By Carrie Decker, ND
Founder and Medical Director,
Blessed Thistle,
Madison, WI
Dr. Decker reports no financial relationships relevant to this field of study.
Synopsis: In this randomized, double-blind, placebo-controlled study, the probiotic strain Lactobacillus casei 01 was provided to women with rheumatoid arthritis at a dosage of 108 colony forming units for a period of 8 weeks and compared to a placebo treatment. Disease activity score and levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-12 were found to be significantly decreased at the end of the intervention. Additional parameters of state and trait anxiety were also evaluated and were not significantly altered by therapies.
Source: Vaghef-Mehrabany E, et al. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition 2014;30:430-435.
Summary Points
- Women with inactive to moderate rheumatoid arthritis (medication stable) were supplemented with 108 colony forming units of Lactobacillus casei 01 or a placebo daily for 8 weeks.
- Levels of proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-12 were observed to be significantly decreased from baseline in the intervention group at the end of the 8 weeks.
- The disease activity score (based on the number of tender and swollen joints, serum C-reactive protein, and visual analog scale questionnaire of global health) was found to be significantly decreased in the probiotic group at the end of the intervention.
- No change was found in state or trait anxiety with the intervention.
Probiotics have been used in a variety of disorders for modulation of immune system function and inflammation. Some strains have been shown to stimulate immune system function,1 while others moderate hyperactive function or type of immune response.2,3 Studies have been performed to investigate the effect of various Lactobacillus spp. and other probiotics strains on immune response and inflammatory markers in animal models4,5 and human studies6,7 of rheumatoid arthritis (RA), a disease with pathology primarily attributable to immune system dysregulation and inflammation.
In this double-blind, placebo-controlled trial, 60 women with inactive to moderate RA were randomized to treatment with probiotics strain Lactobacillus casei 01 or a placebo (maltodextrin) for 8 weeks. Probiotic and placebo were provided in identical capsules and refrigerated, and participants were instructed to take the supplements once daily on an empty stomach. The dosage of L. casei provided was 108 colony forming units (CFU) daily.
Study participants were required to have been diagnosed with RA by the criteria of the American College of Rheumatology for more than 1 year and on a stable medication regime for more than 3 months prior to the intervention. Medications that individuals in the study were allowed to take were methotrexate, hydroxychloroquine, and prednisolone. Individuals were excluded from the study if they were using non-steroidal anti-inflammatory drugs or cytokine inhibitors, were pregnant or lactating, were using hormone therapies, had additional known inflammatory disorders such as inflammatory bowel disease, had digestive disorders including lactose intolerance, or had recent use of antibiotics or other vitamin or probiotic therapies.
Parameters assessed in the study included the levels of interleukin (IL) cytokines IL-1ß, IL-6, IL-10, IL-12, and tumor necrosis factor-α (TNF-α). Disease activity score (DAS), a calculated parameter, was determined based on the number of swollen and tender joints as assessed by a rheumatologist, serum high-sensitivity C-reactive protein (hs-CRP), and a visual analog scale (VAS) questionnaire for global health. State and trait anxiety were assessed using the Spielberger State-Trait Anxiety Inventory Form Y. All parameters were assessed at baseline and 8 weeks after the intervention.
No adverse effects were reported with the intervention. Thirty people were originally enrolled in each group, with 22 and 24 people completing the study in the intervention and placebo groups, respectively. Individuals did not complete the study due to reasons such as medication changes, altered activity level, vacation, and unwillingness to complete therapies.
Upon completion of the 8-week intervention, DAS was significantly decreased in the probiotic group compared to baseline (P < 0.01), but did not change significantly in the placebo group. The parameters used for the DAS calculation (number of tender and swollen joints, VAS score, and hs-CRP) were also all significantly decreased in the probiotics group (P < 0.05); however, values were not reported in this study. The serum levels of the inflammatory cytokines TNF-α, IL-12, and IL-6 significantly decreased (P < 0.05) in the probiotics group but increased (significance not assessed) in the placebo group (see Table 1). Confidence intervals associated with these changes were not assessed. No change was observed in state or trait anxiety in either group. No adverse effects were reported.
Table 1: Serum Levels of Inflammatory |
||
Parameter |
Placebo group |
Probiotic group |
TNF-α (pg/mL) |
||
Baseline |
3.60 (2.32, 5.10) |
5.00 (2.75, 9.60) |
Study End |
3.65 (2.05, 5.40) |
4.05 (1.60, 6.37) |
IL-12 (pg/mL) |
||
Baseline |
187.25 |
422.85 |
Study End |
236.60 |
342.25 |
IL-6 (pg/mL) |
||
Baseline |
8.80 (1.52, 122.67) |
22.30 (1.65, 43.05) |
Study End |
11.55 (0.00, 141.02) |
20.55 (0.90, 41.22) |
Values expressed as median (25th and 75th percentile) |
||
Commentary
Probiotics have been the focus of a wide variety of research for conditions ranging from allergies2 to metabolic syndrome8 to reduction of occurrence of the common cold.9 Within the species Lactobacillus, several strains of L. casei have been isolated, most commonly being found in plant materials, human gastrointestinal tracts, and cheeses.10 Subspecies within the family L. casei have been found in animal studies of RA to reduce levels of proinflammatory cytokines5 and alter the immune response,4 hence the investigation of their use in this clinical study of RA.
The dosage of L. casei utilized in this study (108 CFU/day) is a relatively low dose for probiotic supplementation. Often, studies utilize probiotics dosages a level of magnitude, or even two levels, higher than this. The reasoning behind the low dosage was not discussed in this study, although it was mentioned that L. casei 01 has been reported to have greater adhesion to intestinal cells than the commonly used strain L. casei Shirota.11 Other studies have found similar effectivity with lower and higher probiotics dosages,12 suggesting that dosage may not be critical, or even that the effect can be variable, finding increased inflammation with higher doses.13
Neglected by the authors of this study was consideration for the difference between groups in baseline levels of a majority of the cytokines measured. Each of the cytokines that was found to be significantly decreased from baseline (within group changes) in the probiotics group initially was considerably higher than the placebo group. The baseline median values in the two groups with the 25th and 75th percentile ranges can be seen in Table 1.
Given the known relapse-remission course of autoimmune disease with disease flares, it may have been that more of the individuals randomized to the probiotic group initially were experiencing a greater amount of disease activity. Data utilized for the calculation of the DAS parameter, although not provided in this study but reported in an alternate publication,14 also indicates that this may have been the case, as the serum hs-CPR at baseline was initially higher in the probiotics vs placebo group (3.10 mg/L [1.32, 18.01] vs 2.30 mg/L [1.23, 7.99]). A longer duration of study, with additional times when data were assessed, would have shed light on this.
As with many study protocols using nutritional therapies, the participants were on the standard treatments for disease control, in this case methotrexate, hydroxychloroquine, and prednisolone. The number of individuals in the placebo and probiotics group on each medication was not significantly different (P = 0.229, 0.725, and 1.00, respectively). Some individuals were also on combination therapies of these medications. Although the relative number of individuals in the placebo and probiotic group on each medication was similar, there are many reasons to anticipate the findings would be different depending on the specific pharmaceutical being utilized. Methotrexate has been shown to alter cytokine expression of IL-12 and IL-6, while other cytokines such as IL-18 (not assessed in this study) are not affected by methotrexate in the absence of corticosteroids but are reduced with combination therapies.15 Additional mono and combinatory effects with the other medications participants were using are also anticipated.
In conclusion, although a beneficial effect was observed within the individuals taking the probiotics strain L. casei, the results of this study are at best suggestive that this therapy may improve inflammation and disease symptoms of RA. Other studies utilizing probiotics supplementation (Bacillus coagulans or Lactobacillus rhamnosus GR-1 with Lactobacillus reuteri RC-14) in RA have had similarly mixed results with improvements in pain and functional scores and some or no improvement in markers of inflammation.6,7 However, as no adverse effects were seen with supplementation, it is acceptable for individuals with RA to take a form of probiotics as a supplement if they choose to. It may be that the various strains that have been studied for use in RA are better to select, as they have not been shown to have adverse effects; however, that does not eliminate the possibility that other strains may offer benefit.
References
- Galdeano CM, Perdigón G. The probiotic bacterium Lactobacillus casei induces activation of the gut mucosal immune system through innate immunity. Clin Vaccine Immunol 2006;13:219-226.
- Isolauri E, et al. Probiotics: Use in allergic disorders: A Nutrition, Allergy, Mucosal Immunology, and Intestinal Microbiota (NAMI) Research Group Report. J Clin Gastroenterol 2008;42(Suppl 2):S91-S96.
- Shida K, et al. Flexible cytokine production by macrophages and T cells in response to probiotic bacteria: A possible mechanism by which probiotics exert multifunctional immune regulatory activities. Gut Microbes 2011;2:109-114.
- So JS, et al. Lactobacillus casei suppresses experimental arthritis by down-regulating T helper 1 effector functions. Mol Immunol 2008;45:2690-2699.
- Amdekar S, et al. Lactobacillus casei reduces the inflammatory joint damage associated with collagen-induced arthritis (CIA) by reducing the pro-inflammatory cytokines: Lactobacillus casei: COX-2 inhibitor. J Clin Immunol 2011;31:147-154.
- Mandel DR, et al. Bacillus coagulans: A viable adjunct therapy for relieving symptoms of rheumatoid arthritis according to a randomized, controlled trial. BMC Complement Altern Med 2010;10:1.
- Pineda Mde L, et al. A randomized, double-blinded, placebo-controlled pilot study of probiotics in active rheumatoid arthritis. Med Sci Monit 2011;17:CR347-354.
- Leber B, et al. The influence of probiotic supplementation on gut permeability in patients with metabolic syndrome: An open label, randomized pilot study. Eur J Clin Nutr 2012;66:1110-1115.
- Berggren A, et al. Randomised, double-blind and placebo-controlled study using new probiotic lactobacilli for strengthening the body immune defence against viral infections. Eur J Nutr 2011;50:203-210.
- Cai H, et al. Genotypic and phenotypic characterization of Lactobacillus casei strains isolated from different ecological niches suggests frequent recombination and niche specificity. Microbiology 2007;153:2655-2665.
- Tuomola EM, Salminen SJ. Adhesion of some probiotic and dairy Lactobacillus strains to Caco-2 cell cultures. Int J Food Microbiol 1998;41:45-51.
- Gill HS, et al. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr 2001;74:833-839.
- Zhang L, et al. Alive and dead Lactobacillus rhamnosus GG decrease tumor necrosis factor-alpha-induced interleukin-8 production in Caco-2 cells. J Nutr 2005;135:1752-1756.
- Alipour B, et al. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: A randomized double-blind clinical trial. Int J Rheum Dis 2014;17:519-527.
- Hobl EL, et al. The influence of methotrexate on the gene expression of the pro-inflammatory cytokine IL-12A in the therapy of rheumatoid arthritis. Clin Exp Rheumatol 2011;29:963-969.
In this randomized, double-blind, placebo-controlled study, the probiotic strain Lactobacillus casei 01 was provided to women with rheumatoid arthritis at a dosage of 108 colony forming units for a period of 8 weeks and compared to a placebo treatment. Disease activity score and levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-6, and interleukin-12 were found to be significantly decreased at the end of the intervention. Additional parameters of state and trait anxiety were also evaluated and were not significantly altered by therapies.
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