May 4, 2016

Probiotics for the Prevention of Relapse of Ulcerative Colitis

Emerging trends in integrative gastroenterology
Study finds probiotics may be a promising low- to no-risk intervention to achieve remission for patients with inflammatory bowel disease.


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.

Key Findings 

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.

Practice Implications 

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. 

Clinical usefulness

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.

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