Probiotics for Ulcerative Colitis … Are The Good Bugs Back?

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Sood A, Midha V, Makharia, GK, et al. (Department of Gastroenterology and Medicine, Dayanad Medical College and Hospital, Ludhiana, India; Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India; and Pushpawati Singhania Research Institute, Sheikh Sarai-I, New Delhi, India). The probiotic preparation, VSL#3, induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2009;7:1202–1209.

Our current therapeutic armamentarium for the treatment of ulcerative colitis includes aminosalicylates, steroids, immunosuppressive therapies such as 6-mercaptopurine and azathioprine, and most recently tumor necrosis factor-α antibody. There are a significant number of patients who develop adverse effects with these current therapies. Therefore, new therapies are constantly being investigated. VSL #3 is a high-concentration probiotic with 8 live, freeze-dried bacterial strains including 4 strains of Lactobacilli, 3 strains of Bifidobacteria, and Streptococcus thermophilus. There is little known about the ability of probiotics such as VSL#3 for induction of remission and lack of a large, randomized, placebo-controlled trial. Previous studies of probiotics were inadequately designed or had small sample sizes. The authors of this study conducted a double-blind, placebo-controlled, randomized trial at 3 tertiary care centers in North India between June 2005 and August 2007.

Eligibility criteria included adult subjects (>18 years old) with mild to moderately active ulcerative colitis (UC) extending for >15 cm from the anal verge with ≥1 documented attack of active disease. Mild to moderately active UC was defined by an Ulcerative Colitis Disease Activity Index (UCDAI) score of 3–9, with a minimum sigmoidoscopic score of 2. Exclusion criteria included disease limited to rectum, evidence of severe disease (UCDAI >10), concurrent enteric infection, use of oral steroids within the past 4 weeks, use of antibiotics within the past 2 weeks, change in dose of oral mesalamine within the past 4 weeks, and use of rectal mesalamine or steroids within 7 days. Those requiring hospitalization and imminent need for surgery, lactating and pregnant women, those with other significant comorbid illnesses, and those who received any investigational medicines within 3 months were also excluded. The 147 subjects were randomly assigned to receive either 3.6 × 10¹² CFU VSL#3 (n = 77) or placebo (n = 70), twice daily for 12 weeks. Both investigators and study participants were blinded. At study entry and weeks 6, 9, and 12, a history and physical examination along with sigmoidoscopic examination (weeks 0, 6, and 12) were performed. Adverse events were reported and daily disease activity records were reviewed along with patient compliance. If patients deteriorated clinically, they were withdrawn from the study and placed on standard medical treatment. If patients were taking maintenance oral mesalamine that was stable for 4 weeks before study entry, the drug was continued. Patients were off topical therapy for ≥7 days before study entry and topical mesalamine or steroids, systemic corticosteroids, antibiotics, nonsteroidal anti-inflammatory drugs, and antidiarrheals were not allowed during the study. Patients on thiopurines were maintained on stable dose for ≥3 months before entering the study. The primary end point was a 50% decrease in the UCDAI at 6 weeks. The secondary end points included remission by 12 weeks and reduction in total individual UCDAI parameters from baseline at 12 weeks. An intention-to-treat analysis was performed.

Of the 147 total patients randomized, 77 received VSL#3 and 70 received placebo; 55 patients in the VSL#3 group and 29 patients in the placebo group completed the entire study. Among 22 patients who withdrew from VSL#3 groups, 17 had worsening of symptoms and 5 were lost to follow-up. In the placebo group, 13 patients were lost to follow-up and 28 patients discontinued therapy (18 had worsening disease, 3 were noncompliant, and 7 for other reasons not stated). The demographic and clinical characteristics were overall similar between the 2 groups with regard to age, number of previous relapses, and extent of disease. There were a greater number of patients (69 [89.6%] vs 47 [67.1%]) receiving mesalamine alone in the VSL#3 group compared with the placebo group (P = .02). A greater number of patients in the placebo group were receiving a combination of mesalamine and azathioprine compared with the VSL#3 group (P =. 01).

At week 6, the percentage of patients with an improvement in UCDAI score that was >50% was significantly higher in the group given VSL#3 (n = 25; 32.5%) than the group given placebo (n = 7; 10%; P = .001). The median improvement in the UCDAI at 6 weeks in the VSL#3 and placebo groups was 25% and 0%, respectively (P = .001). At week 12, there were 33 patients given VSL#3 (42.9%) who achieved remission, compared with 11 patients given placebo (15.7%; P < .001). Significantly more patients given VSL#3 (n = 40; 51.9%) achieved a decrease in their UCDAI that was >3 points, compared with those given placebo (n = 13; 18.6%; P < .001). The VSL#3 group had significantly greater decreases in UCDAI scores and individual symptoms at weeks 6 and 12, compared with the placebo group. Mucosal healing rates (mucosal appearance score, 0) at week 12 were much higher in patients in the VSL#3 group compared with the placebo group (n = 24 [32%] vs n = 10 [14.7%]; P < .028). The placebo arm had a greater number of treatment failures (88.6% vs 62.3%; P = .001) defined as those who failed to decrease UCDAI by ≥50% of baseline or by ≥3 points from baseline to 6 weeks. Additionally, there was no difference in response/remission rate between proctosigmoiditis versus left-sided colitis/pancolitis. Although there were no major adverse events reported in either group, 14 (18.2%) of those in the VSL#3 group reported abdominal bloating or discomfort and an unpleasant taste in their mouth. The authors conclude that VSL#3 is safe and effective in achieving clinical responses and remissions in patients with mild-to-moderately active UC.

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Comment 

UC is characterized by periods of relapses and remission. Side effects from conventional therapies can be problematic for patients, and therefore therapies such as probiotics are attractive. Although the exact etiology of IBD remains unknown, the intestinal microbiota has been implicated in the pathogenesis of IBD. Probiotics are nutritional supplements composed of living microorganisms, which have beneficial effects on the host (Food Technology 1999;53:67–77). These microorganisms may play a promising role by manipulating the enteric microbiologic environment to decrease the pathogenic bacterial strains, and enhance the metabolic effects of beneficial bacteria, thereby providing possible therapeutic benefit (Am J Gastroenterol 2009;104:437–443). They may modify the disease and beneficially affect the host by improving intestinal microbial balance (Appl Bacteriol 1989;66:365–378) and blocking adhesion sites on the colonocytes (FEMS Microbial Lett 1993;110:299–305; Gut 1994;35:483–489), thereby enhancing gut barrier function and improving local immune response. Probiotics can be effective in the treatment of many inflammatory gastrointestinal conditions such as pouchitis (Gastroenterology 2003;124:1202–1209), gastroenteritis (Pediatrics 1991;88:90–97), and radiation-induced diarrhea (Am J Gastroenterol 2002;97:2150–2152).

In inflammatory bowel disease, probiotics have been used for inducing remission and maintaining remission in ulcerative colitis. There is evidence to support that Escherichia coli Nissle 1917 may be as effective as mesalamine for maintenance treatment in ulcerative colitis (Lancet 1999;354:635–639; Aliment Pharmacol Ther 1997;11:853–858). A systematic review of trials investigating the efficacy of probiotics for induction of remission in ulcerative colitis suggested that probiotics combined with conventional therapies present no further benefit for induction of remission or clinical improvement in comparison to those receiving standard treatment only (Cochrane Database Syst Rev 2007;4:CD005573). However, most of the studies had methodologic limitations, including a small sample size and lack of power to detect a significant difference. Other methodologic limitations included inadequate information about random allocation (Lancet 1999;354:635–639; Aliment Pharmacol Ther 1997;11:853–858), unclear allocation concealment (Lancet 1999;354:635–639; Aliment Pharmacol Ther 2004;20:1133–1141; Aliment Pharmacol Ther 1997;11:853–858), and problems with double-blinding procedures (Aliment Pharmacol Ther 1997;11:853–858; Aliment Pharmacol Ther 2004;20:1133–1141). Two small studies have shown efficacy and safety of VSL#3 for induction and maintenance therapy in children with UC (Am J Gastroenterol 2009;104:437–443; Inflamm Bowel Dis 2009;15:760–768). Open-labeled trials have shown high remission rates at 4–6 weeks. In 1 study, a 68% remission rate was achieved at week 4 using Saccharomyces boulardii in patients with active UC who failed to respond to mesalamine (Eur J Gastroenterol Hepatol 2004;15:697–698). In 2005, Bibiloni et al induced remission in 63% of UC patients at 6 weeks using VSL#3 (Am J Gastroenterol 2005;100:1539–1546). These open-label trials were limited by the lack of a placebo control group and inclusion of other concomitant medications, such as corticosteroids and topical therapy.

The results of this prospective randomized trial indicate that there still is a promising role for probiotics in mild-to-moderate UC patients. Past studies have not necessarily convinced us to use probiotics for induction therapy of UC in our clinical practice. I applaud the authors on the meticulous design of this project with careful attention to randomization, concealment, and blinding. The large number of patients enrolled also adds merit to the study results.

However, it is important to keep in mind some of the limitations of this study. First and foremost, the number of patients lost to follow-up in the placebo group (13 patients) and the VSL#3 group (5 patients) were disappointing for a randomized trial of this caliber. As such, we cannot account for these patients and certainly this could have altered the results of this study. Patients in each group discontinued intervention of which the reason was not indicated in 5 of the VSL#3 patients and 7 of the placebo patients. Overall, the authors controlled for concomitant medications such as corticosteroids and rectal therapies. However, there was a difference in the number of patients on concomitant medications including mesalamine and immunosuppressives. The placebo group had more patients on combination immunosuppressives and mesalamine. The VSL#3 groups had more patients on only mesalamine. It is possible that the disease phenotype of both patients may be different in each group with possibly more severe disease in the placebo group not apparent based on UCDAI. Another more practical issue is the applicability of these results in the United States, given that it was conducted in India. It is not known whether there is a difference in an individual's bacterial flora based on the country in which they reside.

In summary, the results of this study demonstrate that VSL#3 led to a 50% decrease in UCDAI at week 6 and clinical remission at week 12 in significantly more patients with mild-to-moderately active UC compared with placebo. Although there are some limitations to this study as discussed, the overall design of this trial is excellent. On the basis of these results, there is a possible role of probiotics for patients with mild to moderate UC. Given the safety and tolerability, it may be used as adjunctive induction therapy. Further, well-designed, randomized controlled trials in the United States are justified to confirm these results.