Yoshimatsu Y, Yamada A, Furukawa R, et al. Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis. World J Gastroenterol. 2015; 21(19): 5985-5994.
Single-center, randomized, double-blind, placebo-controlled study to examine the usefulness of 12 months of probiotic therapy in preventing relapse of ulcerative colitis (UC) in patients who were already in remission
Sixty subjects 13 years of age or older were randomly assigned to receive treatment or placebo, with 30 participants in each group. Forty-six subjects completed the study, with 23 in each group. Study participants were patients with UC in remission receiving outpatient treatment at Sakura Medical Center, Toho University.
The probiotic used in the treatment group, Bio-Three, consisted of a live preparation of 2 mg Streptococcus faecalis, 10 mg Clostridium butyricum, and 10 mg Bacillus mesentericus combined with lactose and potato starch. The treatment group received 9 Bio-Three tablets per day for 12 months in addition to their ongoing medications.
Use of agents with similar effects to the study drug, such as other active live microbial preparations, was prohibited.
Parameters Assessed/Primary Outcome Measures
The cumulative non-relapse rate was the primary outcome, using the Kaplan-Meier method to compare the Bio-Three group to the placebo group.
Patients who received treatment beyond maintenance therapies such as mesalazine or salazosulfapyridine were diagnosed with relapse and the study treatment and fecal sample collection discontinued. Fecal samples were collected immediately before and at 3, 6, 9, and 12 months of treatment. Samples were used for DNA extraction and organic acid measurement and results were clustered according to similarity of intestinal microflora.
At 12 months there was no statistically significant difference in the rate of relapse between subjects given Bio-Three compared to those given placebo. However, more detailed analysis revealed that among subjects whose microflora at onset of treatment was characterized by low numbers of Bifidobacteria (as identified via OTU124), the relapse rate was significantly lower in the treatment group and higher in the placebo group.
This study did not find significant difference between the probiotic and placebo groups in preventing relapse in these patients with ulcerative colitis. The beauty of this study is that it highlights 2 emerging trends in integrative gastroenterology; the first is the use of spore-forming microbes as probiotics, and the second is the use of population stratification to improve our ability to individualize therapeutic interventions.
The microbes used in this study
Spore-forming microbes have a significant history in the world market, and 2 (C butyricum and B mesentericus) of the 3 probiotics in Bio-Three are spore-formers.
The nonspore-forming microbes more commonly used in the North American market as probiotics for patients with ulcerative colitis are Lactobacillus and Bifidobacterium species. Five meta-analyses this decade have examined the use of Lactobacillus and Bifidobacterium probiotics to induce and maintain remission for people with ulcerative colitis. Each meta-analysis examined between 4 and 23 trials that included between 441 and 1,763 participants.1-5 They all found probiotics to be non-inferior to mesalamine in maintaining remission from UC, and most found that probiotics provided benefit over placebo at inducing remission as well. In particular, VSL#3 appears to elicit a beneficial response in 21% more subjects than placebo and to induce remission in 19% more subjects than placebo (absolute benefit, not relative benefit).5
Patients with UC in remission who have low fecal Bifidobacteria may be able to significantly prolong their remission with the use of Bio-Three or a comparable product.
Clostridium butyricum has been used as a human probiotic in Japan since 1968.6 It has been studied in pediatric and adult populations, alone and in combination with other probiotics, and has been shown to provide benefit superior to placebo for people experiencing antibiotic-associated diarrhea,7-8 infectious diarrhea,9 and vaginosis,10 and to reduce complications following pancreaticoduodenectomy11 and H pylori eradication therapy.12
Research on the effects of Bacillus mesentericus in isolation is still limited. It has been studied in vitro for its fibrinolytic activity13-14 and its role in antitumor vaccines.15 Additionally, isolates of B mesentericus supernatant have been shown to promote the growth of several strains of Bifidobacterium in vitro.16
Streptococcus faecalis (recently reclassified as Enterococcus faecalis) is not a spore-former. It is one of the 2 most common human isolates of enterococci (E faecalis and Enterococcus faecium), which have been most often represented in the literature for their role in the pathogenesis of endocarditis; urinary tract, intra-abdominal, pelvic, and wound infections; superinfections; and bacteremias.17 However, these species are also well-defined as part of the normal enteric flora in healthy human adults and have been used as probiotics, raising questions about the complex mechanism of the disease processes associated with this genus.18-19
Fecal microbiota population clustering and stratification
Advances in technology used to examine microbial communities have allowed researchers to begin stratifying patient groups based on populations of fecal flora.20-21 In this study the researchers used a clustering analysis to interpret differences in Terminal Restriction Fragment Length Polymorphism (T-RFLP) patterns. Methods to analyze T-RFLP data are still in development, including methodology for stratifying data from groups of more than 2. This analysis technique is being used to examine biomarkers based on intestinal microbiota, strengthening the evidence of a link between the intestinal microbiota and risk for inflammatory bowel disease.22
As in this particular study, stratifying groups of individuals based on pre- and post-intervention differences in symptoms, biomarkers, microbiota, single nucleotide polymorphisms (SNPs), other genetic and epigenetic markers, and other qualifiers may allow us to better individualize therapies in the future.
Patients with UC in remission who have low fecal Bifidobacteria [15% of the group who completed this study had about 3% Bifidobacteria in their stool (cluster I)] may be able to significantly prolong their remission with the use of Bio-Three or a comparable product. The remaining 85% of subjects who completed this study had 18% to 28% fecal Bifidobacteria (clusters II and III), and did not appear to benefit from the use of Bio-Three. There are specialty labs with stool panels that report CFU/g of Bifidobacteria and report a range of normals.23 This might allow clinicians to make better use of spore-forming and other probiotics.
No adverse changes were observed in any clusters of treatment groups compared to placebo, indicating that the use of Bio-Three is safe regardless of intestinal flora at the onset of treatment. Probiotic therapy with Bio-Three or similar probiotic appears to be a low- to no-risk intervention for increasing the likelihood of sustained remission for patients with UC, especially those with low Bifidobacteria. As fecal microbiota stratification becomes more advanced, we may be able to better individualize probiotic interventions for our patients with inflammatory bowel disease.
- Sang LX, Chang B, Zhang WL, Wu XM, Li XH, Jiang M. Remission induction and maintenance effect of probiotics on ulcerative colitis: a meta-analysis. World J Gastroenterol. 2010;16(15):1908-1915.
- Naidoo K, Gordon M, Fagbemi AO, Thomas AG, Akobeng AK. Probiotics for maintenance of remission in ulcerative colitis. Cochrane database Syst Rev. 2011;(12):CD007443.
- Shen J, Zuo ZX, Mao AP. Effect of probiotics on inducing remission and maintaining therapy in ulcerative colitis, Crohn’s disease, and pouchitis: meta-analysis of randomized controlled trials. Inflamm Bowel Dis. 2014;20(1):21-35.
- Fujiya M, Ueno N, Kohgo Y. Probiotic treatments for induction and maintenance of remission in inflammatory bowel diseases: a meta-analysis of randomized controlled trials. Clin J Gastroenterol. 2014;7(1):1-13.
- Mardini HE, Grigorian AY. Probiotic mix VSL#3 is effective adjunctive therapy for mild to moderately active ulcerative colitis: a meta-analysis. Inflamm Bowel Dis. 2014;20(9):1562-1567.
- Takahashi M, Taguchi H, Yamaguchi H, Osaki T, Komatsu A, Kamiya S. The effect of probiotic treatment with Clostridium butyricum on enterohemorrhagic Escherichia coli O157:H7 infection in mice. FEMS Immunol Med Microbiol. 2004;41(3):219-226.
- Seki H, Shiohara M, Matsumura T, et al. Prevention of antibiotic-associated diarrhea in children by Clostridium butyricum MIYAIRI. Pediatr Int. 2003;45(1):86-90.
- Investigating Group for Prevention of AAD in Children with Pneumonia by Clostridium Butyricum and Bifidobacterium. Multicenter, randomized, controlled clinical trial on preventing antibiotic-associated diarrhea in children with pneumonia using the live Clostridium butyricum and Bifidobacterium combined Powder [in Chinese]. Zhonghua Er Ke Za Zhi. 2012;50(10):732-736.
- Chen CC, Kong MS, Lai MW, et al. Probiotics have clinical, microbiologic, and immunologic efficacy in acute infectious diarrhea. Pediatr Infect Dis J. 2010;29(2):135-138.
- Chimura T. Ecological treatment of bacterial vaginosis and vaginitis with Bio-three [in Japanese]. Jpn J Antibiot. 1998;51(12):759-763.
- Nomura T, Tsuchiya Y, Nashimoto A, et al. Probiotics reduce infectious complications after pancreaticoduodenectomy. Hepatogastroenterology. 54(75):661-663.
- Shimbo I, Yamaguchi T, Odaka T, et al. Effect of Clostridium butyricum on fecal flora in Helicobacter pylori eradication therapy. World J Gastroenterol. 2005;11(47):7520-7524.
- Imshenetski? AA, Kasatkina ID, Cherkesova G V, Lebedeva IM. Fibrinolytic activity of Bacillus mesentericus strains [in Russian]. Mikrobiologiia. 1986;55(2):217-222.
- Nesterova NG, Cherkesova GV, Kirillova NF. Substrate specificity of enzymes from Bacillus mesentericus [in Russian]. Mikrobiologiia. 1989;58(4):553-556.
- Zatula DG. Experimental and clinical results of application of antitumor vaccines obtained by means of bacterial metabolism. Neoplasma. 1984;31(1):65-74.
- Seo G, Akimoto Y, Hamashima H, et al. A new factor from Bacillus mesentericus which promotes the growth of Bifidobacterium. Microbios. 2000;101(399):105-114.
- Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev. 1990;3(1):46-65.
- Franz CM, Huch M, Abriouel H, Holzapfel W, Gálvez A. Enterococci as probiotics and their implications in food safety. Int J Food Microbiol. 2011;151(2):125-140.
- Kayser FH. Safety aspects of enterococci from the medical point of view. Int J Food Microbiol. 2003;88(2-3):255-262.
- Schütte UM, Abdo Z, Bent SJ, et al. Advances in the use of terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rRNA genes to characterize microbial communities. Appl Microbiol Biotechnol. 2008;80(3):365-380.
- Andoh A, Sakata S, Koizumi Y, Mitsuyama K, Fujiyama Y, Benno Y. Terminal restriction fragment length polymorphism analysis of the diversity of fecal microbiota in patients with ulcerative colitis. Inflamm Bowel Dis. 2007;13(8):955-962.
- Fukuda K, Fujita Y. Determination of the discriminant score of intestinal microbiota as a biomarker of disease activity in patients with ulcerative colitis. BMC Gastroenterol. 2014;14:49.
- Genova Diagnostics. GI Effects® Comprehensive Profile - Stool. https://www.gdx.net/product/gi-effects-comprehensive-stool-test. Accessed March 11, 2016.