Prebiotics, Probiotics, Synbiotics, and the Immune System
Prebiotics, Probiotics, Synbiotics, and the Immune System
The innate immune system is comprised of many different cell types, and these cells are often the first cells to come in contact with intestinal microbes and their metabolic products. The most commonly described cell types in the probiotics and prebiotics literature are dendritic cells and epithelial cells.
Intestinal dendritic cells are located within specific intestinal lymphoid tissues, collectively termed gut-associated lymphoid tissues (GALT), or diffusely distributed throughout the intestinal lamina propria. Dendritic cells are the primary cell type involved as 'sensors' of microbial ligands through activation of innate immune receptors (e.g. Toll-like receptors and c-type lectin receptors). The signaling pathways triggered by bacterial-derived molecules allow for changes in dendritic cell phenotypes and cytokine secretion, which underlie the integration of microbial and host metabolism with immune functions. Metabolism of vitamin A to retinoic acid is a key immunomodulatory activity associated with intestinal dendritic cells. Certain, but not all, probiotic microbes can induce retinoic acid metabolism by human dendritic cells in vitro and by murine CD103 dendritic cells within the small intestine lamina propria. In addition to vitamin A metabolism, induction of another dendritic cell metabolic enzyme, heme oxygenase-1 (HO-1), was shown to be required for the induction of mucosal T regulatory (TREG) cells within the mesenteric lymph nodes by Lactobacillus rhamnosus.
Bacterial cell wall components and metabolites have been associated with the immunoregulatory effects on dendritic cells. For example, major histocompatibility complex (MHC)-II-dependent presentation of segmented filamentous bacteria antigens by intestinal CD11c dendritic cells is crucial for the local induction of TH17 lymphocytes. In addition, capsular polysaccharide A (PSA) from Bacteroides fragilis has been shown to interact directly with mouse plasmacytoid dendritic cells via TLR-2. PSA-exposed plasmacytoid dendritic cells express molecules involved in protection against colitis and stimulated CD4 cells to secrete IL-10. An exopolysaccharide from Bacillus subtilis prevents gut inflammation stimulated by Citrobacter rodentium, which is dependent on TLR-4 and MyD88 signaling.
The production of SCFAs occurs in the colon following fermentation of dietary fibers, such as prebiotics. Abnormalities in the production of these metabolites (because of dietary factors and dysbiosis) might play a role in the pathogenesis of type 2 diabetes, obesity, inflammatory bowel disease, colorectal cancer, and allergies. Among the SCFAs, butyrate seems to be more potent than acetate or propionate in inducing immunomodulatory effects. Butyrate influences the activity of histone deacetylases (HDAC), which is responsible for decreasing dendritic cell IL-12 and IL-6 cytokine secretion and allows dendritic cells to promote TREG cells. Propionate can also contribute to the induction of Foxp3 expression by dendritic cells, whereas acetate does not have this activity possibly because of the lack of HDAC activity. Butyrate also inhibits intestinal macrophage HDAC. Another recent study has confirmed and extended the observation that butyrate promotes dendritic cell regulatory activity, resulting in the induction of TREG cells and IL-10-secreting T cells. These effects were mediated by the G-protein-coupled receptor Gpr109a on colonic dendritic cells and macrophages. In contrast, butyrate has also been shown to promote IL-23 secretion by murine dendritic cells, which may promote TH17 responses under certain circumstances.
Histamine is another important mucosal metabolite secreted by the gut microbes, and mucosal histamine levels are increased in patients with irritable bowel syndrome and inflammatory bowel disease. Histamine is able to decrease chemokine and proinflammatory cytokine secretion induced by the Toll-like-receptor-stimulated dendritic cells, while increasing IL-10 production. Histamine exerted this effect by activating the histamine 2 receptor (H2R) on dendritic cells and the signaling mechanism required cyclic adenosine monophosphate (cAMP) and exchange protein directly activated by cAMP (EPAC). Administration of a histamine-secreting Lactobacillus strain to mice resulted in rapid weight loss and enhanced Peyer's patch cytokine secretion, which was exaggerated in H2R-deficient animals.
Epithelial cells play an essential role in nutrient absorption. Pathogen-induced reductions in epithelial cell digestive enzyme activity can be blocked by Bifidobacterium infantis 35624, possibly via modulation of mucosal inflammatory responses. In addition to their absorptive function, epithelial cells form a mucosal barrier that protects host tissue from damaging agents such as luminal pathogens and toxic products. One protective barrier mechanism is the production and secretion of antimicrobial peptides, such as defensins and cathelicidins. Probiotic strains have been shown to differentially regulate defensin expression and protein secretion, which is influenced by local inflammatory mediators. Autophagy is an important adaptive response to stress, which promotes cell survival and is required for the maintenance of the epithelial barrier. A number of Bifidobacteria have been recently described that promote autophagy in an intestinal cell line. The mucus layer coating the gastrointestinal tract is an important barrier component and probiotics have been shown to promote mucin production by goblet cells in the intestine. Recently, p40 from Lactobacillus GG was demonstrated to be sufficient for the stimulation of mucin production through transactivation of the epidermal growth factor receptor. Excessive epithelial cell responses to microbial ligands result in local inflammatory responses, which disrupt the epithelial barrier. A wide range of probiotic microbes have been demonstrated to suppress epithelial cell proinflammatory chemokine responses. However, not all chemokine responses are impacted to the same extent by every probiotic strain and a single probiotic strain may reduce the expression of certain chemokines, while increasing the expression of others. For example, Bifidobacterium bifidum PRL2010 suppresses CCL22 expression but enhances CCL19 expression, suggesting that strain-specific and chemokine-specific responses are induced by probiotics. In addition, prebiotics themselves, or SCFAs, can also modulate epithelial barrier function, production of antimicrobial peptides, and secretion of proinflammatory mediators.
Innate Immune System
The innate immune system is comprised of many different cell types, and these cells are often the first cells to come in contact with intestinal microbes and their metabolic products. The most commonly described cell types in the probiotics and prebiotics literature are dendritic cells and epithelial cells.
Dendritic Cells
Intestinal dendritic cells are located within specific intestinal lymphoid tissues, collectively termed gut-associated lymphoid tissues (GALT), or diffusely distributed throughout the intestinal lamina propria. Dendritic cells are the primary cell type involved as 'sensors' of microbial ligands through activation of innate immune receptors (e.g. Toll-like receptors and c-type lectin receptors). The signaling pathways triggered by bacterial-derived molecules allow for changes in dendritic cell phenotypes and cytokine secretion, which underlie the integration of microbial and host metabolism with immune functions. Metabolism of vitamin A to retinoic acid is a key immunomodulatory activity associated with intestinal dendritic cells. Certain, but not all, probiotic microbes can induce retinoic acid metabolism by human dendritic cells in vitro and by murine CD103 dendritic cells within the small intestine lamina propria. In addition to vitamin A metabolism, induction of another dendritic cell metabolic enzyme, heme oxygenase-1 (HO-1), was shown to be required for the induction of mucosal T regulatory (TREG) cells within the mesenteric lymph nodes by Lactobacillus rhamnosus.
Bacterial cell wall components and metabolites have been associated with the immunoregulatory effects on dendritic cells. For example, major histocompatibility complex (MHC)-II-dependent presentation of segmented filamentous bacteria antigens by intestinal CD11c dendritic cells is crucial for the local induction of TH17 lymphocytes. In addition, capsular polysaccharide A (PSA) from Bacteroides fragilis has been shown to interact directly with mouse plasmacytoid dendritic cells via TLR-2. PSA-exposed plasmacytoid dendritic cells express molecules involved in protection against colitis and stimulated CD4 cells to secrete IL-10. An exopolysaccharide from Bacillus subtilis prevents gut inflammation stimulated by Citrobacter rodentium, which is dependent on TLR-4 and MyD88 signaling.
The production of SCFAs occurs in the colon following fermentation of dietary fibers, such as prebiotics. Abnormalities in the production of these metabolites (because of dietary factors and dysbiosis) might play a role in the pathogenesis of type 2 diabetes, obesity, inflammatory bowel disease, colorectal cancer, and allergies. Among the SCFAs, butyrate seems to be more potent than acetate or propionate in inducing immunomodulatory effects. Butyrate influences the activity of histone deacetylases (HDAC), which is responsible for decreasing dendritic cell IL-12 and IL-6 cytokine secretion and allows dendritic cells to promote TREG cells. Propionate can also contribute to the induction of Foxp3 expression by dendritic cells, whereas acetate does not have this activity possibly because of the lack of HDAC activity. Butyrate also inhibits intestinal macrophage HDAC. Another recent study has confirmed and extended the observation that butyrate promotes dendritic cell regulatory activity, resulting in the induction of TREG cells and IL-10-secreting T cells. These effects were mediated by the G-protein-coupled receptor Gpr109a on colonic dendritic cells and macrophages. In contrast, butyrate has also been shown to promote IL-23 secretion by murine dendritic cells, which may promote TH17 responses under certain circumstances.
Histamine is another important mucosal metabolite secreted by the gut microbes, and mucosal histamine levels are increased in patients with irritable bowel syndrome and inflammatory bowel disease. Histamine is able to decrease chemokine and proinflammatory cytokine secretion induced by the Toll-like-receptor-stimulated dendritic cells, while increasing IL-10 production. Histamine exerted this effect by activating the histamine 2 receptor (H2R) on dendritic cells and the signaling mechanism required cyclic adenosine monophosphate (cAMP) and exchange protein directly activated by cAMP (EPAC). Administration of a histamine-secreting Lactobacillus strain to mice resulted in rapid weight loss and enhanced Peyer's patch cytokine secretion, which was exaggerated in H2R-deficient animals.
Epithelial Cells
Epithelial cells play an essential role in nutrient absorption. Pathogen-induced reductions in epithelial cell digestive enzyme activity can be blocked by Bifidobacterium infantis 35624, possibly via modulation of mucosal inflammatory responses. In addition to their absorptive function, epithelial cells form a mucosal barrier that protects host tissue from damaging agents such as luminal pathogens and toxic products. One protective barrier mechanism is the production and secretion of antimicrobial peptides, such as defensins and cathelicidins. Probiotic strains have been shown to differentially regulate defensin expression and protein secretion, which is influenced by local inflammatory mediators. Autophagy is an important adaptive response to stress, which promotes cell survival and is required for the maintenance of the epithelial barrier. A number of Bifidobacteria have been recently described that promote autophagy in an intestinal cell line. The mucus layer coating the gastrointestinal tract is an important barrier component and probiotics have been shown to promote mucin production by goblet cells in the intestine. Recently, p40 from Lactobacillus GG was demonstrated to be sufficient for the stimulation of mucin production through transactivation of the epidermal growth factor receptor. Excessive epithelial cell responses to microbial ligands result in local inflammatory responses, which disrupt the epithelial barrier. A wide range of probiotic microbes have been demonstrated to suppress epithelial cell proinflammatory chemokine responses. However, not all chemokine responses are impacted to the same extent by every probiotic strain and a single probiotic strain may reduce the expression of certain chemokines, while increasing the expression of others. For example, Bifidobacterium bifidum PRL2010 suppresses CCL22 expression but enhances CCL19 expression, suggesting that strain-specific and chemokine-specific responses are induced by probiotics. In addition, prebiotics themselves, or SCFAs, can also modulate epithelial barrier function, production of antimicrobial peptides, and secretion of proinflammatory mediators.