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National Institute of Health and Medical Research, INSERM E9925, Faculté Necker, 156 rue de Vaugirard, 75730 Paris, FRANCE
Address reprint requests to: Dr M. Heyman, INSERM CJF 97-10, Faculté Necker, 156 rue de Vaugirard, 75730 Paris, FRANCE
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMECHANISMS INVOLVED IN DIARRHEAL...EFFECT OF LACTIC ACID...MECHANISMS INVOLVED IN THE...CONCLUSIONREFERENCES |
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Key words: intestinal function, diarrhea, lactic acid bacteria, bifidobacteria, probiotics
Key teaching points:
• Lactic acid bacteria improve lactose intolerance.
• Secretory IgA immune response is enhanced by probiotics.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMECHANISMS INVOLVED IN DIARRHEAL...EFFECT OF LACTIC ACID...MECHANISMS INVOLVED IN THE...CONCLUSIONREFERENCES |
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Various properties of lactic acid bacteria have been proposed as an explanation for their multiple beneficial effects. These properties may include the restoration of a normal intestinal microflora, the contribution to the elimination of pathogenic enteric bacteria, the reinforcement of the intestinal barrier capacity to exogenous antigens and the increase in humoral immunity and in the mucosal secretory IgA response. In addition to strengthening the specific immunity, lactic acid bacteria also seem to reinforce the non-specific mechanisms of defence such as phagocytosis and cytokine production. A trophic role on the intestinal epithelium has also been suggested, as well as the secretion by these probiotics of compounds having anti-inflammatory or antimicrobial effects.
All these in vitro or in vivo studies suggest that synergistic mechanisms are probably involved in the beneficial effects of fermented products in case of diarrheal diseases. A recent review on the treatment and prevention of intestinal infections with biotherapeutics agents has concluded that "there is now evidence that administration of selected microorganisms is beneficial in the prevention and treatment of certain intestinal infections" [2].
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MECHANISMS INVOLVED IN DIARRHEAL DISEASES |
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TOPABSTRACTINTRODUCTIONMECHANISMS INVOLVED IN DIARRHEAL...EFFECT OF LACTIC ACID...MECHANISMS INVOLVED IN THE...CONCLUSIONREFERENCES |
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Diarrhea results from a disequilibrium in the water movements across the gut. Multiple factors can be involved in the regulation of water movements, mostly those interfering with the membrane transport systems in the intestinal epithelium. Water movements are mainly generated by the Na-solutes cotransport systems (Na-glucose) or the chloride (CI-) secretion through the apical membrane of the enterocytes, and these transporters or channels are highly regulated structures. Water movement always follows the ionic movements in the intestine: the Na+ absorption generated by the Na-glucose cotransporter is associated with a net water absorption, whereas the CI- secretion by the enterocyte leads to water secretion in the intestinal lumen. In these conditions, any luminal or serosal factor acting on any element of this transport system is likely to modify the movements of electrolytes and water. In other words, a decreased Na-glucose cotransport or an increased CI- secretion will compromise the hydroelectrolytic homeostasis in the intestine. Factors acting either at the luminal side of the intestinal epithelium or at the serosal (blood) level are capable of affecting electrolyte and water movement, i.e. to induce diarrhea. Among the luminal factors, pathogenic bacteria can adhere to the brush border membrane of the enterocytes and alter the intestinal function by various mechanisms. They can induce attaching-effacing lesions of the brush border membrane or release enterotoxins stimulating chloride secretion or cytotoxin disrupting the epithelial integrity. A congenital defect in Na-glucose cotransport (glucose galactose malabsorption) is associated with a defect in Na and water absorption leading to diarrhea. Various serosal factors are also involved in the regulation of water movements: they compose the stimulation of the underlying immune system (mast cells, phagocytes, lymphocytes) and the release of immune mediators (cytokines), some of which are capable of directly or indirectly stimulate chloride secretion. The stimulation of the intrinsic nervous system in the intestinal mucosa leads to the release of neuromediators (Met-enkephalin, acetylcholine) known to activate directly the chloride secretion. Finally, complex interactions between the different cell types present in the submucosa are also involved in the regulation of intestinal secretion. Besides the specific mechanisms involved in water movement in the gut, osmotic diarrhea can also be induced when a non absorbable compound reaches the intestinal lumen and maintains an osmotic gradient between the intestinal lumen and the blood, leading to water secretion and diarrhea. A typical case of osmotic diarrhea is that induced by lactose malabsorption due to lactase deficiency or to the malabsorption of poorly absorbable saccharides (lactulose). Taken into account the multiple factors capable of regulating water and electrolyte absorption and secretion, it is probable that the beneficial effects, observed after administration of probiotics, on diarrheal diseases involve many different mechanisms.
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EFFECT OF LACTIC ACID BACTERIA ON DIARRHEA OF VARIOUS ETIOLOGIES |
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TOPABSTRACTINTRODUCTIONMECHANISMS INVOLVED IN DIARRHEAL...EFFECT OF LACTIC ACID...MECHANISMS INVOLVED IN THE...CONCLUSIONREFERENCES |
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Diarrhea Due to Lactose Malabsorption
The most documented beneficial effect of yogurt on the intestinal function is observed in the case of lactose intolerance. Intestinal lactase deficiency is a frequent condition causing maldigestion and intolerance to lactose. Lactose digestion and absorption has been currently measured using breath hydrogen (H2) tests. In 1984, Kolars [4] and Savaiano [5], using breath hydrogen tests in lactase deficient subjects, showed that there was a much better absorption of lactose from yogurt than from milk, probably due to intraintestinal digestion of lactose by lactase released from the yogurt microorganisms. In 1987, these results were confirmed by Dewit et al. [6], who showed in addition that the ingestion of yogurt or heated yogurt in lactose malabsorbers restored the secretion of insulin to control levels and that the ingestion of fresh, unheated yogurt increased the absorption of free fatty acids. It is not absolutely proven however, that the lactase activity (optimal activity at pH 6–8) persists in vivo at the duodenal level, since at pH 5.0 which is the pH observed in the duodenum, the beta-galactosidase activity in yogurt drops by 80%, probably preventing the bacterial beta-galactosidase from hydrolyzing lactose in the duodenum [7]. However, it was shown that in a lactase deficient population, lactose present in yoghurt was better tolerated than that in milk. One fifth of the lactase activity contained in yoghurt was still found in the terminal ileum, suggesting the persistence of the protein along the digestive tract. In addition, fresh yogurt was more efficient in facilitating lactose digestion than heated yoghurt [7].
In a study of lactose absorption in lactase deficient Gabonese children, a beneficial effect of a spray-drying of fermented milk was observed and ascribed to the persistence of lactase activity in the fermented milk [8]. A better efficiency of live versus pasteurized yogurt was suggested [9]. Altogether, these results indicate that bacterial beta-galactosidase present in yogurt partly resists luminal hydrolysis and can hydrolyze lactose, at least in the mid and distal part of the small intestine where the pH is compatible with its enzymatic activity. The mechanisms by which the lactic acid bacteria improve the digestion of lactose are described in more detail below.
Treatment of Diarrhea
Acute Viral Diarrhea.
Perhaps one of the most documented effects of bacteriotherapy concerns acute viral enteritis in children. The use of oral bacteria therapy in childhood during acute enteritis has early been described as beneficial in the treatment of diarrhea [10–12] and in restoring a normal intestinal ecosystem [13]. The immuno-potentiating effect of lactic acid bacteria was also early shown to have a favorable effect on infantile diarrhea by Perdigon et al. in Argentina [14]. Human isolates of Lactobacillus casei (Strain GG), now named Lactobacillus rhamnosus, has been extensively used in Finland to promote recovery from acute rotavirus diarrhea in children. L. casei GG in the form of fermented milk or freeze-dried powder was effective in shortening the course of acute diarrhea [15]. The same effect was recently observed in children with rotavirus diarrhea fed Lactobacillus reuteri, since the duration of watery diarrhea was 1.5 days in the treated infants versus 2.5 days in the matched control infants [16]. One of the beneficial effects of L. casei GG during the time course of rotavirus diarrhea was to reinforce the local immune defences through specific IgA response to rotavirus [17]. The enhancing effect on sIgA against rotavirus was significantly higher with the strain L. casei GG than with L. casei subsp rhamnosus (Lactophilus) or with a combination of Streptococcus thermophilus and Lactobacillus delbrückii subsp. bulgaricus (Yalacta) [18]. Moreover, the administration of viable L. casei GG was more efficient in promoting rotavirus specific IgA in serum than inactivated bacteria [19]. In Pakistan, the course of acute diarrhea in hospitalized children was improved in the group supplemented with L. casei GG since the frequency of vomiting and diarrhea was decreased in this group, as well as the percentage of children with persistent diarrhea at 48 hours (31% versus 75% in the treated and control group respectively, p<0.01) [20]. In Karelian republic, L. casei GG was shown to decrease the duration of acute diarrhea (2.7 vs. 3.7 days) in children with viral acute diarrhea but not in those with bacterial diarrhea [21]. In Thailand, the mean duration of acute non-bloody diarrhea in children fed with freeze-dried preparation of L casei GG was lower (1.9 days) than that observed in the placebo group (3.3 days, p<0.055) [22].
In a double-blind, placebo-controlled trial, a preventive effect on the development of diarrhea and on the shedding of rotavirus in feces in infants aged five to 24 months was observed in the group receiving a milk formula supplemented with Bifidobacterium bifidum and S. thermophilus compared to infants receiving the control formula [23].
Bacterial Diarrhea.
The data concerning a protective role of lactic acid bacteria in bacterial diarrhea are scanty in humans, and contradictory results are often reported in animals. Most studies have been done in animals (calves, piglets, mice, rabbit and horses) with various results. In a rabbit model of E. coli enterotoxin induced diarrhea, a Lactobacillus-containing preparation injected in infected ileal loops exhibited a significant anti-enterotoxin response [24]. The administration of killed Lactobacillus acidophilus in mice infected with a strain of enterotoxigenic E. coli extended their survival, but contradictory results were obtained later [25]; however a protective effect of probiotic fermented food mixture was found in a similar model of mice infected with E. coli [26]. A supplementation of calves with lactic-acid producing bacteria did not protect the animals against infection with the parasite Cryptosporidium parvum nor the fecal shedding of C. parvum oocysts [27]. A clinical trial of probiotic administration for prevention of Salmonella shedding in the postoperative period in horses with colics had no effect on Salmonella shedding and prevalence of diarrhea [28]. However, an in vivo study using conventional or germ-free mice orally infected with Salmonella typhimurium has shown that the human isolates Lactobacillus acidophilus strain LA1 had an antibacterial activity. The antibacterial activity was reproduced, in vitro, using Caco2 cells infected with Salmonella typhimurium and was shown to be linked to a factor insensitive to proteases and independent of lactic acid production, present in the culture supernatant of strain LA1 [29].
Besides the effect of probiotics observed on the time course of infection, a preventive effect has also been suggested in mice [30].
In humans, in case of recurrent clostridium difficile colitis, a successful treatment was obtained by using L. rhamnosus (strain GG) [31,32].
In Karelian republic, L. casei GG was shown to decrease the duration of acute diarrhea in children with viral acute diarrhea but not in those with bacterial diarrhea [21]. In adult volunteers inoculated orally with E. coli strains producing heat-stable and heat-labile enterotoxins, the course of the diarrhea was not improved by a commercial preparation (Lactinex), containing dried Lactobacillus acidophilus and L. bulgaricus [33,34].
Taken together, although beneficial effects have been reported in different animal or cell culture models; these results raise some doubt on the beneficial effect of a bacteriotherapy in case of bacterial diarrhea in humans.
Persistent or Chronic Diarrhea.
Persistent diarrhea is defined as a diarrhea starting acutely but lasting at least two weeks. Interestingly, the beneficial effect of feeding fermented milk was also shown in Algerian children with persistent diarrhea. Those children had experienced a diarrhea for more than 13 days and were fed for five days with yogurt or milk. The clinical failure was observed in 14% in the children fed yogurt versus 42% in those fed milk, indicating a clinical advantage of feeding yogurt rather than milk in children with persistent diarrhea [35].
In a controlled randomized single blind clinical trial, the treatment of children with a specific chronic diarrhea with crystalline lactulose or with oral preparations of micro-organisms (Lactipan) promoted the complete remission of intestinal disorders. The authors suggested that the beneficial effect was due to the restoration of a balanced microflora [36].
Other non-controlled studies have reported a beneficial effect of fermented products on the time course of diarrhea. Feeding fermented milk to children (South America) with post-gastroenteritis syndrome eliminated the disease in 4.0 days and was even more beneficial in the patients with malnutrition [37]. Bhan et al., in 1987, suggested that a beneficial effect of yogurt in comparison to milk was demonstrated in malnourished children with acute diarrhea [38]; however, a recent controlled study including 96 malnourished children indicated that routine substitution of yogurt in small frequent feedings to malnourished children with acute diarrhea as an addition to semisolid food did not achieve any significant clinical benefit versus milk [39].
In a study performed in Pakistan, the comparative use of a local fermented product containing yogurt and of a soya-based diet, in children under three months of age, showed that the local fermented diet allowed a better in gain weight and a lower stool volume than the soya-based diet [40].
On the other hand, chronic diarrhea is often observed in children with a lactose intolerance secondary to a villus atrophy (for example in untreated coeliac disease) and leads to malnutrition. An Algerian study of nine children aged seven to 29 months presenting with chronic diarrhea has been done on the possible beneficial effect of fermented milk (lactose intake: 0.9 g/kg) compared to milk (lactose intake: 1.8 g/kg) in the lactose malabsorption and the diarrhea. The results have shown that yogurt significantly reduced the lactose intolerance as well as the volume and the occurrence of acidic feces [41].
Antibiotics-Associated Diarrhea or Radiotherapy-Induced Diarrhea.
It is known that antibiotics used in various infectious pathologies may alter the intestinal microflora and the equilibrium in the bowel ecosystem.
Compared with children having received amoxicillin for only ten days, those who were given the antibiotics treatment, supplemented with lactobacilli, showed a lower incidence of diarrhea [42]. Similar beneficial effects of oral bacterial therapy with lactobacilli was reported in the prevention of diarrhea caused by amoxicillin administration in infancy [42]. However, Lactinex, a culture of L. acidophilus and L. bulgaricus was unable to prevent diarrhea in these patients [43]. By contrast, in adults, prophylactic administration of Lactinex in ampicillin-treated patients was effective in preventing the diarrhea [44]. In healthy volunteers, the erythromycin-associated diarrhea was decreased in those receiving L. casei GG but not in those taking pasteurized yogurt [45], indicating that the viability of lactic acid bacteria is mandatory to the beneficial effect. However, one study of antibiotic therapy in children suffering from extraintestinal pathologies showed that a treatment with inactivated Lactobacillus acidophilus was efficient in preventing the intestinal dysmicrobism affections [46]. It has to be noted that complication of antibiotherapy can lead to Clostridium difficile colitis. A successful treatment of children with such a colitis was obtained with freeze-dried powder of L. casei GG containing 5x109 viable bacteria per gram [32].
In children with intractable diarrhea (having started after an antibiotherapy), the administration of Bifidobacterium or Bifidus yogurt dramatically improved the stool frequency within three to seven days [47].
Finally, in patients undergoing abdominal irradiation, the prevention of intestinal side effects (diarrhea) was obtained by the administration of live Lactobacillus acidophilus cultures [48].
Prevention of Diarrhea in Children
A few studies have been done on the potential preventive effect of fermented milks on the development of diarrhea. In 1989, Brunser et al. in Chile evaluated the effect on diarrheal disease of an acidified, modified powdered cow’s milk infant formula (Pelargon) in 82 infants (Group I) for six months; 104 infants who received the same formula but non acidified served as controls (Group II). The incidence of diarrhea was lower in Group I (p<0.001). The proportion of days during which the children suffered from acute diarrhea and the duration of the episodes were also lower in the children given the acidified milk (p<0.001). These results indicated that acidified milk exerts a protective effect against diarrheal disease.
In 1994, Boudraa et al. in Algeria showed that feeding a dehydrated fermented milk containing Bifidobacterium breve and S. thermophilus (Lactofidus) to children at early weaning, significantly reduced the number of diarrheal episodes compared with feeding children an adapted milk formula during the three months of the study [49].
Importance of the Viability of Lactic Acid Bacteria on their Beneficial Effects
The viability of the lactic acid bacteria in the fermented milks used in the treatment of diarrhea is one of the factors possibly involved in their beneficial effect. In fresh yogurt or fermented milks, the bacterial counts normally reach 108 to 109 bacteria/mL. In some other fermented milks, such as L. casei GG enriched milk, the counts can reach 1010 to 1011 bacteria/mL. This is due to the fact that L. casei GG do not hydrolyze lactose and that ß-galactosidase has to be added to the preparation to allow the milk fermentation. Therefore, L. casei GG is often used in the form of bacteria-enriched preparation, in which a defined number of bacteria are added. Other fermented products are commercially available as powder to be reconstituted in water. According to the method of dehydration (freeze-drying, evaporation) and the need to heat the product, the number of viable bacteria is greatly reduced to an extent which is not always defined. It is obvious that all these factors can interfere with the final effect.
It seems that the viability of the lactic acid bacteria is important when considering certain diarrheal disease, whereas it is less important in other cases such as lactose intolerance.
In 1987, Dewit et al. [6] showed that the ingestion of yogurt or heated yogurt in lactose malabsorbers restored the secretion of insulin to control level and that the ingestion of fresh, unheated yogurt increased the absorption of free fatty acids. Indeed, it seems that the lactase activity (i.e., the intact ß-galactosidase protein) can persist in the small intestine [7], explaining why heated yogurt is still efficient in lactose malabsorbers. However, in a lactase deficient population, fresh yogurt is more efficient in facilitating lactose digestion than heated yogurt [7]. In the same way, a study of lactose absorption in lactase deficient children showed a beneficial effect with a spray-drying fermented milk, and this effect was ascribed to the persistence of lactase activity in the fermented milk [8]. In another study of lactase deficient children, the efficiency of live yogurt was maximal and that of pasteurized yogurt was intermediate [9]. The lower effect of pasteurized product could be due both to the decrease of live bacteria and/or to the decrease of lactase content.
The use of live versus heated L. casei GG on the time course of rotavirus diarrhea has also been tested. It was shown that the fermented milk and the freeze-dried powder were both effective in shortening the course of acute diarrhea [15]. However, the administration of viable L. casei GG was more efficient in promoting rotavirus specific IgA in serum than heat inactivated bacteria [19].
In healthy volunteers, erythromycin-associated diarrhea was decreased in those receiving L. casei GG but not in those taking pasteurized yogurt [45], indicating that the viability of lactic acid bacteria is mandatory to the beneficial effect. Other studies tend to substantiate the efficiency of inactivated or freeze-dried products in case of antibiotherapy. In a study of antibiotic therapy in children suffering from intestinal or extraintestinal pathologies, a treatment with inactivated Lactobacillus acidophilus was efficient in preventing the intestinal dysmicrobism affections [46]. Also, a successful treatment of children with Clostridium difficile colitis was obtained with freeze-dried powder of L. casei GG containing 5x109 viable bacteria per gram [32].
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MECHANISMS INVOLVED IN THE BENEFICIAL EFFECT OF LACTIC ACID BACTERIA |
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TOPABSTRACTINTRODUCTIONMECHANISMS INVOLVED IN DIARRHEAL...EFFECT OF LACTIC ACID...MECHANISMS INVOLVED IN THE...CONCLUSIONREFERENCES |
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Effect on the Resident Microflora and Pathogens
The development of an indigenous gut flora in neonates is a prerequisite to the protection of the intestinal function. During the neonatal period, the intestinal flora are enriched in bifidobacteria in breast-fed infants, while enterobacteria are predominent in case of bottle-fed infants [52] although most often a mixed population is found (R. Ducluzeau, personal communication). It is possible that the beneficial effect of fresh lactic acid bacteria is due to the transient proliferation of these bacteria in the digestive tract, in vivo. On the one hand, these bacteria need lactose to grow and therefore consume it and decrease its concentration in the intestinal lumen. On the other hand, the transient passage in the intestine of lactic acid bacteria may represent a microbial barrier against the development of pathogenic bacteria.
Some data have indicated in Peruvian children, that orally administered L. casei GG can survive to transit, although an efficient colonization was not demonstrated [53]. The fate of ingested lactic acid bacteria has also been studied extensively in normal volunteers. After ingestion of a fermented milk containing L. acidophilus and bifidobacterium sp, living bacteria were recovered in the ileum in quantities representing 1.5 and 37.5% of the ingested bacteria respectively [54]. Similar results were obtained in a study of six healthy adults indicating the survival of bifidobacterium species at the terminal ileum level [55].
In human neonates, the administration of a fermented whey-adapted infant formula containing viable bifidobacteria during the first two months of life allowed them to reach a prevalence of colonization with bifidobacteria similar to that of breast-fed infants [56].
The protective effect of the resident microflora is often weakened in case of antibiotherapy. There is an increasing amount of evidence that antibiotic treatment alters the protective flora and therefore predisposes to later infections. Although antibiotherapy has resolved many problems, it has also created a disequilibrium of the resident microflora and a decrease of colonization resistance to pathogens. The introduction of probiotic strains to reinforce human gut flora has therefore been tested. Lactobacilli are part of the normal anaerobic microflora, although they do not constitute the dominant microflora. By producing lactic and acetic acids, hydrogen peroxide and possibly antimicrobial substances, these microorganisms may contribute to the maintenance of colonization resistance. In view of these suspected beneficial effects, it has appeared important to maintain or increase the levels of lactobacilli in the intestinal microflora [57].
In addition, yogurt has been tested for its antibacterial properties [58]. This property has mostly been studied in vitro, by investigating the bactericidal and bacteriostatic effects of yogurt on three strains of Escherichia coli (two pathogenic and one nonpathogenic). It was concluded that both the live yogurt bacteria and an acidic pH around 4.5 are necessary for the bactericidal activity of the yogurt. However, the same bactericidal activity was observed for pathogenic or nonpathogenic strains of E. coli; this raises suspicion of the potential beneficial effect, in vivo. Another in vitro study using the Caco2 intestinal cell line [59] has suggested that the adherence of certain strains of lactobacillus to the intestinal epithelial cells, even when these are heat-killed lactobacilli, can significantly inhibit the binding of enteric pathogens. However, an in vivo study in rabbits infected with the enteroadherent pathogenic strain RDEC-1 and receiving either a milk- or yogurt-enriched diet showed that the duration of diarrhea and the fecal excretion of bacteria was the same in the milk- and yogurt-fed groups indicating that in vivo, yogurt did not interfere with the growth of the pathogenic E. coli [60].
Taken together, these studies indicate that although some bactericidal effects of yogurt have been found in vitro, it seems difficult to extrapolate to the in vivo situation, and some doubts can be raised on its efficiency in eliminating pathogenic bacteria from the intestinal tract.
Nonspecific Immune Defence
Nonspecific, anti-infective mechanisms of defence can be enhanced by ingestion of specific lactic acid bacteria strains. It has been postulated that these strains could be used as nutritional supplements to improve the weakened immune function of particular age groups such as neonates or elderly persons. In a study of the immunomodulation of human blood cells following lactic acid bacteria ingestion, the consumption of fermented milks (with Bifidobacterium bifidum or L. acidophilus [strain LA1]) induced an increased phagocytosis of E. coli, in vitro [61]. In animals, lactic acid bacteria also exhibit immunostimulating capacity: Perdigon et al., in 1995 reported that different strains of Lactobacillus and Streptococcus thermophilus were capable of stimulating non-specific (macrophages) and specific (lymphocytes B and T) immunity in mice.
Effect on the Intestinal Barrier Function
The intestinal barrier function involves various factors capable of decreasing the absorption of potentially harmful microbial or soluble antigens. It includes various components contributing to the luminal degradation of antigens by digestive enzymes and a physical epithelial barrier comprising the mucus layer in which secretory IgA are trapped and the epithelial cells attached together through tight junctions. Therefore, lactic acid bacteria, by interfering with some of these components of the intestinal barrier can reinforce the host defenses. Different studies have suggested that L. casei GG was able to stabilize the intestinal permeability to macromolecules, particularly in the case of acute gastroenteritis in rats [62], but also to reverse the increase in intestinal permeability induced by cow’s milk in suckling rats [63]. A recent study using a guinea-pig model of cow’s milk allergy showed that feeding the guinea-pigs with a dried fermented milk led to a decrease in ß-lactoglobulin absorption at the jejunal level, compared with feeding animals milk [64].
Specific Immunity.
The effect of lactic acid bacteria on the secretory immune system has also been described. When antigens penetrate by the oral route, a secretory immune response is obtained which is mediated by secretory IgA or IgM. Various observations have reported that the administration of lactic acid bacteria improves the systemic and secretory immune response to particulate antigens and perhaps to soluble antigens.
In healthy volunteers, the oral administration of the L. johnsonii Strain LA1 was shown to increase the serum IgA concentration [65]; however, this result was not confirmed by others [66], who showed that the increase in serum IgA was small and that no modification of other Ig was detected.
In human volunteers ingesting an attenuated Salmonella typhi strain to mimic an enteropathogenic infection, the specific serum IgA titer was four-fold higher after three weeks in those who were supplemented with fermented milk (Lactobacillus acidophilus LA1 and bifidobacteria) than in those in the control group [65].
L. casei GG had an immunostimulating effect on oral rotavirus vaccination in infants. Infants who received L. casei GG showed an increased response with regard to rotavirus specific IgM secreting cells [67]. In addition, the same strain L. casei GG administered during acute rotavirus diarrhea in children has been shown to promote clinical recovery. This was associated with an augmentation of the local immune response to rotavirus since at convalescence 90% of the children supplemented with L. casei GG versus 46% in the control group developed an IgA specific antibody secreting cell response to rotavirus [17]. Viable L. casei GG were more efficient than heat inactivated L. casei GG in stimulating rotavirus-specific IgA secreting cells [19]. Although the hypothesis, that the beneficial effect of L. casei GG occurs through the increased secretory IgA response against rotavirus, seems to be attractive, one may wonder whether the IgA secretory response can be rapid enough (two to four days) to interfere with the infection, and other unknown mechanisms cannot be excluded.
Another effect of L. casei GG during rotavirus diarrhea could be the down-regulation of urease-producing bacteria overgrowth, thereby counteracting the disturbance of microbial balance observed during viral diarrhea [68].
The enhancement of the IgA secretory response against a soluble food antigen was also described in one study. The intestinal mucosal IgA response to ß-lactoglobulin was compared in two groups of mice fed a whey protein diet with or without a culture condensate of Bifidobacterium longum. Both total IgA and anti-ß-lactoglobulin IgA levels in tissue extracts of the small intestine were significantly higher in mice fed the B. Longum-containing diet than in control mice [69].
Other Possible Mechanisms
Trophic Effect.
Recently, in vitro studies of the modulation of proliferation and morphotype expression of rat intestinal epithelial cell line IEC-6 by fermented milk were described. Different fermented milks (Lactobacillus helveticus, Lactobacillus paracasei or bifidobacterium) or yogurt, as well as non-fermented milk were shown to enhance trophic response of IEC cells in a dose-dependent manner. Fermented milk was more efficient than milk in stimulating mitochondrial dehydrogenase activity and DNA synthesis [70]. However, it is not known whether yogurt presents the same trophic properties in vivo.
Down Regulation of Cow’s Milk Allergy?
Several studies from E. Isolauri’s group in Finland have suggested that probiotics (mainly L. casei GG) might be a novel approach in the management of food allergy. Indeed, in children allergic to cow’s milk proteins and presenting with atopic eczema, feeding an extensively hydrolyzed whey formula supplemented with L. casei GG improved the clinical score of atopic dermatitis and decreased the intestinal excretion of 
1-antitrypsin and TNF, compared with children fed the extensively hydrolyzed formula alone [71]. In addition, a possible mechanism was suggested since a mixture of bovine caseins hydrolyzed with L. casei GG-derived enzymes induced a suppression of lymphocyte proliferation [72] and a down regulation of anti-CD3 antibody-induced IL4 production [73], in vitro.
However, in the latter studies, it is not possible to analyze the respective role of casein-derived peptides and lactobacilli byproducts on these effects.
A short study of nine milk-hypersensitive adults, challenged with milk or L. casei GG-supplemented milk, suggested that the presence of the lactobacillus prevented the induction of phagocytosis through the complement receptor in monocytes [74].
Finally, in a guinea-pig model of cow’s milk allergy, the administration of milk or fermented milks (with Streptococcus thermophilus and bifidobacterium breve) were equally able to induce ß-lactoglobulin sensitization, suggesting that the ingestion of fermented milk instead of milk does not down-regulate the appearance of cow’s milk allergy [64].
Anti-inflammatory Effect?
Although results in that field are scanty, it has been reported that fermented milks may have some anti-inflammatory properties through their capacity to inhibit PAF. PAF is one of the most potent inflammatory phospholipid mediators secreted by proinflammatory cells. It is found in small amounts in dairy products. Recently, Antonopoulou et al. studied lipids with PAF and anti-PAF activity in cow’s milk and yogurt and found that Streptococcus thermophilus and Lactobacillus bulgaricus biosynthesized important quantities of PAF inhibitors [75].
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMECHANISMS INVOLVED IN DIARRHEAL...EFFECT OF LACTIC ACID...MECHANISMS INVOLVED IN THE...CONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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