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VSL#3 for Ulcerative Colitis: Growing Evidence?

      Tursi A, Brandimarte G, Papa A, et al. Treatment of relapsing mild-to-moderate ulcerative colitis with the probiotic VSL#3 as adjunctive to a standard pharmaceutical treatment: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2010;105:2218–2227.
      Tursi et al performed a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy of VSL#3 in mild to moderate ulcerative colitis. Eligible subjects were >18 years of age, had an endoscopically confirmed diagnosis of active, mild to moderate ulcerative colitis (defined as an Ulcerative Colitis Disease Activity Index [UCDAI] of 3–8 and an endoscopic UCDAI score ≥3) involving at least the rectosigmoid colon, and symptoms <4 weeks in duration. In addition, subjects could also be prescribed an oral mesalamine or immunomodulator (IM), as long as the dose of these medications was stable for >4 weeks in the case of the mesalamine or >3 months for the IM.
      Patients meeting inclusion and exclusion criteria were randomized to receive either 3.6 × 1012 colony-forming units (CFU) VSL#3 in 2 divided sachets or placebo, taken in similar fashion, for 8 weeks. Subjects on maintenance mesalamine or IM continued these medications at the same dose throughout the study. The primary end point was defined as a decrease in the UCDAI of ≥50% from baseline to week 8. Secondary end points included assessment of remission, defined as UCDAI ≤2 at week 8, improvement in endoscopic score in the endoscopic subgroup at week 8, change in objective symptoms such as rectal bleeding and stool frequency, change in subjective symptoms, and lack of effect, defined as the need to modify pharmacologic therapy or discontinue the study medication.
      A total of 144 subjects were randomized. Six of the 71 patients in the VSL#3 arm and 7 of the 73 subjects in the placebo arm withdrew from the study. There were no significant differences between the 2 groups in terms of gender, mean age, previous relapses, mean UCDAI at entry, disease location, mesalamine use, or IM use. Forty-one of the of the 71 subjects (57.7%) in the treatment arm met the primary end point of a 50% reduction in UCDAI at 8 weeks, compared with 29 of 73 (39.7%) of the placebo group (P = .031). This analysis was repeated with exclusion of those on immunomodulators, with similar, significant results. For the secondary end points of a decrease of ≥3 points on the UCDAI scale and reduction in rectal bleeding, the VSL#3 group had significantly higher response rates compared with the placebo group. There was no significant difference with regards to induction of remission (43.7% vs 31.5%, intention to treat; P = .132), reduction in stool frequency, physician rating of disease activity, or mean endoscopic scores. There were no major adverse events in the study. The authors of this study concluded that VSL#3 supplementation is safe and able to reduce UCDAI scores and rectal bleeding in patients with relapsing mild-to-moderate UC who are also on mesalamine and immunomodulators. The authors also noted that VSL#3 seems to induce remission, but that this did not attain significance.

      Comment

      Ulcerative colitis is a chronic inflammatory disorder of the colon that, along with Crohn's disease, comprises the group of disorders known as inflammatory bowel disease (IBD). Although the pathophysiology of IBD remains incompletely understood, it is currently thought to involve a complex interplay between genetic predisposition of the host and aberrant intestinal microbial homeostasis resulting in inflammation (Nature 2010;8:564–577). Current therapies for ulcerative colitis, include topical anti-inflammatories such as mesalamine, the systemic “immunomodulators,” such as azathioprine and 6-mercaptopurine, and the “biologic therapy” infliximab. All of these therapies are known not only for their potential efficacy, but for a wide range of side effects as well.
      As our understanding of IBD has progressed, there has been a growing interest in modifying not only the inflammatory response, but the gut microbiota as well. It has long been posited that modifications of the composition and structure of bacterial populations in the gut may play a significant role in human disease and enteric infection (Clin Microbiol Rev 1990;3:335–344). As such, there have been many attempts to identify the potential beneficial effects of probiotics supplementation for various indications. Probiotic supplements have potential benefit in pouchitis, irritable bowel syndrome, traveler's diarrhea, acute gastroenteritis, antibiotic-associated diarrhea, Clostridium difficile–associated diarrhea, and radiation-induced diarrhea. There have been several studies assessing the efficacy of various probiotics in the treatment of ulcerative colitis. Several early studies assessed the efficacy of Escherichia coli Nissile 1917 for maintenance of remission compared with mesalamine via double-blinded, randomized, controlled trials and found them to have equivalent efficacy (Aliment Pharmacol Ther 1997;11:853–858; Lancet 1999;354:635–639). There have also been several randomized, controlled trials of Bifidobacteria, with mixed results (Aliment Pharmacol Ther 2004;20:1133–1141; Gut 2005;54:242–249). Lactobacillus GG has also been assessed in comparison to mesalamine in prevention of relapse, without significant difference between groups (Aliment Pharmacol Ther 2006;23:1567–1574). VSL#3, a combination of 4 strains of Lactobacilli, 3 strains of Bifidobacteria, and 1 strain of Streptococcus thermophilus, has also been evaluated in several small studies, demonstrating the ability to induce remission (Am J Gastroenterol 2005;100:1539–1546) in a noncontrolled study, and superiority when used in combination with balsalazide compared with balsalazide or mesalamine alone (Med Sci Monit 2004;10:PI126–131).
      A recent, multicenter, double-blind, randomized, controlled trial by Sood et al demonstrated the safety and efficacy of VSL#3 3.6 × 1012 CFU in reducing symptoms of mild to moderate colitis (Clin Gastroenterol Hepatol 2009;7:1202–1209, 1209.e1) over the course of 12 weeks. In this study, 32.5% of patients in the treatment arm achieved the primary end point of a UCDAI reduction of >50% at 6 weeks compared with 10% in the placebo group (P = .001). Furthermore, 42.9% of patients in the treatment arm achieved remission by 12 weeks, compared with 15.7% in the placebo arm (P < .001). This study also demonstrated improved mucosal healing (32% vs 14.7%) and a UCDAI decrease >3 points (51.9% vs 18.6%). Furthermore, there was no difference regarding disease location, and no side effects demonstrated. However, as previously published, this study did have a significant number of patients lost to follow-up in both arms. Also, the VSL#3 arm had a significantly increased number of patients on mesalamine-only therapy, whereas the placebo arm had more patients on mesalamine + azathioprine combination therapy, perhaps indicating a difference in disease severity or phenotype (Gastroenterology 2010;139:1054–1056).
      Both the Sood study and the Tursi study reached their primary end point of a significant decrease of UCDAI <50% utilizing high-dose VSL#3. The question is whether this translates to a meaningful clinical improvement. Tursi et al were unable to achieve a significant improvement in rates of remission after 8 weeks of treatment, perhaps secondary to a shorter length of their trial as compared with the 12-week Sood trial. The Sood study also had lower placebo response rates compared with the Tursi study, which may have biased their findings away from the null. The lower placebo response in the Sood study may have been a reflection of more patients on immunomodulators in the placebo arm compared with a more balanced randomization in the Tursi study. Both studies demonstrated similar response rates, defined as UCDAI decreases of >3. No major adverse events were noted.
      Although several bacteria species fit under the category of probiotics, their effectiveness in treating ulcerative colitis are not necessarily equal. Additionally, there may be a dose–response curve with probiotics with the most recent VSL#3 studies using 2–4 times the dosing for pouchitis. A Cochrane analysis in 2007 showed no evidence that probiotics were superior to ASA compounds or placebo for induction of remission (Cochrane Database Syst Rev 2007;4:CD005573), but this was before the Tursi and Sood studies and included other probiotics at varying doses. Also, questions remain regarding the generalizability of the safety of these products to all patients with ulcerative colitis, particularly those on immunosuppression, with several reports of immunosuppressed patients developing lactobacillus bacteremia while taking probiotics (Am J Clin Nutr 2006;83:1256–1264).
      In summary, VSL#3 may have clinical benefit as an adjunctive therapy in the treatment of mild to moderate ulcerative colitis, with 2 recent randomized, controlled trials demonstrating efficacy in reducing UCDAI but with conflicting results regarding inducing remission. A longer, randomized, clinical trial is needed with remission as a primary end point to further demonstrate VSL#3's efficacy and safety.