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Abstract: Benecial eects exerted by probiotic bacteria in the treatment of human disease may be broadly classied as those eects which arise due to activity in the large intestine and are related to colonization or inhibition of pathogen growth; and those eects which arise in both the small and large intestine, and are related to enhancement of the host immune response and intestinal barrier function. In a strain dependent fashion, probiotic bacteria can enhance intestinal barrier function and modulate signal transduction pathways and gene expression in epithelial and immune cells. Oral administration of live probiotics and bacterial structural components can also dierentially modulate dendritic cells resulting in an increased production of IL-10 and regulatory T cells. Both innate and adaptive immune responses can be modulated by probiotic bacteria. Key words: Lactobacillus, Bidobacteria, epithelium, dendritic cells, Treg cells (J Clin Gastroenterol 2006;40:232234)
robiotic bacteria interact with and inuence all cells within the gut. Mechanisms of probiotic actions include eects on luminal microbial ecology,1 modulation of immune function,2,3 and enhancement of epithelial barrier function.4,5 Probiotic bacteria exhibit host-specic and strain-specic dierences in their actions, and also in their resistance to acid and bile, ability to colonize the gastrointestinal tract, and clinical ecacy. Furthermore, the activity of individual strains of bacteria may be enhanced, or alternatively, eliminated, by the presence of other strains in vivo. Also, eects of probiotic bacteria in vitro may not always translate into similar in vivo behavior.6
adaptive immune function. Probiotic bacteria can interact with epithelial cells and alter cytokine production through modulation of cellular signal transduction pathways.79 Epithelial cells recognize and respond to whole bacteria and bacterial components in a dierential manner, releasing proinammatory cytokines such as interleukin (IL)-8 in response to pathogenic bacteria, although showing no response to probiotic strains.10 Certain probiotic strains can elicit anti-inammatory responses and/or inhibit the nuclear factor-kB pathway in epithelial cells through various mechanisms, including blocking inhibitor kB degradation by inhibiting ubiquination11; by inhibiting proteasome function12; and by regulating nuclear-cytoplasmic movement of RelA through a peroxisome proliferator activated receptorgamma dependent pathway.13 The probiotic Lactobacillus rhamnosus GG can prevent cytokine-induced apoptosis in colon cells by activation of the antiapoptotic Akt and protein kinase B, and inactivation of the propaptoptic p38 mitogen-activated protein kinase signalling pathway.14 Two secreted proteins elicited the same activity as did the live bacteria.14 However, anti-inammatory eects of probiotics are not limited to live bacteria or secreted protein products. Bacterial DNA is also recognized in a dierential manner by epithelial cells; with pathogenic strains evoking a phosphorylation of the extracellular signal-regulated kinase pathway and activation of activator protein-1,15 and probiotic strains modulating the nuclear factor-kB pathway.12 Probiotic bacteria DNA can also suppress systemic inammatory responses to pathogenic bacterial DNA.12 Studies to date have shown a requirement for Toll-like receptor 9 (TLR9) for cellular recognition and response to bacterial DNA.16 Intestinal epithelial cells express several antigenpresenting molecules and costimulatory molecules and play a role in the activation and expansion of both CD4+and CD8+ regulatory T-cell (Treg) subsets.17 Proteasomes have a key role in the degradation of endogenous and exogenous proteins for antigen presentation by both major histocompatability complex class 1 and 2 molecules.17 Probiotic bacteria modulate epithelial cell proteasomal activity,12,18 thus providing a potential mechanism for probiotic-induced alterations in epithelialdriven T-cell activation in the gut. Probiotics can modulate epithelial barrier function,4 possibly through interactions with TLR2.19 TLR2 recognizes bacterial lipoproteins, lipoteichoic acid, and zymosan. Studies have shown that the synthetic bacterial lipopeptide PamcCysSK4, a peptidoglycan, can induce
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activation of protein kinase C and a tightening and sealing of tight junction associated zonula-occludins-1 (ZO-1).20
homeostasis within the gut lumen. Further, both innate and adaptive immune responses can be modulated by probiotic bacteria in a strain-dependent and dosedependent fashion through interactions with mucosal DC and intestinal epithelial cells.
REFERENCES
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CONCLUSIONS
The commensal bacteria in the gastrointestinal tract are the primary stimulus for the intestinal mucosal immune system and are necessary for normal immune development. Interactions between microbial species and dendritic and epithelial cells are key to the maintenance of
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