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Expert Rev Clin Immunol. 2010;6(1):47-54. © 2010 Expert Reviews Ltd.
Abstract and Introduction
Abstract
Probiotics have had many applications in the past few years, and inflammatory conditions of the GI tract – including chronic disorders such as inflammatory bowel disease (IBD) – have received the most attention by investigators. In fact, the experimental basis to expect clinical efficacy of probiotics in IBD is quite robust. In spite of this however, only minimal evidence of benefit by any probiotic is currently available in Crohn's disease, either in adult or in pediatric populations. In ulcerative colitis, on the other hand, several probiotic formulations and especially the proprietary preparation VSL#3 (a high-concentration mixture) have been found effective as adjuvant therapy, both in inducing and maintaining remission.
Introduction
The introduction of biological agents has markedly improved our ability to treat patients with the chronic, incurable inflammatory disorders grouped under the name inflammatory bowel disease (IBD); namely Crohn's disease, ulcerative colitis and indeterminate colitis. However, improved clinical efficacy has come at the cost of increased risks, including malignancies.[1,2] Thus, it is not surprising that the use of 'alternative' remedies is very frequent in patients with IBD, and especially in children.[3] In this regard, the possible use of probiotics appears as a natural consideration, especially because the intestinal bacterial flora plays an important role in IBD. Some microorganisms, mostly lactic acid bacteria, show properties that can be beneficial to maintaining or improving health functions, and in some cases can potentially even prevent or treat diseases by modifying the microflora. Such microorganisms are referred to as 'probiotics', defined by the Food and Agriculture Organization of the United Nations–WHO as "live microorganisms which, when consumed in adequate amounts as part of food, confer a health benefit on the host".
While their areas of application have been many, inflammatory conditions of the GI tract – both infectious and noninfectious – understandably have been the focus of active research. On one hand probiotics display features, such as anti-inflammatory action and enhancement of the gut barrier, that seem logically suited to be helpful in IBD; and on the other, there is convincing evidence that the inflammation in IBD results from an altered mucosal immune response to luminal bacterial antigens, thus suggesting that the use of live microorganisms may have a positive impact on shifting the microbial balance of the enteric flora. Support for this hypothesis also comes from a study showing that children with Crohn's disease treated with exclusive and partial polymeric enteral nutrition and experiencing remission with this regimen also showed profound changes in their microflora, as measured by temperature-gradient gel electrophoresis.[4] Such evidence will be briefly examined and the currently available clinical evidence of efficacy of probiotics in pediatric IBD will be reviewed.
Experimental Basis for the Theoretical Use of Probiotics in IBD
Even though the mechanisms of action of probiotics are still largely unknown and a matter of speculation, several lines of laboratory-generated evidence support their protective role in intestinal inflammation.
Probiotics have been shown to be effective against enteric pathogens by several mechanisms. They produce bacteriocins, a diverse group of low-molecular-weight peptides produced mostly by Lactobacilli that possess antimicrobial action against a number of bacteria, especially Gram-positive bacteria (reviewed in [5–7]). Similar substances, active against both Gram-positive and -negative bacteria, are also produced by Bifidobacteria.[8] In addition, Lactobacilli and Bifidobacteria are able to reduce the intracolonic pH by producing organic acids such as butyrate, lactic acid and propionic acid, thus creating an acidic pH milieu that is detrimental to the survival of several enteric pathogens, including Salmonella.[9]
One of the earliest findings in examining the actions of probiotics was their ability to prevent the attachment of pathogens to the enterocytes and to even displace bound pathogens from their binding site. These characteristics were shown to be possessed, to various degrees, by many of the commercially available probiotics.[10]
However, arguably the most important attribute that makes probiotics appealing for use in IBD is their ability to regulate the host mucosal immune response. Since it became known that immune as well as epithelial cells of the small intestine can discriminate between various microorganisms through the activation of Toll-like receptors (TLRs),[11] it was postulated that probiotics may act by modulating both the innate and adaptive branch of immunity, as well as the epithelial function in the small intestine. In fact, probiotics may affect barrier function by interacting with TLRs, in particular TLR2 and TLR4.[12,13] Interaction with these receptors results in the subsequent stimulation of protective cytokine production: IL-6 and KC-1, both known to mediate epithelial cell regeneration and inhibit their apoptosis.
However, not all effects of probiotics on epithelial barrier integrity appear to be mediated via interaction with TLRs. Probiotics have also been shown to stimulate epithelial cells' health by promoting the integrity of the tight junctional barrier between enterocytes. This effect has been shown in numerous animal models and in relation to a variety of agents causing the disruption of tight junction function. Examples include:
* VSL#3 in a murine model of colitis [14]
* Lactobacillus GG (LGG) in CaCO2 cell monolayers on the hydrogen peroxide-induced disruption of tight junctions and barrier function [15]
* Lactobacillus rhamnosus and Lactobacillus acidophilus in Shigella dysenteriae infection in rats [16]
* Bifidobacterium infantis in IL-10-deficient mice [17]
* Strains of Bifidobacterium lactis and Lactobacillus salivarius in CaCO2 cells challenged by Escherichia coli O157:H7 [18,19]
* B. lactis and Lactobacillus fermentum in CaCO2 cells against the damage induced by gliadin [19]
* E. coli Nissle 1917 in T84 cells challenged with enteropathogenic E. coli (EPEC) strain E2348/69 [20]
* The heat-killed L. acidophilus strain LB in HT cells [21]
Furthermore, Dalmasso et al. showed in an animal model of IBD that the probiotic yeast Saccharomyces boulardii has a unique action on inflammation by a specific alteration of the migratory behavior of T cells, which accumulate in mesenteric lymph nodes.[22] In that setting, S. boulardii treatment limited both the infiltration of Th1 cells in the inflamed colon and the amplification of inflammation induced by proinflammatory cytokine production.
As reviewed in [23], probiotics can be internalized by the M cells and then interact with dendritic cells to activate both T- and B-cell responses. As a result, anti-inflammatory cytokines, including IL-10, are produced.[12,13] In addition, probiotics reduce the inflammatory response elicited by bacteria or other inflammatory stimuli by suppressing the production of proinflammatory cytokines. This effect has been shown in different animal models and for various strains, including LGG,[24] Lactobacillus caseiShirota,[25] E. coli Nissle 1917[26] and, directly in patients with IBD, for L. caseiDN114-01[27] and the patented probiotic preparation VSL#3.[28]
In our laboratory, LGG was able to prevent the fall in transepithelial resistance in an in vitro monolayer system of CaCO2 cells, caused by an E. coli strain (CD1033) identified from cultures of biopsies from the terminal ileum of children with Crohn's disease [Khaled Z et al., Manuscript in Preparation]. We proved this effect to be related to a derangement of the tight junction barrier induced by a reduction of the expression of the zonula occludens (ZO)-1 protein. Similarly, Zyrek et al. had shown that E. coli Nissle 1917 prevents the disruptive effects of EPEC on T84 epithelial cell monolayers by altering protein kinase C signaling and causing the redistribution of ZO-2 proteins.[20]
Vanderpool et al.recently reviewed mechanisms of probiotic action that may be involved in controlling intestinal inflammation.[29]
To summarize, it can therefore be seen that we have quite an extensive documentation of effects, which probiotics exert both in vivo and in vitro, that may be considered as useful in treating IBD patients as follows:
* Maintenance of the intestinal microbial balance in the presence of potential threats by pathogens;
* Regulation of the host mucosal immune function by inhibiting proinflammatory stimuli and enhancing the anti-inflammatory response;
* Protection of the integrity of the gut mucosal barrier by a variety of stimuli known to disrupt it.
Abstract and Introduction
Abstract
Probiotics have had many applications in the past few years, and inflammatory conditions of the GI tract – including chronic disorders such as inflammatory bowel disease (IBD) – have received the most attention by investigators. In fact, the experimental basis to expect clinical efficacy of probiotics in IBD is quite robust. In spite of this however, only minimal evidence of benefit by any probiotic is currently available in Crohn's disease, either in adult or in pediatric populations. In ulcerative colitis, on the other hand, several probiotic formulations and especially the proprietary preparation VSL#3 (a high-concentration mixture) have been found effective as adjuvant therapy, both in inducing and maintaining remission.
Introduction
The introduction of biological agents has markedly improved our ability to treat patients with the chronic, incurable inflammatory disorders grouped under the name inflammatory bowel disease (IBD); namely Crohn's disease, ulcerative colitis and indeterminate colitis. However, improved clinical efficacy has come at the cost of increased risks, including malignancies.[1,2] Thus, it is not surprising that the use of 'alternative' remedies is very frequent in patients with IBD, and especially in children.[3] In this regard, the possible use of probiotics appears as a natural consideration, especially because the intestinal bacterial flora plays an important role in IBD. Some microorganisms, mostly lactic acid bacteria, show properties that can be beneficial to maintaining or improving health functions, and in some cases can potentially even prevent or treat diseases by modifying the microflora. Such microorganisms are referred to as 'probiotics', defined by the Food and Agriculture Organization of the United Nations–WHO as "live microorganisms which, when consumed in adequate amounts as part of food, confer a health benefit on the host".
While their areas of application have been many, inflammatory conditions of the GI tract – both infectious and noninfectious – understandably have been the focus of active research. On one hand probiotics display features, such as anti-inflammatory action and enhancement of the gut barrier, that seem logically suited to be helpful in IBD; and on the other, there is convincing evidence that the inflammation in IBD results from an altered mucosal immune response to luminal bacterial antigens, thus suggesting that the use of live microorganisms may have a positive impact on shifting the microbial balance of the enteric flora. Support for this hypothesis also comes from a study showing that children with Crohn's disease treated with exclusive and partial polymeric enteral nutrition and experiencing remission with this regimen also showed profound changes in their microflora, as measured by temperature-gradient gel electrophoresis.[4] Such evidence will be briefly examined and the currently available clinical evidence of efficacy of probiotics in pediatric IBD will be reviewed.
Experimental Basis for the Theoretical Use of Probiotics in IBD
Even though the mechanisms of action of probiotics are still largely unknown and a matter of speculation, several lines of laboratory-generated evidence support their protective role in intestinal inflammation.
Probiotics have been shown to be effective against enteric pathogens by several mechanisms. They produce bacteriocins, a diverse group of low-molecular-weight peptides produced mostly by Lactobacilli that possess antimicrobial action against a number of bacteria, especially Gram-positive bacteria (reviewed in [5–7]). Similar substances, active against both Gram-positive and -negative bacteria, are also produced by Bifidobacteria.[8] In addition, Lactobacilli and Bifidobacteria are able to reduce the intracolonic pH by producing organic acids such as butyrate, lactic acid and propionic acid, thus creating an acidic pH milieu that is detrimental to the survival of several enteric pathogens, including Salmonella.[9]
One of the earliest findings in examining the actions of probiotics was their ability to prevent the attachment of pathogens to the enterocytes and to even displace bound pathogens from their binding site. These characteristics were shown to be possessed, to various degrees, by many of the commercially available probiotics.[10]
However, arguably the most important attribute that makes probiotics appealing for use in IBD is their ability to regulate the host mucosal immune response. Since it became known that immune as well as epithelial cells of the small intestine can discriminate between various microorganisms through the activation of Toll-like receptors (TLRs),[11] it was postulated that probiotics may act by modulating both the innate and adaptive branch of immunity, as well as the epithelial function in the small intestine. In fact, probiotics may affect barrier function by interacting with TLRs, in particular TLR2 and TLR4.[12,13] Interaction with these receptors results in the subsequent stimulation of protective cytokine production: IL-6 and KC-1, both known to mediate epithelial cell regeneration and inhibit their apoptosis.
However, not all effects of probiotics on epithelial barrier integrity appear to be mediated via interaction with TLRs. Probiotics have also been shown to stimulate epithelial cells' health by promoting the integrity of the tight junctional barrier between enterocytes. This effect has been shown in numerous animal models and in relation to a variety of agents causing the disruption of tight junction function. Examples include:
* VSL#3 in a murine model of colitis [14]
* Lactobacillus GG (LGG) in CaCO2 cell monolayers on the hydrogen peroxide-induced disruption of tight junctions and barrier function [15]
* Lactobacillus rhamnosus and Lactobacillus acidophilus in Shigella dysenteriae infection in rats [16]
* Bifidobacterium infantis in IL-10-deficient mice [17]
* Strains of Bifidobacterium lactis and Lactobacillus salivarius in CaCO2 cells challenged by Escherichia coli O157:H7 [18,19]
* B. lactis and Lactobacillus fermentum in CaCO2 cells against the damage induced by gliadin [19]
* E. coli Nissle 1917 in T84 cells challenged with enteropathogenic E. coli (EPEC) strain E2348/69 [20]
* The heat-killed L. acidophilus strain LB in HT cells [21]
Furthermore, Dalmasso et al. showed in an animal model of IBD that the probiotic yeast Saccharomyces boulardii has a unique action on inflammation by a specific alteration of the migratory behavior of T cells, which accumulate in mesenteric lymph nodes.[22] In that setting, S. boulardii treatment limited both the infiltration of Th1 cells in the inflamed colon and the amplification of inflammation induced by proinflammatory cytokine production.
As reviewed in [23], probiotics can be internalized by the M cells and then interact with dendritic cells to activate both T- and B-cell responses. As a result, anti-inflammatory cytokines, including IL-10, are produced.[12,13] In addition, probiotics reduce the inflammatory response elicited by bacteria or other inflammatory stimuli by suppressing the production of proinflammatory cytokines. This effect has been shown in different animal models and for various strains, including LGG,[24] Lactobacillus caseiShirota,[25] E. coli Nissle 1917[26] and, directly in patients with IBD, for L. caseiDN114-01[27] and the patented probiotic preparation VSL#3.[28]
In our laboratory, LGG was able to prevent the fall in transepithelial resistance in an in vitro monolayer system of CaCO2 cells, caused by an E. coli strain (CD1033) identified from cultures of biopsies from the terminal ileum of children with Crohn's disease [Khaled Z et al., Manuscript in Preparation]. We proved this effect to be related to a derangement of the tight junction barrier induced by a reduction of the expression of the zonula occludens (ZO)-1 protein. Similarly, Zyrek et al. had shown that E. coli Nissle 1917 prevents the disruptive effects of EPEC on T84 epithelial cell monolayers by altering protein kinase C signaling and causing the redistribution of ZO-2 proteins.[20]
Vanderpool et al.recently reviewed mechanisms of probiotic action that may be involved in controlling intestinal inflammation.[29]
To summarize, it can therefore be seen that we have quite an extensive documentation of effects, which probiotics exert both in vivo and in vitro, that may be considered as useful in treating IBD patients as follows:
* Maintenance of the intestinal microbial balance in the presence of potential threats by pathogens;
* Regulation of the host mucosal immune function by inhibiting proinflammatory stimuli and enhancing the anti-inflammatory response;
* Protection of the integrity of the gut mucosal barrier by a variety of stimuli known to disrupt it.
