Prebiotics, Probiotics, Synbiotics, and the Immune System
Prebiotics, Probiotics, Synbiotics, and the Immune System
The adaptive immune system receives polarizing signals from the innate cells to expand an appropriately controlled lymphocyte response to bacterial and metabolic factors. Recent evidence has suggested a role for probiotic and prebiotic effects on TREG cells, effector T cells, natural killer T (NKT) cells, and B cells.
The beneficial effect of prebiotics, probiotics, and synbiotics against diseases such as allergy or colitis is often associated with enhancement of TREG cells. Specific probiotics, but not all, have been shown to induce an increase in TREG cells. Notably, consumption of B. infantis 35624 by healthy human volunteers resulted in an increased proportion of Foxp3 lymphocytes in peripheral blood, whereas administration of this probiotic to psoriasis patients, chronic fatigue syndrome patients, or ulcerative colitis patients consistently resulted in reduced levels of serum proinflammatory biomarkers such as C-reactive protein, possibly mediated by increased numbers of TREG cells.
In addition to probiotics, effects on lymphocytes can also be mediated by SCFAs such as acetate, propionate, butyrate, and n-butyrate. Oral administration of a mixture of 17 Clostridia strains to mice attenuated the severity of colitis and allergic diarrhea in a TREG–TGF-[beta]-dependent mechanism. This process is most likely because of SCFAs produced by the Clostridia strains. G-protein-coupled receptor (GPCR) 43 has been described as receptor for SCFAs. GPR43 signaling ameliorates diseases such as colitis, inflammatory arthritis, and allergic airway diseases. In addition to the expression on neutrophils and eosinophils, GPCR43 is expressed on colonic inducible TREG cells and promotes their expansion and IL-10 secretion.
As already described above for dendritic cells, SCFAs inhibit HDAC activity also in lymphocytes enhancing histone H3 acetylation in the promoter and conserved noncoding sequence regions of the Foxp3 locus.
Probiotic and commensal bacteria have been shown to suppress TH17 responses through both direct and indirect mechanisms. TH17 cells secrete IL-17 that induces tissue inflammation. Probiotic strains inhibit TH17 and IL-17 activity by inducing TREG and TH1 subsets, by induction of IL-27 production, which suppress the generation of IL-17 and induce IL-10 or by stimulation of TLR9 on TH17 cells.
NKT cells are central mediators of intestinal inflammation and pathogenic NKT cell activation is mediated by CD1d bone-marrow-derived cells, whereas CD1d epithelial cells protect against intestinal inflammation. It has been shown that NKT cells can be influenced by the gut microflora and certain probiotic lipid antigens may directly activate NKT cells. Recently, a healthy human volunteer study showed that the combination of xylo-oligosaccharide with Bifidobacterium animalis reduced CD16/CD56 expression on NKT cells and reduced IL-10 secretion from peripheral blood mononuclear cells in response to lipopolysaccharide. The functional consequences of altered NKT cell activation by the microbiome in humans remain to be determined.
B lymphocytes have an essential role in humoral immune responses via their secretion of antigen-specific antibodies. In addition, B cells can limit aggressive immune reactivity. B cells regulate immune responses mainly via IL-10, which has been shown in the experimental models of infection, allergic inflammation, and tolerance.
B-cell-dependent modulation of the microbiome was shown in IgA-deficient mice. IgA-deficient mice had persistent intestinal colonization with [gamma]-Proteobacteria that cause sustained intestinal inflammation and increased susceptibility to neonatal and adult models of intestinal injury. The group also identified an IgA-dependent mechanism responsible for the maturation of the intestinal microbiota in mice. Recently, another group showed that the number of gut-homing IgG and IgA B cells was significantly higher in infants compared with adults. This suggests that activation of naïve B cells in the gut overlaps with the establishment of the gut microbiota in humans. Oral administration of Lactobacillus gasseri SBT2055 (LG2055) induced IgA production and increased the number of IgA cells in Peyer's patches and in the lamina propria. Combined stimulation of B cells with B-cell activating factor and LG2055 enhanced the induction of IgA production. IgA plays an important role in host defense against mucosally transmitted pathogens, prevents commensal bacteria from binding to epithelial cells, and neutralizes their toxins to maintain homeostasis at the mucosal surfaces.
It was recently shown that the gut microbiota induces dendritic cells and macrophages to produce IL-1[beta] and IL-6, which both drive TH17 differentiation and arthritis. The same signals also induced the differentiation of IL-10-producing B regulatory cells. These data suggest that the commensal microbiota is important for inducing both proinflammatory and regulatory responses in order to rapidly clear infections and minimize the inflammation-associated tissue damage. Interestingly, supplementation with xylo-oligosaccharide and B. animalis in a human study led to reduced expression of CD19 on B cells.
Adaptive Immune System
The adaptive immune system receives polarizing signals from the innate cells to expand an appropriately controlled lymphocyte response to bacterial and metabolic factors. Recent evidence has suggested a role for probiotic and prebiotic effects on TREG cells, effector T cells, natural killer T (NKT) cells, and B cells.
T Lymphocytes
The beneficial effect of prebiotics, probiotics, and synbiotics against diseases such as allergy or colitis is often associated with enhancement of TREG cells. Specific probiotics, but not all, have been shown to induce an increase in TREG cells. Notably, consumption of B. infantis 35624 by healthy human volunteers resulted in an increased proportion of Foxp3 lymphocytes in peripheral blood, whereas administration of this probiotic to psoriasis patients, chronic fatigue syndrome patients, or ulcerative colitis patients consistently resulted in reduced levels of serum proinflammatory biomarkers such as C-reactive protein, possibly mediated by increased numbers of TREG cells.
In addition to probiotics, effects on lymphocytes can also be mediated by SCFAs such as acetate, propionate, butyrate, and n-butyrate. Oral administration of a mixture of 17 Clostridia strains to mice attenuated the severity of colitis and allergic diarrhea in a TREG–TGF-[beta]-dependent mechanism. This process is most likely because of SCFAs produced by the Clostridia strains. G-protein-coupled receptor (GPCR) 43 has been described as receptor for SCFAs. GPR43 signaling ameliorates diseases such as colitis, inflammatory arthritis, and allergic airway diseases. In addition to the expression on neutrophils and eosinophils, GPCR43 is expressed on colonic inducible TREG cells and promotes their expansion and IL-10 secretion.
As already described above for dendritic cells, SCFAs inhibit HDAC activity also in lymphocytes enhancing histone H3 acetylation in the promoter and conserved noncoding sequence regions of the Foxp3 locus.
Probiotic and commensal bacteria have been shown to suppress TH17 responses through both direct and indirect mechanisms. TH17 cells secrete IL-17 that induces tissue inflammation. Probiotic strains inhibit TH17 and IL-17 activity by inducing TREG and TH1 subsets, by induction of IL-27 production, which suppress the generation of IL-17 and induce IL-10 or by stimulation of TLR9 on TH17 cells.
Natural Killer T Cells
NKT cells are central mediators of intestinal inflammation and pathogenic NKT cell activation is mediated by CD1d bone-marrow-derived cells, whereas CD1d epithelial cells protect against intestinal inflammation. It has been shown that NKT cells can be influenced by the gut microflora and certain probiotic lipid antigens may directly activate NKT cells. Recently, a healthy human volunteer study showed that the combination of xylo-oligosaccharide with Bifidobacterium animalis reduced CD16/CD56 expression on NKT cells and reduced IL-10 secretion from peripheral blood mononuclear cells in response to lipopolysaccharide. The functional consequences of altered NKT cell activation by the microbiome in humans remain to be determined.
B cells
B lymphocytes have an essential role in humoral immune responses via their secretion of antigen-specific antibodies. In addition, B cells can limit aggressive immune reactivity. B cells regulate immune responses mainly via IL-10, which has been shown in the experimental models of infection, allergic inflammation, and tolerance.
B-cell-dependent modulation of the microbiome was shown in IgA-deficient mice. IgA-deficient mice had persistent intestinal colonization with [gamma]-Proteobacteria that cause sustained intestinal inflammation and increased susceptibility to neonatal and adult models of intestinal injury. The group also identified an IgA-dependent mechanism responsible for the maturation of the intestinal microbiota in mice. Recently, another group showed that the number of gut-homing IgG and IgA B cells was significantly higher in infants compared with adults. This suggests that activation of naïve B cells in the gut overlaps with the establishment of the gut microbiota in humans. Oral administration of Lactobacillus gasseri SBT2055 (LG2055) induced IgA production and increased the number of IgA cells in Peyer's patches and in the lamina propria. Combined stimulation of B cells with B-cell activating factor and LG2055 enhanced the induction of IgA production. IgA plays an important role in host defense against mucosally transmitted pathogens, prevents commensal bacteria from binding to epithelial cells, and neutralizes their toxins to maintain homeostasis at the mucosal surfaces.
It was recently shown that the gut microbiota induces dendritic cells and macrophages to produce IL-1[beta] and IL-6, which both drive TH17 differentiation and arthritis. The same signals also induced the differentiation of IL-10-producing B regulatory cells. These data suggest that the commensal microbiota is important for inducing both proinflammatory and regulatory responses in order to rapidly clear infections and minimize the inflammation-associated tissue damage. Interestingly, supplementation with xylo-oligosaccharide and B. animalis in a human study led to reduced expression of CD19 on B cells.
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