Probiotics in experimental animal models

Several animal models such as pigs, transgenic mice and knockout mice, have been used to study the effects of probiotics. In this respect,

Ohashi et al. (58) described several studies in which they determined the effect of fermented milk prepared with L. casei strain Shirota on indigenous lactobacilli in pig large intestine for 2 weeks. A significant increase of acetate, propionate, and fecal organic acid concentration was observed. The fer­mented milk significantly reduced the fecal pH. Although the number of Shirota-strain bacteria in the intestinal contents (104) was much smaller than those of indigenous lactobacilli (108) CFU/g, the number of indigenous lactobacilli and bifidobacte­ria in pig intestine increased with fermented milk. Moreover, the phenotypic diversity of indigenous lactobacilli increased from three to eight with the fermented milk supplementation. The conclusion was that the fermented milk affected the in­digenous Lactobacillus population and constitution (58).

In another study, Ohashi et al. (59) determined the effect of fermented milk prepared with L. casei strain Shirota on colonic motility by the strain gauge force transducer in a pig model. The con­tractions of the circular muscle layer of the cecum, upper colon, lower colon, and terminal colon in pigs were directly measured using this method in conscious animals. Feeding significantly stimulat­ed the motility of the upper and lower colon and defecation significantly stimulated the motility of the upper and terminal colon. Feeding pigs with fermented milk for 2 weeks significantly activated the response to feeding in four portions of the large intestine. It increased motility of the terminal colon that did not promote defecation. The effects may be related to the stimulation of colonic fermentation as shown by a decrease in fecal pH (59).

In a 4-week ovalbumin-specific T-cell receptor transgenic mice food allergy model, Shida et al. (60) studied the ability of heat-killed Lactobacillus Shirota by using allergen-synthesized murine splenocyte cultures. The transgenic mice were fed a diet containing ovalbumin and injected with Lactobacillus Shirota intraperitoneally three times in the first week. Serum IgE and IgG1 responses as well as cytokine and antibody secretion by splenocytes were examined. Lactobacillus Shirota suppressed IgE production through promoting a dominant Th1-type response mediated by IL-12 in­duction. Furthermore, the inhibitory effect of Lactobacillus Shirota on systemic anaphylaxis in­duced by intravenous challenge of ovalbumin-fed ovalbumin-specific T-cell receptor transgenic mice with ovalbumin was tested. The results of this study suggested that intraperitoneal injection of Lactobacillus Shirota induced an IL-12 response in the serum of ovalbumin-specific T-cell receptor transgenic mice. In the food allergy model, Lactobacillus Shirota administration skewed the pattern of cytokine production by splenocytes to­ward Th1 dominance, and suppressed IgE and IgG1 secretion by splenocytes. On the other hand, anti-IL-12 antibody treatment seems to blocked the ability of Lactobacillus Shirota to modulate cytokine production. Moreover, Lactobacillus Shirota inhibit­ed serum ovalbumin-specific IgE and IgG1 re­sponses and also diminished systemic anaphylax­is. This suggests a possible use of this lactic acid bacterium in preventing food allergy.

In mouse feeding trials, milk-containing L. sali­varius strain UCC118 was found to successfully colonize the murine gastroint~stinpl tract (18). In another study, Kato et al:(61) described the marked antitumor activities and ability to modify immune responses of the lactic acid bacterium L. casei strain Shirota. In this study, they examined the possibility of Lactobacillus Shirota to induce the production of IL-12 as in Shida et al., and also ex­amined IFN-y. These are important cytokines for antitumor and antimicrobial immunity, from murine splenocytes in vitro in order to clarify the mechanisms of its immune modification. Stimulation by Lactobacillus Shirota induced a marked production of IL-12 by X-ray-irradiated splenocytes. IFN-y was produced by splenocytes by the stimulation with concanavalin A. Lactobacillus Shirota showed a synergistic stimulatory effect on the concanavalin A-induced production of IFN-y, which was reduced by anti-IL-12 antibody treatment. IFN-y production by splenocytes resulted from the production of IL­12 from X-ray-irradiated splenocytes stimulated by Lactobacillus Shirota. Furthermore, in BALB/c mice, the oral administration of viable Lactobacillus Shirota increased the production of IFN-y but not that of IL-4 or IL-5 by splenocytes.

With regard to inflammatory bowel disease, it is interesting that in an experimental model, IL-10 deficient mice develop spontaneous colitis with fea­tures similar to the inflammation observed in patients with Crohn's disease. Histological damage begins within 4 weeks and reaches a plateau after 8 weeks. In these mice, within 2 weeks of age and before injury, there is alteration in bacterial colo­nization and an increase in translocated and mu­cosal adhered bacteria. These alterations reached a steady state 1 month before maximal histological O. Karimi and A.S. Pena injury and persisted for months. It is of note that the concentration of Lactobacillus spp., a species that prevents adhesion of pathogens, was reduced within 2 weeks and reduced in a pattern paralleling mucosal injury (62).

L. plantarum attenuated an established colitis in the same knockout model (49). In a recent study, Konrad et al. (63) investigated the effect of soluble bacterial antigens extracted from E. coli (strain Laves) on the disease activity of murine colitis. C3H. IL-10 deficient and BALB/c mice with dextran sulfate sodium-induced colitis were treated with a bacterial lysate from E. coli or with placebo. Mice were monitored and inflammation was assessed by histological scoring, analysis of fecal IL-1 p and measurement of cytokine production by ELISA. Tcell proliferation was quantified by 3H-thymidine incorporation. The results showed that the use of E. coli lysate was effective in the improvement of murine colitis. This effect may be caused by a decreased Th1 reaction and by an induction of tolerance against bacterial antigens.



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