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Synbiotics: enhancing children's defences.

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Gastrointestinal, ear-nose-throat and respiratory infections are very common in children, especially during their first years of social interaction; at this time, their immune systems, and also their digestive microflora, are still in maturation. In fact, we now know that the gut microflora plays an important protective role in the body, interacting with what is described as the body's primary site of immune defence. In this context, the potential of probiotics to influence the intestinal immune response has come under considerable scrutiny and the number of positive scientific publications on the subject has increased significantly during the last few years. However, when it comes to probiotics, one must bear in mind the fact that all strains are different--and that the benefits exerted by a particular microbial strain or blend of strains cannot be extended to others. This article describes the development of a synbiotic (prebiotic + probiotic) destined for children, based on the extensive knowledge of specific probiotic strains and their effects, alone or in combination, on certain elements of the immune response. A recent clinical study showed the efficacy of such a synbiotic in reducing the risks of common infections in children, adding weight to the potential efficacy of carefully selected probiotic strains with regard to immunity.

Probiotics and Immunity

Research has shown that certain probiotics are able to interact with each of the gut's three lines of defence (see sidebar). First, and probably the most obvious, is their barrier effect. By enhancing the natural gut microbiota, probiotics can help to keep pathogens at bay through several mechanisms (Figure 1):

* By occupying available space at the surface of the gut epithelium, certain probiotics will prevent the adhesion of pathogens that pass through but don't colonize the gut.

* Probiotics can also prevent the growth of pathogens by creating a hostile environment. Most commonly used probiotics are lactic acid producers and most pathogens won't multiply under acidic conditions. (1)

* Other probiotics have been shown to compete with pathogens for the same nutrients.

* Some probiotics can produce antimicrobial substances such as the bacteriocins secreted by many lactobacilli. (2)

* Another method of protection against pathogens is known as competitive exclusion. For example, it has been shown that Lactobacillus Rosell-52 binds to the attachment sites of pathogenic bacteria such as enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC)--the causes of protracted diarrhoea in infants and hemorrhagic colitis, respectively--on intestinal epithelial cells, avoiding pathogen installation and translocation. (3, 4) Similarly, Bifidobacterium Rosell-33 shares some binding specificities to intestinal cells with several pathogens, including H. pylori and E. coli. (5)

* Probiotics have also been shown to improve the intestinal barrier function and enhance epithelium permeability and integrity. (6) They can even play a role in mucus production. (7)

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A significant body of literature advocates the fact that probiotics also have the ability to influence the immune system in situ and modulate both the innate and immune response. Probiotics such as lactobacilli and bifidobacteria have been shown to influence selected aspects of immune function. Generally, the enhanced production of secretory antigens (IgA) may be observed during probiotic treatment. (8) Studies have shown that the strain Lactobacillus Rosell-52 was able to induce the production of antibodies in a nonspecific fashion owing to a mitogenic effect on B cells, thus increasing the pool of antibodies in the gut lumen that were ready to react to infections. (9) Moreover, several studies have demonstrated the beneficial effects of lactic acid bacteria in boosting a non-specific immune response by enhancing the phagocytosis of pathogens as well as by modifying cytokine production. (8)

Formulating a Child-Specific Synbiotic

Babies are born with a bacteria-free gastrointestinal tract (GIT). Within a few days, a specific microflora colonizes their GIT as a result of breastfeeding and the environment. This microflora is organized into populations and evolves with time, especially after weaning: children have a totally different microbiotic profile than adults. Bifidobacteria is the predominant bacterial group in the normal intestinal flora of healthy breastfed newborns, representing more than 95% of the total population. However, the numbers of these organisms gradually decrease from the time of weaning and may account for only 25% of the total intestinal flora in healthy adults. According to many studies, bifidobacteria play an important role in maintaining the intestinal microflora balance in children.10 Moreover, the prebiotic fructooligosaccharide (FOS) has the ability to increase the bifidobacteria population in the gut. Indeed, FOS is selectively digested by bifidobacteria. Breast milk contains relatively high levels of FOS and it has been shown that the population of bifidobacteria is ten times higher in the gut of breastfed babies when compared with those that are formula fed.

Based on this information and the documented characteristics and properties of specific probiotic strains, a synbiotic formula was developed to help balance children's microflora and interact positively with their immune defences. Fructo-oligosaccharides, chosen for their bifidogenic effect, were combined with three probiotic strains. The prebiotic should enhance probiotic survival and facilitate their inoculation into the colon. In addition, it should also induce growth and increase the activity of the resident bifidobacteria. The three probiotic strains were selected from Institut Rosell's own collection according to their potential to influence each level of immune defence:

* Lactobacillus Rosell-52

* Bifidobacterium Rosell-71

* Bifidobacterium Rosell-33.

These naturally occurring probiotic strains are fully characterized and documented. All three are resistant to acidity and bile salts, meaning that they are able to reach the intestine alive. They also have the ability to adhere to intestinal epithelial cells. The reason why strains from different genera and species were selected is that the distribution of microbial species along the gut varies according to their ability to resist oxygen, acid and bile salts (Figure 2). Hence, the combination of lactobacilli and bifidobacteria allows for the probiotic effects to be exerted in both the distal end of the small intestine and throughout the colon, thus balancing the whole intestinal flora. Finally, the synbiotic (ProbioKid, Institut Rosell-Lallemand, Canada) had been formulated in an easy to use sachet format to be diluted in water, juice or milk, a galenic form well adapted to children (Figure 3).

Clinical Evidence

A randomized double-blind placebo-controlled study was conducted in young children to evaluate the efficacy of the synbiotic in preventing common infectious diseases. The multicentre study was done in France during the winter of 2006/2007 and involved 135 healthy, school-age children (3-7 years old) who had suffered from at least three episodes of an ear-nose-throat (ENT), bronchopulmonary or gastric disorder during the course of the previous winter. Children were supplemented with either the synbiotic preparation or a matched placebo for 3 months on a daily basis. During this period, all emergent health episodes of any type were recorded in a diary by the parents. Investigators subsequently checked the diaries during regular monthly visits. The main outcome was the percentage of children that were free of any episode during the course of the study. The results suggest that synbiotic supplementation is able to decrease the risk of common infectious diseases in children and limits the risk of school day loss owing to these episodes. Fifty per cent of the children in the synbiotic group did not develop any ENT, bronchopulmonary or gastric problems during the winter compared with 32.9% of children in the placebo group (p<0.05). This represents a 25% reduction of the relative risk of infectious disease in the ProbioKid group compared with the placebo group (p<0.05). In addition, it was shown that only 25.8% of children in the synbiotic group missed at least one day of school compared with 42.5% in the placebo group (p<0.05). No treatment-related side-effects were reported (Figures 4 and 5). Dr Jean-Charles Kerihuel, from Vertical (Paris, France), who took part in the study, concluded: "Our study strongly supports a positive effect of ProbioKid in the prevention of infectious episodes in children; and, even though we do not have a clear picture of the synbiotic modes of action, it is clear that its benefits are linked to the strains used and the product formula ... and these benefits cannot be extrapolated to other products."

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Possible Modes of Action

Several in vivo studies with the selected bacteria strains and the finished formula support its observed benefits and have helped to elucidate possible modes of action. First, as mentioned earlier, the individual strains have documented barrier effects and Lactobacillus Rosell-52 has the ability to stimulate the production of antibodies. (3-5, 8) Furthermore, L. Rosell-52 and B. Rosell-71 have shown immunomodulatory activity: they have the ability to reduce the amount of transforming growth factor beta (TGF-[beta]). This particular cytokine down-regulates both innate and acquired immunity. Thus, by lowering the production of this messenger, they may enhance the generation of an immune response. In fact, the finished formula itself has been shown to exert immunomodulatory effects in vivo, as shown by cytokine profiles. Cytokines act as the messengers of the immune system and are involved in reactions such as the pro/anti-inflammatory balance. Because stimulation of both specific and non-specific immunity results in the production of cytokines, their assessment may be an important indicator of the immune response. Indeed, most of the knowledge about how probiotics affect the intestinal immune system is derived from cytokine measurement and profile analysis. Studies investigating cytokine production by immune cells subjected to ProbioKid have shown that the synbiotic is able to influence the cytokine profile and seems to induce an anti-inflammatory effect. These effects appear to be strain-dependent.

The immunomodulatory effects of the synbiotic have been further substantiated by animal studies. An initial study done in co-operation with INRA Toulouse in 2007 involved an animal model of parasitic infection. Some rats received a 10-day treatment with ProbioKid prior to parasitic challenge (Nippostrongylus brasiliensis). Three days post-infection, levels of pro-inflammatory cytokines (IL-1[alpha] and TNF-[alpha]) decreased in the treated animals when compared with the controls. A slight but not significant decrease of IL-10 was observed. As IL-10 is a cytokine involved in immunomodulation, the fact that it is not significantly decreased favours positive immunosurveillance. Another study looked into cytokine profiles following bacterial infection (E. coli challenge in rats). This showed that a 2-week preventive treatment with the synbiotic exerted a significant effect on the animals' health and immune status. Weight loss following E. coli infection was decreased compared with the controls, showing improved resistance against infection. Moreover, levels of proinflammatory cytokines (IL-1[alpha], IL-1[beta], IL-6, IFN-[gamma] and TNF-[beta]) were decreased, whereas anti-inflammatory cytokine IL-4 increased. The proven immunomodulatory effects of the synbiotic formula help us to understand its benefits. These results advocate the use of specifically formulated probiotic combinations to enhance the immune system in the fight against infections, particularly during times of high risk owing to pathogenic challenge.

References

(1.) A.L. Servin, "Antagonistic Activities of Lactobacilli and Bifidobacteria Against Microbial Pathogens," FEMS Microbiol. Rev. 28, 405-440 (2004).

(2.) V. Mihal, et al., "Protective Effect of Lactobacillus helveticus and Lactobacillus casei on Encephalomyocarditis-Virus-Induced Disease in Mice," Food Agric. Immunol. 2, 205-209 (1990).

(3.) P.M. Sherman, et al., "Probiotics Reduce Enterohemorrhagic Escherichia coli O157:H7- and Enteropathogenic E. coli O127:H6-Induced Changes in Polarized T84 Epithelial Cell Monolayers by Reducing Bacterial Adhesion and Cytoskeletal Rearrangements," Infect. Immun. 73(8), 5183-5188 (2005).

(4.) K.C. Johnson-Henry, et al., "Surface-Layer Protein Extracts from Lactobacillus helveticus Inhibit Enterohaemorrhagic Escherichia coli O157:H7 Adhesion to Epithelial Cells," Cell. Microbiol. 9(2), 356-367 (2006).

(5.) M. Kostrzynska, et al., "Receptors Recognized by Bifidobacteria on Intestinal Epithelial Cells," presented at the 3rd Joint Symposium RRI-INRA: Beyond Antimicrobials--The Future of Gut Microbiology (Aberdeen, UK, 12-15 June 2002).

(6.) M. Zareie, et al., "Probiotics Prevent Bacterial Translocation and Improve Intestinal Barrier Function in Rats Following Chronic Psychological Stress," Gut 55(11), 1553-1560 (2006).

(7.) D.R. Mack, et al., "Extracellular MUC3 Mucin Secretion Follows Adherence of Lactobacillus Strains to Intestinal Epithelial Cells In Vitro," Gut 52, 827-833 (2003).

(8.) K.L. Erickson and N.E. Hubbard, "Probiotic Immunomodulation in Health and Disease," J. Nutr. 130, 403S-409S (2000).

(9.) J.G. Easo, et al., "Immunostimulatory Actions of Lactobacilli: Mitogenic Induction of Antibody Production and Spleen Cell Proliferation by Lactobacillus delbrueckii subsp. bulgaricus and Lactobacillus acidophilus," Food Agric. Immunol. 14, 73-83 (2002).

(10.) H.P. Bartram, et al., "Does Yogurt Enriched with Bifidobacterium longum Affect Colonic Microbiology and Faecal Metabolites in Healthy Subjects?" Am. J. Clin. Nutr. 59, 428-432 (1994).

For more information

Sylvie Roquefeuil-Dedieu

Press Officer

Institut Rosell-Lallemand

Tel. +33 6 8472 7610

sroquefeuil-dedieu@rosell.com

www.institut-rosell.com

The Gut is the Body's Major Site of Immune Defence

The immune system operates throughout the body. However, there are certain sites where the cells of the immune system are organized into specific structures. These are classified as central lymphoid tissues (bone marrow, thymus) and peripheral lymphoid tissues (lymph nodes, spleen, mucosa-associated lymphoid tissue). Mucosa-associated lymphoid tissue is located in the respiratory and urogenital tracts, but mostly in the gastrointestinal tract, presenting one of the largest exchange surfaces in the body. This is known as the gutassociated lymphoid tissue or GALT. GALT represents the body's primary immune defence as it contains 60-70% of all the immune cells in the body. These cells are found either diffusely distributed within the lamina propria of the gut (the part of the mucosa that underlies the gut's epithelium) or organized in lymphoid follicles known as Peyer's patches, located in the small intestine. Putting it simply, the gut's defences are organized into three lines that protect the body from pathogens:

1. Commensal bacteria from the gut microflora that compete for nutrients and prevent pathogens from adhering to and invading the gut surface act as a first barrier to protect the internal organs. The epithelial cells and mucous layer complete the barrier. When pathogens evade this first line of defence, the immune system enters an attack mode to eliminate the invader, involving the two arms of the immune response.

2. The non-specific or innate immune response that rapidly destroys pathogens that have passed through the epithelium or outgrown the good bacteria in the gut is the first arm. This response recognizes all types of invaders and stops most of them before an infection develops. Key players in the innate immune response include phagocytic cells such as neutrophils, monocytes and macrophages, Natural Killer and dendritic cells. The mechanisms involved include phagocytosis and inflammatory reactions, during which mediators such as cytokines may be released.

3. The adaptive or specific immune response takes time to develop but is a strong response that's specific to each pathogen. It involves T and B lymphocytes with receptors for a specific antigen and the production of specific antibodies by activated B cells. Because B cells and T cells are capable of "memorizing" an antigen, their response is faster and more efficient following a second encounter with the invader.
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Title Annotation:gut health
Author:Roquefeuil-Dedieu, Sylvie
Publication:Nutraceutical Business & Technology
Article Type:Report
Geographic Code:1USA
Date:Nov 1, 2009
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