D25+ regulatory T cells reverses the beneficial effects of scGOS/lcFOS/pAOS treatment on atopic dermatitis in mice [107]. Both of these direct and indirect mechanisms are likely involved in the action of milk oligosaccharides on suppressing excessive immune responses. Though there are few human trials for the use of prebiotics to prevent allergic diseases other than atopic dermatitis, support can be found from animal studies. In an ovalbumin (OVA)-induced mouse model for allergic asthma, scGOS/lcFOS reduces symptoms including bronchial inflammation, skin lesions and lung resistance, probably through a reduction in IgE and increased OVA-specific IgG and regulatory T cells in serum [108,109]. Unfortunately a small proportion (0 ?.5 ) of the population is allergic to GOS, though this is dependent on the particular formulation [110]. More research will be needed to take these promising results into clinical testing and select a prebiotic with the least allergic properties, particularly in children at risk for developing allergic asthma. While there is a clear link between inflammation and allergic diseases, long-term inflammation more subtly contributes to a number of chronic problems such as cancer, cardiovascular, and lungNutrients 2016, 8,9 ofdiseases. There is, therefore, a growing interest in modulating immune responses to decrease long-term inflammation. Elderly people, who are generally most affected by the comorbidities of chronic inflammation, also commonly experience gut dysbiosis with a decreased proportion of bifidobacteria [111]. A number of studies have shown that prebiotics can benefit the elderly by improving their gut microbiota and immune function, ultimately reducing inflammation. An 8 g daily oligofructose/inulin mixture given for three weeks to the elderly reduced expression of pro-inflammatory IL-6 by peripheral blood mononuclear cells (PBMCs) and improved T cell counts [112]. Others have observed that B-GOS (5.5 g daily for 10 weeks) lowers circulating levels of inflammatory cytokines such as IL-6, IL-1, and TNF-, and raises immunomodulatory IL-10 [113,114]. Furthermore, B-GOS stimulates natural killer T cells, potentially improving antiviral activity [113]. Distant effects of prebiotics on the immune system are likely mediated by fermentation products of gut bacteria that pass through enterocytes to tissue and circulating immune cells, or in rare cases, direct binding of prebiotics to immune cells. As an example, SCFAs, especially butyrate, derived from microbial degradation of inulin, hi-maize and -glucan can reduce production of IFN-, IL-12, TNF-, and TGF-1, and elevate IL-4 and IL-10 release from lipopolysaccharide-stimulated PBMCs [115]. It has been postulated that IL-10 acts as an overarching mediator of anti-inflammatory effects on a range of cytokines. This is not the complete story for all prebiotics, since AUY922 site soluble dextrins can reduce proinflammatory cytokines even in the absence of IL-10 [116], however in most cases, IL-10 is elevated following prebiotic administration. Alternatively, some indigestible carbohydrates may actually PG-1016548 cost permeate through the colonic barrier and act on immune cells by binding sugar-specific receptors. The well-characterized dectin-1, a monocyte and macrophage receptor protein, has particular affinity for -glucan prebiotics [117,118]. Binding of -glucan activates this receptor to adhere to pathogenic Candida albicans and induce phagocytosis, thereby improving antimicrobial properties i.D25+ regulatory T cells reverses the beneficial effects of scGOS/lcFOS/pAOS treatment on atopic dermatitis in mice [107]. Both of these direct and indirect mechanisms are likely involved in the action of milk oligosaccharides on suppressing excessive immune responses. Though there are few human trials for the use of prebiotics to prevent allergic diseases other than atopic dermatitis, support can be found from animal studies. In an ovalbumin (OVA)-induced mouse model for allergic asthma, scGOS/lcFOS reduces symptoms including bronchial inflammation, skin lesions and lung resistance, probably through a reduction in IgE and increased OVA-specific IgG and regulatory T cells in serum [108,109]. Unfortunately a small proportion (0 ?.5 ) of the population is allergic to GOS, though this is dependent on the particular formulation [110]. More research will be needed to take these promising results into clinical testing and select a prebiotic with the least allergic properties, particularly in children at risk for developing allergic asthma. While there is a clear link between inflammation and allergic diseases, long-term inflammation more subtly contributes to a number of chronic problems such as cancer, cardiovascular, and lungNutrients 2016, 8,9 ofdiseases. There is, therefore, a growing interest in modulating immune responses to decrease long-term inflammation. Elderly people, who are generally most affected by the comorbidities of chronic inflammation, also commonly experience gut dysbiosis with a decreased proportion of bifidobacteria [111]. A number of studies have shown that prebiotics can benefit the elderly by improving their gut microbiota and immune function, ultimately reducing inflammation. An 8 g daily oligofructose/inulin mixture given for three weeks to the elderly reduced expression of pro-inflammatory IL-6 by peripheral blood mononuclear cells (PBMCs) and improved T cell counts [112]. Others have observed that B-GOS (5.5 g daily for 10 weeks) lowers circulating levels of inflammatory cytokines such as IL-6, IL-1, and TNF-, and raises immunomodulatory IL-10 [113,114]. Furthermore, B-GOS stimulates natural killer T cells, potentially improving antiviral activity [113]. Distant effects of prebiotics on the immune system are likely mediated by fermentation products of gut bacteria that pass through enterocytes to tissue and circulating immune cells, or in rare cases, direct binding of prebiotics to immune cells. As an example, SCFAs, especially butyrate, derived from microbial degradation of inulin, hi-maize and -glucan can reduce production of IFN-, IL-12, TNF-, and TGF-1, and elevate IL-4 and IL-10 release from lipopolysaccharide-stimulated PBMCs [115]. It has been postulated that IL-10 acts as an overarching mediator of anti-inflammatory effects on a range of cytokines. This is not the complete story for all prebiotics, since soluble dextrins can reduce proinflammatory cytokines even in the absence of IL-10 [116], however in most cases, IL-10 is elevated following prebiotic administration. Alternatively, some indigestible carbohydrates may actually permeate through the colonic barrier and act on immune cells by binding sugar-specific receptors. The well-characterized dectin-1, a monocyte and macrophage receptor protein, has particular affinity for -glucan prebiotics [117,118]. Binding of -glucan activates this receptor to adhere to pathogenic Candida albicans and induce phagocytosis, thereby improving antimicrobial properties i.