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Department of Medicine B, Rabin Medical Center, Beilinson Campus, and Laboratory of Physiopathology of Joints and Inflammation, Felsenstein Medical Research Center, Petah Tiqva, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;
* Weizmann Institute of Science, Rehovot, Israel;
Department of Pathology, Rabin Medical Center, Golda Campus, Petah Tiqva, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2To whom correspondence should be addressed. E-mail: avrahamw{at}post.tau.ac.il.
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ABSTRACT |
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-tropomyosin (TRM) or complete Freund’s adjuvant (CFA) to induce tropomyosin arthritis (TA) or adjuvant arthritis (AA), respectively. In both models, the rats were divided into 6 groups and fed 0.5 mL/d of the following suspensions: 1) heat-killed Lactobacillus GG (LGG) bacteria; 2) live LGG, both 1011 colony-forming units (cfu)/L; 3) sterilized milk; 4) plain yogurt; 5) yogurt containing 1011 cfu/L LGG; or 6) sterilized water. In the disease-prevention experiments, feeding started 1 wk before or after disease induction. In the therapeutic experiments, feeding was initiated at the onset of clinical arthritis. In all experiments, there were significant interactions between time and treatment (P < 0.001), except for milk, which had no effect in the therapeutic experiment. Histologically, rats fed yogurt containing LGG had a milder inflammation in all experiments (P < 0.05), whereas rats fed plain yogurt exhibited a moderate inflammatory score only in the prevention experiments. Anti-TRM antibody titers were not affected by any of the treatments in any of the experiments. Ingestion of live or heat-killed human LGG had a clinically beneficial effect on experimental arthritis. Our observation of the remarkable preventive and curative effect on arthritis using commercial yogurts containing lactobacilli, especially LGG, suggests the need for investigation of these agents in arthritic patients.
KEY WORDS: • Lactobacillus GG • experimental autoimmune arthritis • tropomyosin • adjuvant arthritis • milk products
Probiotics are viable microorganisms (bacteria or yeasts) that have a beneficial effect on the health of the host. They are used in foods, especially in fermented dairy products, and in pharmaceutical preparations. The most popular lactic acid bacteria are members of the genera Lactococcus and Lactobacillus, which have a long history of safe use (1). Humans and murine animals continue to secrete Lactobacillus GG (LGG)3 for up to 7 d after ingestion, and colon mucosa biopsies reveal intestinal colonization (2,3). Because probiotics modulate immune responses at the gut level, they are useful in the prevention or alleviation of certain intestinal infections, such as antibiotic-associated diarrhea (4), rotavirus enteritis (5), and pseudomembranous enterocolitis (6). They are also beneficial during cotreatment of other nonintestinal infections, namely, vaginosis, urinary tract infections (7), Helicobacter pylori gastritis (8), and in preventing respiratory tract infections in children (9). Studies on the use of probiotics in the treatment of noninfectious inflammatory disorders found that 4 strains of Lactobacillus and 1 strain of Streptococcus were effective in maintaining remission of ulcerative colitis and reducing the postoperative recurrence of Crohn’s disease (10). Although LGG improved the clinical status of children with Crohn’s disease (11), it did not affect endoscopic findings or clinical remission in adults, even after 12 mo of use (12). It also did not improve symptoms of irritable bowel syndrome (13). In a placebo-controlled trial, LGG ingestion prevented early atopic disease and reduced the frequency of atopic eczema in children at high risk of this disorder (14). The aim of the present study was to determine whether oral LGG might also attenuate extraintestinal inflammatory processes such as those found in a rat model of arthritis.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Tropomyosin arthritis (TA). Arthritis was induced in 9-wk-old Lewis rats in accordance with the methods described by Mor et al. (16). In the TA model, 2 strategies were followed. In the first strategy (designated Expt. 1, the preinduction prevention experiment) designed to assess the disease preventive properties of the feeding treatments, 72 rats were divided into 6 groups (n = 12) and fed daily via a rigid orogastric tube 1 of the following suspensions (0.5 mL), starting 1 wk (d –7) before disease induction (d 0): 1) sterile water (controls); 2) 108 colony-forming units (cfu) of heat-killed (autoclaved) LGG (Culturelle, Klaire Laboratories) suspended in 1 mL sterile water; 3) 108 cfu of live LGG suspended in 1 mL sterile water; 4) sterilized skimmed milk, 1% fat (Tnuva); 5) plain yogurt, 1% fat (fermented with 1011/L Lactobacillus bulgaricus) (Tnuva); and 6) yogurt, 1% fat, enriched with 1011/L LGG (Emmi). Rats were killed by CO2 inhalation on d 31, 10 d after the acute disease peaked and before the decline in joint inflammation.
The second strategy (designated Expt. 2, the therapeutic experiment) was designed to assess the therapeutic capacity of the treatments in the TA model induced in 72 rats [6 groups (n = 12)] that were fed the aforementioned suspensions, starting on d 14 after vaccination, when the arthritis was already clinically established. On the day of initiation, the clinical arthritis scores of all 6 treatment groups were similar. All rats were killed on d 44.
Adjuvant arthritis (AA). In this animal model, we induced arthritis in Lewis rats as described by Pearson (17) and Culigan et al. (18). Rats (n = 42) were divided into 6 treatment-feeding groups as described in TA Expt. 1 (n = 7). Feeding was started on d 7 after disease induction, during the latent phase of disease before the signs of clinical arthritis became apparent; this model was designated Expt. 3, the postinduction prevention experiment. These rats were killed on d 27 at the peak of the acute disease.
In both models, rats received 100 mg/kg daily of Paracetamol (Teva Pharmaceuticals) to relieve pain at disease onset.
All dairy products used in the experiments were purchased at the local grocery store, and were manufactured by the same company (Tnuva). The products were stored at 4°C and replaced by fresh products every 3 d. Both the viable and heat-inactivated bacterial suspensions were maintained at 4°C. All experiments were performed in accordance with the guidelines established by the Institutional Animal Care and Use Committee, Tel Aviv University, Israel.
Clinical disease activity score. In both experimental models, the rats were examined every 2 d for clinical arthritis. Each limb was scored on a 5-point scale for disease severity as follows: 0, no arthritis; 1, redness or swelling of 1 toe/finger joint; 2, redness and swelling of more than 1 toe/finger joint; 3, ankle and tarsal-metatarsal joint involvement; 4, entire paw red or swollen. We determined the total score by adding the 4 individual leg scores to a maximum score of 16 (18).
Histology score.
After the rats were killed, legs were removed up to the knees and fixed in 10% formalin containing 
4% v:v formaldehyde, and thereafter decalcified, dehydrated, paraffin-embedded, and cut into 4-µm sections. All of the sections were stained routinely with hematoxylin and eosin. A pathologist (M.H.), unaware of the group allocation and clinical activity score, evaluated the rats using a semiquantitative grading scale of 0–4. The following parameters were rated: 1) inflammatory cell infiltration into joint tissue; 2) synovial lining cell hyperplasia; 3) pannus formation; and 4) joint cartilage destruction. In addition, we rated bone damage/erosion on a scale of 0 to 5 as follows: 0, normal; 1, minimal loss of cortical bone at a few sites; 2, mild loss of cortical trabecular bone; 3, moderate loss of bone at many sites; 4, marked loss of bone at many sites; 5, marked loss of bone at many sites with fragmenting and full-thickness penetration of inflammatory process or pannus into the cortical bone (19,20). The total histology score was defined as the mean score of all the histological variables.
Measurement of anti-tropomyosin (TRM) IgG titer. The level of anti-TRM antibodies was detected by ELISA. Briefly, the ELISA plates were covered with 50 g/L TRM dissolved in 0.01 mmol/L bicarbonate buffer, pH 9.5, overnight at 4°C. Plates were blocked with standard Dulbecco’s PBS containing 50 g/L bovine serum albumin, and then washed. Rat sera, 100 µL diluted 1:40, were incubated overnight at 4°C. Plates were then washed, incubated with alkaline-phosphatase-conjugated goat anti-rat IgG monoclonal antibodies (Santa Cruz Biotechnology) diluted 1:2000 for 4 h at 37°C, and washed again. The enzyme substrate p-nitrophenyl phosphate (1 g/L) in the bicarbonate buffer was added, and the optical density in the wells was read at 405 nm. All materials, unless otherwise stated, were purchased from Sigma Chemical.
Statistics.
To assess the clinical effect of treatment, time exposure to treatment, and their interaction on arthritis intensity, the data were analyzed by two-way ANOVA with repeated measures ( = 0.05; SPSS program, version 11); post-hoc Tukey tests were used for multiple comparisons. To evaluate the differences between the various treatment groups in clinical and histology scores on the last day of the experiments, one-way ANOVA and post-hoc Tukey tests were conducted. A P-value < 0.05 was considered significant. Values in the text are expressed as means ± SD.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Experiment 3. Because the probiotic products possessed preventive and even therapeutic properties in the TA model, their prophylactic value was tested in a second murine autoimmune arthritis model (AA). Treatment was initiated after disease induction and 1 wk before its clinical manifestation (d 7) (Fig. 4). Results were similar to those of Expt. 1. Rats with AA benefited when the treatments were initiated after disease induction during the clinical latent phase. There was a significant interaction (P < 0.001) between time and treatment. Time had a significant (P < 0.001) effect
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In rats killed at the peak of clinical arthritis (d 27), histology score (Table 1) did not differ in inflammatory processes between the rats fed with Emmi and plain yogurt; these yogurt-treated groups differed (P < 0.05) from the milk-treated group. However, all 3 treatment groups had lower (P < 0.05) microscopic arthritis variables compared with the joint histology of the heat-killed LGG, live LGG, and water-treated groups. Anti-TRM antibodies were not detected by ELISA in sera of naïve rats (n = 5) or sera of AA rats (data not shown).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Therefore, it was important to explore the effect of human LGG in other autoimmune experimental models. The TA model is a novel T-cell dependent autoimmune disorder with clinical and histological features resembling Behçet disease in humans (16). Adjuvant arthritis is a classic murine model for rheumatoid arthritis (RA) since 1956 (17) and has been considered a prototype of Th1 disorders. Our data indicated that feeding dairy products fermented with lactobacilli, especially LGG, to rats with AA had a noticeable beneficial effect, surpassing even the effect of oral LGG alone. These results are in line with previous observations that the effects of probiotics on the host go beyond the adhesion, colonization, and proliferation of these microorganisms in the alimentary tract. Oral feeding of Lactobacillus casei to young nonobese diabetic mice inhibited the occurrence of autoimmune diabetes, prevented the disappearance of insulin-secreting ß cells, and regulated the host immune system response, as reflected by lower interferon-
and higher IL-2 production (27).
In the present study, a variety of preparations of LGG bacteria were employed. Live and heat-killed LGG in aqueous suspension had similar preventive effects in both experimental models, regardless of the timing of treatment (preinduction or preclinical phase, 7 d after induction). However, the underlying mechanism of this action remains unknown. Earlier studies demonstrated that different bacterial inactivation methods affect the intestinal mucosa adhesion capacity of probiotic strains in various ways. Inactivation by heat or gamma radiation generally decreased adhesion, whereas inactivation by UV radiation had no such effect (28). Furthermore, infants treated with the viable Lactobacillus casei strain had higher titers of serum IgA antibodies against rotavirus than infants treated with the inactivated bacteria (5).
The results of the present series of experiments indicated that the anti-inflammatory effect of LGG does not depend on the viability of the microorganism. Thus, we assume that a heat-stable bacterial wall, cell-membrane component, or intracellular component is responsible for this effect. Indeed, others reported that the cytoplasmic extract of heat-killed LGG, but not the cell wall extract, suppressed human mononuclear cells. Thus, probiotic bacteria apparently possess one or more heat-stable antiproliferative components (29). Another possibility is the induction of systemic immunomodulation by factors secreted by the bacteria or by the degraded milk ingredient metabolites. This is supported by in vitro studies showing that LGG-degraded casein suppressed T-cell activation and reduced IL-2 mRNA expression and protein kinase C translocation (30). It is also consistent with our observation that sterilized skimmed milk has a preventive effect similar to that of LGG in aqueous suspensions. Lactobacilli species are present in fresh milk before industrial processing, and heat-stable mediators may still be present in the commercial end products.
Of major interest is the impressive reduction in joint inflammation demonstrated by plain yogurt fermented with Lactobacillus bulgaricus and the yogurt containing LGG. Both of these products contain large amounts (1011 cfu/L) of live bacteria, which may exert their effects via changes in the microenvironmental flora of the intestines, or interactions with the gut epithelial cells or the bowel local immune cells. Accordingly, Rovensky et al. (31) treated AA rats with methotrexate and lyophilized probiotic bacteria Enterococcus faecium, enriched with organic selenium, alone or in combination, starting on the day of disease induction. Rats given the combination treatment had a significantly greater reduction in disease intensity than the methotrexate group; lyophilized Enterococcus faecium alone had no effect. In our study, however, even in an aqueous solution, the LGG bacteria had a significant anti-inflammatory effect. This discrepancy could be explained by the different probiotic bacteria tested, i.e., analysis of 8 different common lactobacillus strains in relation to mucosal induction of pro- and anti-inflammatory cytokines, IgA production by gut plasma cells, and systemic antibody responses against a parenterally administered antigen yielded different mucosal cytokine profiles and different adjuvant capacities (32). Kano et al. (33) demonstrated that oral intake of skimmed milk fermented with Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1 prevented collagen-induced arthritis in mice. A weaker beneficial effect was noted with fresh skimmed milk and with skimmed milk fermented with another strain of the Lactobacillus bulgaricus, OLL 1102. A polysaccharide fraction secreted by the OLL 1073R-1 bacteria also had an inhibitory effect on the development of collagen-induced arthritis.
Given these facts, our finding that a commercial dairy product containing LGG had the best anti-inflammatory effect in rats with clinically active arthritis is of major importance. When patients with RA were fed a combined diet of uncooked vegetables and lactobacilli- and chlorophyll-rich drinks, a decrease in subjective symptoms of arthritis was reported, although there was no discernible change in the objective measures of disease activity. However, 50% of the patients experienced adverse effects (nausea, diarrhea) and stopped the experiment prematurely (34). The agent responsible for this high rate of adverse effects was not identified. However, it is unlikely that the culprit was yogurt-containing LGG, which is consumed by millions of people every day. Other diet-related components associated with RA have been published. An epidemiologic study in Sweden found that early initiation of breast-feeding during inpatient care after delivery was positively associated with the prevalence of RA later in life (35). The "Mediterranean diet" was found to be beneficial in the reduction of arthritic pain in patients with RA (36). High-dose fish oil containing long-chain (n-3) PUFA as well as antioxidant consumption has a beneficial effect on arthritis intensity (37). Thus, the search for other possible beneficial dietary supplements, such as probiotics, may contribute to the continuous search for relief for patients suffering from such chronic disorders.
We noted no change in anti-TRM antibody titers among the treatment groups and no correlation between antibody titers and arthritis intensity. Therefore, this factor cannot serve as a serological marker for TA disease activity.
In conclusion, the human probiotic bacteria LGG, especially in the form of fermented yogurt, apparently exerts both preventive and therapeutic effects on the T-cell-dependent experimental arthritis employed. This finding has important implications for planning dietary intervention strategies in patients with RA. Further controlled, clinical studies are warranted to confirm our results.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AA, adjuvant arthritis; CFA, complete Freund’s adjuvant; cfu, colony-forming units; IL, Interleukin; LGG, Lactobacillus GG; RA, rheumatoid arthritis; TA, tropomyosin arthritis; TRM, tropomyosin.
Manuscript received 18 November 2003. Initial review completed 14 December 2003. Revision accepted 29 April 2004.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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