VSL#3 Probiotic Mixture

Abstract

VSL#3 (VSL#3®) is a high-concentration probiotic preparation of eight live freeze-dried bacterial species that are normal components of the human gastrointestinal microflora, including four strains of lactobacilli (Lactobacillus casei, L. plantarum, L. acidophilus and L. delbrueckii subsp. bulgaricus), three strains of bifidobacteria (Bifidobacterium longum, B. breve and B. infantis) and Streptococcus salivarius subsp. thermophilus. Data from noncomparative trials suggest that VSL#3 has clinical potential in the treatment of active mild to moderate ulcerative colitis and as maintenance therapy for patients with ulcerative colitis in remission. In addition, a randomised, open-label, multicentre trial showed that VSL#3 in combination with low-dose balsalazide (a prodrug of mesalazine [mesalamine; 5-aminosalicylic acid]) was more effective than standard doses of basalazide or mesalazine monotherapy in the treatment of acute mild to moderate ulcerative colitis. Randomised, double-blind, placebo-controlled studies have shown VSL#3 is effective in preventing the onset of acute pouchitis in patients with newly formed surgical pouches, and in maintaining remission following antibacterial treatment of acute pouchitis in patients with a history of refractory or recurrent pouchitis. Treatment guidelines from the US and the UK include VSL#3 as a therapeutic option for the prevention of pouchitis relapse in patients with chronic pouchitis. In general, VSL#3 was well tolerated in clinical trials. Large, well designed, controlled confirmatory clinical trials will further determine the place of VSL#3 in the treatment of ulcerative colitis. VSL#3 contains a high concentration (450 billion viable cells/sachet) of a mixture of eight live freeze-dried bacterial species that are part of the normal human gastrointestinal microflora. Although the precise mechanism of action of VSL#3 is not fully understood at present, preclinical studies have shown that VSL#3 modulates the host immune response. VSL#3 has been shown to increase the secretion of the anti-inflammatory cytokine interleukin (IL)-10, and DNA isolated from VSL#3 inhibited nuclear factor-κB activation, IL-8 secretion, p38 mitogen-activated protein kinase activity and secretion of proinflammatory cytokines, including tumour necrosis factorα, interferon-γ and IL-1β. DNA isolated from VSL#3 has also been shown to inhibit experimentally induced colitis in mice. Although most data on the immunological effects of VSL#3 are derived from in vitro studies and animal models, and further study is warranted into the immune responses associated with VSL#3, these results appear to be supported by data from patients, which generally showed similar changes to the immune response following oral treatment with VSL#3. The bacterial components of VSL#3 remain viable in human ileostomy effluent and, in vivo, VSL#3 bacteria are able to survive passage through the ileocaecal tract and reach the large bowel. Analysis of faecal samples obtained from healthy volunteers and/or patients with inflammatory bowel disease showed that, in general, S. thermophilus, B. infantis and B. breve persisted in the gastrointestinal tract during treatment and for a short period after discontinuation of VSL#3. In a noncomparative trial, treatment with VSL#3 for 12 months effectively maintained remission in 15 of 20 patients (75%) with ulcerative colitis who were allergic to or unable to tolerate mesalazine. Another noncomparative study showed that treatment with VSL#3 for 6 weeks effectively induced remission in 18 of 34 patients (53%) with active mild to moderate ulcerative colitis not responding to conventional therapy. The combination of VSL#3 plus low-dose balsalazide was also effective in treating patients with active mild to moderate ulcerative colitis in a randomised, open-label, multicentre trial (n = 90). Treatment with VSL#3 plus balsalazide 2.25 g/day resulted in significantly better rates of remission than balsalazide 4.5 g/day or mesalazine 2.4 g/day alone in the intent-to-treat population (80% vs 70% and 53%; p < 0.02). Results of three randomised, double-blind, placebo-controlled trials (n = 36–40) indicate that VSL#3 is effective when used as maintenance therapy following antibacterial-induced remission of acute pouchitis, and in the prevention of pouchitis when administered to patients with newly formed surgical pouches. In one study, significantly fewer patients with ileal pouch-anal anastomosis (IPAA) receiving VSL#3 for 12 months experienced an episode of acute pouchitis than those receiving placebo (10% vs 40%; p < 0.05). In the other two trials, remission was maintained in significantly more patients receiving VSL#3 than placebo for 9 or 12 months. In patients who underwent IPAA for ulcerative colitis, treatment for 12 months with VSL#3 significantly improved health-related quality of life compared with baseline and placebo at study end, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) score. Similarly, in patients with recurrent or refractory pouchitis in remission, a significantly higher median IBDQ score was seen in recipients of VSL#3 compared with the placebo group at the time of relapse or after 12 months of treatment. These clinical responses in patients receiving VSL#3 were associated with a significant increase in the faecal concentration of lactobacilli, bifidobacteria and S. thermophilus; however, there were no significant changes in faecal concentrations of potentially pathogenic microorganisms, including Bacteroides spp., coliforms, clostridia and enterococci, or total aerobes and anaerobes in patients receiving VSL#3 compared with baseline. A few patients with ulcerative colitis in remission receiving VSL#3 experienced mild constipation and, although no clinical or biochemical adverse effects considered...