOS.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
