Lwwus_mcg_201620 139.144

Probiotics in the Treatment of Human Inflammatory Bartolomeus Joannes Meijer, MSc and Levinus Albert Dieleman, MD, PhD therapies are still relatively insufficient to cure IBD.
Abstract: Crohn’s disease, ulcerative colitis, and pouchitis after ileal Patients often become intolerant or refractory to standard pouch anal anastomosis in ulcerative colitis patients are often treatments, some of them with significant adverse effects.
refractory to standard therapy. Over the last decade, the rational to As a result, novel treatments have been studied to abrogate use probiotics and its beneficial efficacy in the treatment of chronic patients’ debilitating symptoms. Some of the alternative inflammatory bowel disease (IBD) is increasingly under scrutiny.
treatment options have included modulation of the Although it has become clear that intestinal epithelial-mucosalimmune interactions and enteric bacteria play a critical role in the intestinal microflora using probiotics.
development of IBD, the substantial clinical efficacy of probiotics The aim of this review is to provide a brief historical in these disorders is less evident. This review outlines the clinical perspective of the available evidence for the use of studies regarding probiotics before October 2007. These studies probiotics in IBD followed by a recent update of the formed the foundation of probiotic clinical trials in IBD, but they literature. The intent is to enhance the clinician perspective also indicated the need of larger and better-controlled studies than about the role of probiotic therapy within the array of the past experimental approaches. Furthermore, this review also examines in-depth the probiotic clinical trials published between2007 and December 2010, providing new insights into the role ofprobiotics for inducing and maintaining remission of IBD, and highlighting some of the breakthroughs, especially regarding A systematic literature search was conducted in the induction of remission for ulcerative colitis.
following databases: EMBASE, BIOSIS Previews, Medline, Key Words: Crohn’s disease, inflammatory bowel diseases, and PubMed. The following terms were used for searching: pouchitis, probiotics, ulcerative colitis, lactobacillus, bifidobacter- Crohn’s disease, ulcerative colitis, pouch, pouchitis, in- flammatory bowel diseases, and probiotic. Search resultswere separated into 2 groups with the first group consisting (J Clin Gastroenterol 2011;45:S139–S144) of results published before October 2007, and the secondgroup consisting of publications from 2007 throughDecember 2010. Results were restricted to human patients, Since 1997, when the treatment of chronic inflammatory written in the English language, and original research bowel disease (IBD) with Escherichia coli Nissle articles using only larger randomized controlled trials was studied, probiotic treatment for human IBD, including pouchitis, has been investigated and reviewed numerously.
At present, accumulating evidence suggests that thedynamic balance between microbes, particularly commen- sal flora, and host defensive responses at the mucosal frontier has a pivotal role in the initiation and pathogenesis of chronic In addition, susceptibility genes andenvironmental agents have shown importance in a dysfunc- For CD, a total of 9 studies were conducted before tional mucosal immune system in IBD. Despite an October 2007. However, only 2 small studies were increased understanding of its pathogenesis, the present associated with inducing remission for CD.
From the Department of Medicine, Center of Excellence for Gastro- Bousvaros et alreported no significant difference in intestinal Inflammation and Immunity Research, University of probiotic efficacy [4 Â 1010 colony forming units (CFU)] when compared with a placebo. In this RCT, 18 of the 75 Dr L.A. Dieleman is supported by Canadian Institutes of Health and patients relapsed, 33% of these relapsing patients had Research (CIHR), Crohn’s and Colitis Foundation of Canada(CCFC), and by the Broad Medical Research Program. Dr earlier surgery, 22% had not. Guslandi et randomized Dieleman is also a member of the Alberta Inflammatory Bowel 32 patients to either treatment with Saccharomyces Disease Consortium, funded by Alberta Innovates Health Solution.
boulardii or mesalamine (3 g/d). Both research arms were Dieleman is a consultant for Abbott Canada, Merck Canada Inc., homogenous for previous bowel resection, the probiotic Ferring and Abbott Nutrition. He has received research supportfrom Beneo-Orafti. The other author declares that he has nothing group showed an increased time to relapse relative to the mesalamine control In a 1-year trial in patients who Reprints: Levinus Albert Dieleman, MD, PhD, University of Alberta, did not undergo surgery,oral administration of E. coli Division of Gastroenterology, 2-24 Zeidler Ledcor Centre, Edmon- Nissle 1917 did not significantly increase the time to relapse ton, AB T6G 2 Â 8, Canada (e-mail: [email protected]).
Copyright r 2011 by Lippincott Williams & Wilkins J Clin Gastroenterol  Volume 45, Supp. 3, November/December 2011 J Clin Gastroenterol  Volume 45, Supp. 3, November/December 2011 Prantera et alreported no significant difference in Pouchitis is a relatively common occurrence in patients probiotic efficacy (Lactobacillus GG, 1.2 Â 1010 CFU) when with UC who undergo ileal pouch anal anastomosis after compared with a placebo. Similarly, Marteau et aland van colectomy. Trials examining the use of probiotics for Gossum et al,respectively, reported that Lactobacillus inducing remission of pouchitis have either been too small johnsonii did not prolong the time to relapse after surgery or uncontrolled to draw any conclusions regarding for CD, indicating that this probiotic strain was ineffective for maintenance therapy in CD, although these results were In maintaining remission, probiotic therapy was bene- weakened due to a high dropout rate.
ficial in all larger placebo-controlled studies using VSL In addition, a synbiotic preparation was studied by and 1 study using Lactobacillus rhamnosus Each study Chermesh et in 2007, who conducted a RCT to examine found significant improvements in extending the time to the efficacy of Synbiotic 2000 (a commercial mixture relapse. In fact, the placebo-controlled study by Gionchetti et containing 4 probiotics and 4 prebiotics) to extend the was the first report on the efficacy of probiotics for an duration of remission after surgery for CD. This was a small study and also suffered from a lot of dropouts.
During this 2-year follow-up, there were no significant differences with respect to either endoscopic or clinical relapses. However, the majority of patients had fistulizingCD, and their response to this treatment may differ from those who have inflammatory nonpenetrating disease No RCTs were found in which probiotics were used to induce remission in patients with CD.
Two large randomized controlled studies examining probiotic treatment for inducing remission in UC con- There were no studies regarding probiotics to prevent cluded that there were significant reductions in disease relapses in patients with CD. However, it is noteworthy to activity relative to the control One of these mention that Vilela et alresearched the effects of studies, conducted by Tursi et studied the efficacy of Saccharomyces boulardii on the intestinal permeability of balsalazide and a high potency probiotic mixture (VSL#3) patients with CD in remission. A small RCT with 15 and compared it to a group-administered balsalazide, or to patients on S. Boulardii versus 19 patients on placebo a group-administered mesalamine. The combination treat- demonstrated that patients treated with S. Boulardii and ment was most effective; it outperformed the comparator who remained in remission also improved their abnormal groups on symptoms assessment, endoscopic appearance, and histologic evaluation. The other study on preventing mild-to-moderate UC flares, conducted by Matthes et al,explored the effect of dosing probiotics, randomizing 90 patients to either 40 mL, 20 mL, or 10 mL enemas contain- Adding to open-label studies reported by Bibiloni ing E. coli Nissle 1917 (1 Â 108 CFU/mL) or placebo, et and Tursi et on the beneficial therapeutic effect concluding that remission rates significantly decreased of VSL#3 in inducing remission for UC, Sood et al according to dosing; 53%, 44%, and 27%, respectively.
performed a large randomized placebo-controlled trial in A third large randomized controlled study concluded that 2009 on adults with mild-to-moderate activity of UC, probiotic treatment was as effective as the standard administering 3600 Â 109 CFU of VSL#3. Concomitant mesalamine but this study suffered from a treatment with oral mesalamine, azathioprine, or 6- subtherapeutic mesalamine dose in the control group. In mercaptopurine, was continued on a stable dose. After 12 addition, findings on reductions in disease activity when weeks of treatment the remission rates in VSL#3 versus comparing probiotics to a mesalamine control group were placebo were 42.9% and 15.9%, respectively. Although this supported by Kato et alin a smaller RCT and in 2 open- study was well designed, a large dropout in the placebo group (20%) was an important limitation for this study.
For maintaining remission, 2 studies concluded Tursi et randomly assigned 144 adults with independently that E. coli Nissle 1917 did not significantly relapsing mild-to-moderate UC to either 3600 Â 109 CFU increase the time to versus 1.2 or 1.5 g/d of VSL#3 or placebo, as an adjunct to standard main- mesalamine. A third larger study also found that the same tenance treatment. Although there were no significant probiotic strain was as effective as the control group differences in obtaining clinical remission, there was a receiving mesalamine (significant equivalence, P=0.003).
significant clinical response in the VSL#3 group.
The low dose of mesalamine in the control group may have In addition, VSL#3 was investigated in children. Miele generated a “placebo” effect, thereby casting doubt as to et alstudied the efficacy of VSL#3 in adjunct to standard the efficacy of E. coli treatment for this indication. Two treatment with steroids and 5-aminosalicylic acid in the large studies using Lactobacillus salivarius or Bifidobacter- induction and maintenance of remission in 29 newly ium infantis did not show significant difference in preventing diagnosed patients with UC in a small randomized placebo- UC relapse versus placebo or 2.4 g mesalamine,but controlled trial. After steroid induction therapy, a high Zocco et concluded that Lactobacillus GG did prolong induction remission rate (92.8%) was achieved in patients on the length of remission. A combination of this probiotic VSL#3 (dose range from 450 to 1800Â 109CFU based on and mesalamine did not induce a synergistic therapeutic age) while on a stable dose of oral 5-aminosalicylic acid. In the placebo group, only 36.4% of patients obtained clinical J Clin Gastroenterol  Volume 45, Supp. 3, November/December 2011 TABLE 1. Summary of Studies Investigating the Effect of Probiotic Treatment on the Induction and Maintenance of Remission inInflammatory Bowel Disease Published Before October 2007 (symptoms assessment,endoscopic appearance,and histologicevaluation) treatment group: 27.3%(10 mL); 44.4% (20 mL),and 52.9% (40 mL) Bifidobacteriuminfantus (1 Â 109CFU) n=52/group VSL#3: commercial mixture containing Bifidobacterium longum, B. infantis, B. breve. Lactobacillus acidophilus, L. casei, L. delbrueckii subsp bulgaricus, L.
plantarum, and Streptococcus salivarius subsp thermophilus.
C indicates controlled; CAI, clinical activity index; CFU, colony forming units; DB, double-blind; L.GG, Lactobacillus rhamnosus GG; L. salivarius, Lactobacillus salivarius subsp Salivarius UCC118 strain; MP, mercaptopurine; NSD, no significant difference; R, randomized.
remission. VSL#3 was well tolerated in both adults and Matthes et confirmed Tursi previous findings; time to remission was indeed shortest in the E. coli Nissle 1917 In 2004, Tursi et studied a dose effect of E. coli 40 mL high-dose group. However, this trial was hampered Nissle 1917 for the induction of remission. A larger trial by by the high number of excluded patients.
J Clin Gastroenterol  Volume 45, Supp. 3, November/December 2011 corticosteroid induction or response. A relapse was defined In 2009, Miele et alreported that 21.4% of the if the Lichtiger colitis activity index score had increased >3 children treated with VSL#3 relapsed within 1 year after points. The relapse rate was 73.3% in the placebo arm.
TABLE 2. Summary of Studies Investigating the Effect of Probiotic Treatment on the Induction and Maintenance of Remission inInflammatory Bowel Disease Published After October 2007 in 32.5%VSL#3 vs. 10% inplacebo (P=0.001). 12 wk 51.9% VSL#3 vs. 18.9%placebo (P<0.001). 42.9%remission in VSL#3 vs.
15.7% in placebo(P<0.001).
63.1% VSL#3 vs. 40.8%placebo (P=0.01).
60.5% VSL#3 vs. 41.4%placebo (P=0.017).
NSD for remission andendoscopic scores corticosteroids in 92.8%(VSL#3) vs. 36.4% (placebo)(P<0.001).
after 3,6, and 12 mo inpatients on VSL#3 (P<0.01)Increased T-reg. cells.
VSL#3: commercial mixture containing Bifidobacterium longum, B. infantis, B. breve, Lactobacillus acidophilus, L. casei, L. delbrueckii subsp bulgaricus, L.
plantarum, and Streptococcus salivarius subsp thermophilus.
6-MP indicates 6-mercaptopurine; C, controlled; CFU, colony forming units; DB, double-blind; EcN, E. Coli Nissle 1917; IBDQ, inflammatory bowel disease questionnaires; NSD, no significant difference; O, open label; PDAI, pouchitis disease activity index; R, randomized, UCDAI: ulcerative colitis disease activity index.
J Clin Gastroenterol  Volume 45, Supp. 3, November/December 2011 The effects of Bifidobacterium Longum on the quality sistent use of conventional adjuvant medicines. Moreover, of life was investigated by Fujimori et by assessing some studies often lack appropriate randomization, blind- inflammatory bowel disease questionnaire (IBDQ) scores from 120 randomly assigned patients with UC who were in Long-term maintenance studies using probiotics are remission or had only mildly active UC. These patients still lacking. As a result, the effectiveness of prolonged were randomly assigned to either probiotics (2 Â 109CFU of probiotic use and potential adverse events over an extended Bifidobacterium Longum), prebiotics (8 g psyllium), or their period of time still remains unknown.
combination, also called synbiotics.After 4 weeks, there The clinician has a responsibility to communicate the was no improvement in IBDQ scores in the prebiotic or use of probiotic treatment to patients with IBD as a probiotic group. However, there was a significant improve- potential treatment option, especially for UC.Many ment in the synbiotic group. The authors also reported that patients with IBD do not disclose probiotic usage to their hemoglobin and hematocrit increased overtime (P=0.04) clinicians either voluntarily, or in response to a direct in the probiotic group, C-reactive protein decreased in the Indeed, a German survey indicated that 43% synbiotic group, and that no such changes were found using of patients with IBD consumed probiotic treatments on a regular basis.This situation is not restricted to adult oradolescent patients with IBD, as a large proportion of patients are provided with probiotics by their fellow patients.However, patients with IBD should be Between 2007 and 2010 no RCTs were found in which informed that for some indications, such as CD, the probiotics induced remission in patients with chronic improvements may be marginal and that probiotic treat- ment does not replace standard medicines. By providingsufficient information on their use and efficacy, the patientis less prone to be confused by online information, “patient testimonies,” and the “media hype” that may be misleading In 2008, a randomized controlled study by Pronio et alreported that VSL#3, administered at various times Future studies to investigate probiotics regarding their after ileal pouch anal anastomosis, reduced the Pouchitis clinical efficacy in IBD, and studies on the pathogenesis of Disease Activity Score slightly but significantly in patients IBD and bacterial species in the gut biome, will provide without acute pouchitis (n=18) compared with the placebo necessary information and help develop more effective and arm (n=13). This beneficial effect was accompanied by an rational probiotic therapies in the quest to find a cure for expansion of regulatory T lymphocytes in the pouch.
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