Clinical research
A meta-analysis of the benefit of probiotics in maintaining remission of human ulcerative colitis: evidence for prevention of disease relapse and maintenance of remission

Introduction
Ulcerative colitis (UC) is a chronic inflammatory process, which diffusely affects the superficial mucosa of the colon [1]. Although the aetiology of UC is unknown, genetic and environmental factors are thought to be involved in the pathophysiology of UC [2-6]. The role of intestinal microorganisms in inflammatory bowel disease cannot be ignored. It has been found that inflammation is more frequent in areas with the highest bacterial concentration and in active UC viable enteric bacteria invade mucosal ulcers, which results in fistula. A germ-free environment attenuates or prevents inflammation in many transgenic or knockout mutant murine models of colitis [7]. Thus, change of the luminal contents with antibiotics or probiotics may be a potentially effective therapeutic option [8, 9]. Our recent meta-analysis studies demonstrated the effectiveness of antibiotics in inducing remission in UC [10] and Crohn’s disease (CD) [11] and probiotics in the management of pouchitis [12] but failed to demonstrate the efficacy of probiotics in maintaining remission and preventing clinical and endoscopic recurrence in CD [13]. Probiotics are living microorganisms such as lactic acid bacilli, Lactobacillus, Bifidobacterium, Escherichia coli Nissle 1917, Clostridium butyricum, Streptococcus salivarius thermophilus, and the nonpathogenic yeast Saccharomyces boulardii. Classically, the natural history of UC includes periods of disease flare-up and remission, and treatment in UC is directed towards inducing and maintaining remission of symptoms and mucosal inflammation. Once remission is achieved with any of the therapeutic schemes available, up to 70% of the patients given no treatment are expected to relapse within a 1-year period [14, 15]. Aminosalicylates are well established for maintaining remission in patients with UC [16] but their use was limited by side effects. Currently, probiotics are suggested for maintaining remission in UC and preventing relapse of inactive disease [14, 17]. There have been no reports of severe adverse events with the use of probiotics in humans in the context of clinical trials [18]. Because of the potential benefits and safety of probiotics, we considered performing a meta-analysis of the efficacy of probiotics in preventing relapse and comparing the efficacy of them with mesalazine as a standard treatment for maintaining remission in patients with UC.
Material and methods
PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched for studies investigating the efficacy of probiotics in maintaining remission in patients with UC. Data were collected from 1966 to 2008 (up to January). The search terms were: “probiotic” and “ulcerative colitis”. The search was limited to English language. The reference list from retrieved articles was also reviewed for additional applicable studies. Relapse rate was the key outcome of interest. Relapse was defined as the appearance of UC symptoms and/or signs which needed additional medical treatment or any increase in colitis activity index (CAI) to more than 4 points. Three reviewers independently examined the title and abstract of each article to eliminate duplicates, case studies, and uncontrolled trials. Studies that did not determine our desirable outcome (relapse rate) and those whose target groups were not patients with UC (patients with CD or pouchitis) were excluded from the meta-analysis. Data from selected studies were extracted in the form of 2 × 2 tables. All included studies were pooled and weighted. The data were analyzed using StatsDirect ver. 2.6.2. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated using the Mantel-Haenszel method. The Breslow-Day test was used to test for heterogeneity. The event rate in the experimental (intervention) group against the event rate in the control group was calculated using a L’Abbé plot, as an aid to explore the heterogeneity of effect estimates. Funnel plot analysis was used as a publication bias indicator.
Results
The electronic searches yielded 739 items: 209 from PubMed, 2 from Cochrane Central, and 528 from Embase. Of those, 10 trials were scrutinized in the full text. Six reports were considered eligible and thus included in the meta-analysis (Figure 1) [14, 17-21]. The final comparison included 2 randomized controlled trials [17, 18] which compared the efficacy of probiotics against placebo and 4 randomized controlled trials [14, 19-21] which compared the efficacy of probiotics against mesalazine for maintaining remission in patients with UC. Two controlled trials represented 55 patients with UC who were randomized to receive probiotics or placebo [17, 18]. Patients’ characteristics, type and dosage of probiotic, duration of treatment, treatment before the study and relapse rate are shown in Table I. Relapse rate in the probiotic group was 23.1% (6 of 26) and in the placebo group was 92% (23 of 25). The summary OR (fixed effects) for relapse of disease under probiotic therapy in two trials [17, 18] was 0.0269 with a 95% CI of 0.0049-0.1478, a significant OR (P<0.0001, Figure 2A). The Breslow-Day test for heterogeneity (P=0.6267) indicated that the studies are not significantly heterogeneous (Figure 2B) and the fixed effects meta-analysis for individual and summary of OR was applied. Regression of normalized effect versus precision for included studies for “relapse with probiotic therapy” cannot be calculated because of too few strata. Four controlled trials represented 533 patients with UC who were randomized to receive probiotics or mesalazine [14, 19-21]. Patients’ characteristics, type and dosage of probiotic, mesalazine dosage, duration of treatment, treatment before the study and relapse rate are shown in Table II. Relapse occurred in 31.8% (84 of 264) of the probiotic group and 32.7% (88 of 269) of the mesalazine group. The characteristics of these four studies are shown in Table II. The summary OR for relapse of disease among probiotics intake vs. mesalazine therapy in four trials [14, 19-21] was 0.99 with a 95% CI of 0.67 to 1.48, a non-significant OR (P=0.9419, Figure 3A). The Breslow-Day test for heterogeneity (P=0.6957) indicated that the studies were homogeneous and could be combined and the fixed effects meta-analysis for individual and summary of OR was applied (Figure 3B). Regression of normalized effect versus precision for included studies for “relapse with probiotic therapy” was –0.465895 (95% CI –6.734089 to 5.8023, P=0.7794), and Kendall’s test on standardized effect vs. variance indicated tau =0.333333, P=0.75 (Figure 3C).
Discussion
The present meta-analysis showed that probiotics are effective in maintaining remission and their effect in preventing relapse is comparable with mesalazine. It has been well established that the composition of gut microflora in IBD patients changes to increased pathogenic bacteria and decreased bifidobacteria and lactobacilli. This imbalance between aggressive and beneficial bacterial species results in the development of chronic intestinal inflammation and thus positive effects of probiotics seem rational [22, 23]. Three main mechanisms for beneficial effects of probiotics can be illustrated including alteration of the enteric microbiota, modulation of the host immune response, and enhancement of the barrier function through interactions with epithelial and immune cells in the gut [23]. The results of our recent meta-analysis showed that probiotics are not more beneficial than placebo for maintaining remission and preventing clinical and endoscopic relapses in patients with CD [13]. It should not be forgotten that the type of probiotics varies and this issue might influence the efficacy of probiotics. In most of the trials included in that meta-analysis, lactobacillus was the main bacteria of the probiotic preparation, while in the present meta-analysis bifidobacterium was the major component. Thus, the different results obtained from these two meta-analyses may be due to different probiotic preparations used for treatment. Moreover, the dominant bacterial flora in patients with UC differs from those diagnosed with CD, and this implicates that a different strategy targeting bacterial flora should be used for these patients [24, 25]. It is also important to remember that the efficacy of one probiotic may not be the same in all patients or in the same patient with different types of disease. Responsiveness to treatment is dependent on several variables, including characteristics of the host (age, sex, lifestyle, compliance), the lesions (site, extent, type of gross lesions), previous history (presence, number and type of resections), and risk factors (smoking, appendectomy, familial history of inflammatory bowel disease) [26]. The collected studies evaluating the efficacy of probiotics in maintaining remission in patients with UC indicate a benefit of probiotics in prevention of disease relapse equal to that of mesalazine as a standard treatment. This positive effect of probiotics is most commonly mediated through antagonistic activity against pathogenic bacteria either by inhibition of adherence and translocation or by production of antibacterial substances, modulation of intestinal cytokine production, anti-inflammatory properties, and improvement of gut permeability [27, 28]. Comparing mesalazine and probiotics, probiotics are known to have fewer side effects, more tolerability and better compliance of the patients. Therefore, considering the similar efficacy in preventing relapse shown by both types of treatment, probiotics seem to be an appropriate alternative to mesalazine or a supplement in maintaining remission in patients with UC. The role of probiotics in the maintenance treatment of UC needs to be further assessed by larger controlled trials in future.
References
1. Shen EH, Das KM. Current therapeutic recommendations: infliximab for ulcerative colitis. J Clin Gastroenterol 2004; 38: 741-5. 2. Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006; 12 (Suppl 1): S3-9. 3. Andus T, Gross V. Etiology and pathophysiology of inflammatory bowel disease-environmental factors. Hepatogastroenterology 2000; 47: 29-43. 4. Koutroubakis I, Manousos ON, Meuwissen SG, Pena AS. Environmental risk factors in inflammatory bowel disease. Hepatogastroenterology 1996; 43: 381-93. 5. Rezaie A, Parker RD, Abdollahi M. Oxidative stress and pathogenesis of inflammatory bowel disease: an epiphenomenon or the cause? Dig Dis Sci 2007; 52: 2015-21. 6. Jahanshahi G, Motavasel V, Rezaie A, Hashtroudi AA, Daryani NE, Abdollahi M. Alterations in antioxidant power and levels of epidermal growth factor and nitric oxide in saliva of patients with inflammatory bowel diseases. Dig Dis Sci 2004; 49: 1752-7. 7. Gionchetti P, Rizzello F, Campieri M. Probiotics and antibiotics in inflammatory bowel disease. Curr Opin Gastroenterol 2001; 17: 331-5. 8. Mach T. Clinical usefulness of probiotics in inflammatory bowel diseases. J Physiol Pharmacol 2006; 57 (Suppl 9): 23-33. 9. Ewaschuk JB, Tejpar QZ, Soo I, Madsen K, Fedorak RN. The role of antibiotic and probiotic therapies in current and future management of inflammatory bowel disease. Curr Gastroenterol Rep 2006; 8: 486-98. 10. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of antibiotic therapy for active ulcerative colitis. Dig Dis Sci 2007; 52: 2920-5. 11. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of broad spectrum antibiotic therapy in patients with active Crohn’s disease. Clin Ther 2006; 28: 1983-8. 12. Elahi B, Nikfar S, Derakhshani S, Vafaie M, Abdollahi M. On the benefit of probiotics in the management of pouchitis in patients underwent ileal pouch anal anastomosis: a meta-analysis of controlled clinical trials. Dig Dis Sci 2008; 53: 1278-84. 13. Rahimi R, Nikfar S, Rahimi F, et al. A meta-analysis on the efficacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohn’s disease. Dig Dis Sci 2008 [Epub ahead of print]. 14. Zocco MA, dal Verme LZ, Cremonini F, et al. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 2006; 23: 1567-74. 15. Gionchetti P, Rizzello F, Habal F, et al. Standard treatment of ulcerative colitis. Dig Dis 2003; 21: 157-67. 16. Moum B. 5-aminosalicylic acid in the treatment of ulcerative colitis and Crohn’s disease. Tidsskr Nor Laegeforen 2003; 123: 2565-7. 17. Ishikawa H, Akedo I, Umesaki Y, Tanaka R, Imaoka A, Otani T. Randomized controlled trial of the effect of bifidobacteria-fermented milk on ulcerative colitis. J Am Coll Nutr 2002; 22: 56-63. 18. Cui HH, Chen CL, Wang JD, et al. Effects of probiotic on intestinal mucosa of patients with ulcerative colitis. World J Gastroenterol 2004; 10: 1521-5. 19. Kruis W, Schütz E, Fric P, Fixa B, Judmaier G, Stolte M. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997; 11: 853-8. 20. Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet 1999; 354: 635-9. 21. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004; 53: 1617-23. 22. Sheil B, Shanahan F, O’Mahony L. Probiotic effects on inflammatory bowel disease. J Nutr 2007; 137 (3 Suppl 2): 819S-24S. 23. Rioux KP, Madsen KL, Fedorak RN. The role of enteric microflora in inflammatory bowel disease: human and animal studies with probiotics and prebiotics. Gastroenterol Clin North Am 2005; 34: 465-82. 24. Bibiloni R, Mangold M, Madsen KL, Fedorak RN, Tannock GW. The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn’s disease and ulcerative colitis patients. J Med Microbiol 2006; 55: 1141-9. 25. Sokol H, Seksik P, Rigottier-Gois L, et al. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis 2006; 12: 106-11. 26. Biancone L, Tosti C, Fina D, et al. Review article: maintenance treatment of Crohn’s disease. Aliment Pharmacol Ther 2003; 17 (Suppl 2): 31-7. 27. Jones JL, Foxx-Orenstein AE. The role of probiotics in inflammatory bowel disease. Dig Dis Sci 2007; 52: 607-11. 28. Gionchetti P, Rizzello F, Campieri M. Probiotics in gastroenterology. Curr Opin Gastroenterol 2002; 18: 235-9.