Nutritional Interventions to Prevent the Development of Atopic Diseases: A Focus on Cow's Milk Allergy.

In the western world the prevalence of atopic diseases such as food allergies is increasing highly significantly. One of the earliest and most prevalent food allergies occurring in the first year of life is cow's milk allergy. No treatment is available and only avoidance of the cow's milk allergens prevents the occurrence of an allergic reaction. Since cow's milk allergic children have an increased risk of developing other allergies later in life, investigating nutritional strategies to prevent the development of cow's milk allergy by developing oral tolerance is of high interest. Nutritional components such as prebiotics, probiotics, synbiotics and long-chain polyunsaturated fatty acids possess potential to support the maturation of the immune system early in life that might prevent the development of cow's milk allergy. The available research, so far, shows promising results particularly on the development of eczema. However, the preventive effects of the nutritional interventions on the development of food allergy are inconclusive. Future research may benefit from the combination of various dietary components. To clarify the preventive effects of the nutritional components in food allergy more randomized clinical trials are needed.

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

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

Supplementation of dietary non-digestible oligosaccharides from birth onwards improve social and reduce anxiety-like behaviour in male BALB/c mice.

Objective: The intestinal microbiota is acknowledged to be essential in brain development and behaviour. Their composition can be modulated by prebiotics such as short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharide (lcFOS). Several studies reported potential health benefit of prebiotics on behaviour. As the prebiotic mixture of scGOS and lcFOS is included in infant formula, we investigated the effects of dietary supplementation with this specific mixture from the day of birth onwards on behaviour and intestinal microbiota development in mice. Method: Healthy male BALB/cByJ mice received, from day of birth, a dietary supplement with or without 3% scGOS:lcFOS (9:1). Behavioural tests were performed pre-weaning, in adolescence, early adulthood and adulthood. We assessed faecal microbiota compositions over time, caecal short-chain fatty acids as well as brain mRNA expression of Htr1a, Htr1b and Tph2 and monoamine levels. Results: Compared to control fed mice, scGOS:lcFOS fed mice showed reduced anxiety-like and repetitive behaviour over time and improved social behaviour in adulthood. The serotonergic system in the prefrontal cortex (PFC) and somatosensory cortex (SSC) was affected by the scGOS:lcFOS. In the PFC, mRNA expression of brain-derived neurotrophic factor (Bdnf) was enhanced in scGOS:lcFOS fed mice. Although the bacterial diversity of the intestinal microbiota was unaffected by the scGOS:lcFOS diet, microbiota composition differed between the scGOS:lcFOS and the control fed mice over time. Moreover, an increased saccharolytic and decreased proteolytic fermentation activity were observed in caecum content. Discussion: Supplementing the diet with scGOS:lcFOS from the day of birth is associated with reduced anxiety-like and improved social behaviour during the developmental period and later in life, and modulates the composition and activity of the intestinal microbiota in healthy male BALB/c mice. These data provide further evidence of the potential impact of scGOS:lcFOS on behaviour at several developmental stages throughout life and strengthen the insights in the interplay between the developing intestine and brain.

Superior Cervical Ganglia Neurons Induce Foxp3+ Regulatory T Cells via Calcitonin Gene-Related Peptide.

The nervous and immune systems communicate bidirectionally, utilizing diverse molecular signals including cytokines and neurotransmitters to provide an integrated response to changes in the body's internal and external environment. Although, neuro-immune interactions are becoming better understood under inflammatory circumstances and it has been evidenced that interaction between neurons and T cells results in the conversion of encephalitogenic T cells to T regulatory cells, relatively little is known about the communication between neurons and naïve T cells. Here, we demonstrate that following co-culture of naïve CD4+ T cells with superior cervical ganglion neurons, the percentage of Foxp3 expressing CD4+CD25+ cells significantly increased. This was mediated in part by immune-regulatory cytokines TGF-ß and IL-10, as well as the neuropeptide calcitonin gene-related peptide while vasoactive intestinal peptide was shown to play no role in generation of T regulatory cells. Additionally, T cells co-cultured with neurons showed a decrease in the levels of pro-inflammatory cytokine IFN-γ released upon in vitro stimulation. These findings suggest that the generation of Tregs may be promoted by naïve CD4+ T cell: neuron interaction through the release of neuropeptide CGRP.

Alterations in regulatory T cells induced by specific oligosaccharides improve vaccine responsiveness in mice.

UNLABELLED: Prophylactic vaccinations are generally performed to protect naïve individuals with or without suppressed immune responsiveness. In a mouse model for Influenza vaccinations the specific alterations of CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) in the immune modulation induced by orally supplied oligosaccharides containing scGOS/lcFOS/pAOS was assessed. This dietary intervention increased vaccine specific DTH responses. In addition, a significant increased percentage of T-bet(+) (Th1) activated CD69(+)CD4(+) T cells (p<0.001) and reduced percentage of Gata-3(+) (Th2) activated CD69(+)CD4(+)T cells (p<0.001) was detected in the mesenteric lymph nodes (MLN) of mice receiving scGOS/lcFOS/pAOS compared to control mice. Although no difference in the number or percentage of Tregs (CD4(+)Foxp3(+)) could be determined after scGOS/lcFOS/pAOS intervention, the percentage of CXCR3 (+) /T-bet(+) (Th1-Tregs) was significantly reduced (p<0.05) in mice receiving scGOS/lcFOS/pAOS as compared to mice receiving placebo diets. Moreover, although no absolute difference in suppressive capacity could be detected, an alteration in cytokine profile suggests a regulatory T cell shift towards a reducing Th1 suppression profile, supporting an improved vaccination response. IN CONCLUSION: These data are indicative for improved vaccine responsiveness due to reduced Th1 suppressive capacity in the Treg population of mice fed the oligosaccharide specific diet, showing compartmentalization within the Treg population. The modulation of Tregs to control immune responses provides an additional arm of intervention using alternative strategies possibly leading to the development of improved vaccines.