Within three months of stopping treatment, all patients in the VSL#3 group had relapsed. Likewise, fecal lactobacillus and bifidobacterial concentrations returned to pretreatment levels within one month after therapy was discontinued, indicating that permanent colonization with the probiotic species did not occur. A second study from the same group included 36 patients with recurrent or refractory pouchitis who had required antibiotics at least twice in the previous year [31]. After achieving remission, patients were randomly assigned to VSL#3 or placebo once daily for one year. Significantly more patients in the probiotic group remained in remission (85 versus 6 percent). Patients randomized to VSL#3 also had significantly better quality of life. A third study from the same group included 40 consecutive patients who underwent IPAA for ulcerative colitis [32]. Patients were randomly assigned to receive VSL#3 3 g/day or placebo immediately after ileostomy closure for one year. Patients receiving the probiotic had significantly fewer episodes of pouchitis (10 versus 40 percent). Probiotic treatment was also associated with significant improvement in quality of life compared with placebo. Somewhat different conclusions were reached in an observational study involving 31 patients with antibiotic-dependent pouchitis who were treated with VSL#3 after achieving remission with ciprofloxacin [33]. After eight months, only a minority of patients remained on priobiotic therapy and in symptomatic remission (most having stopped it due to recurrence of symptoms or adverse effects).
No benefit from another probiotic (Lactobacillus rhamnosus GG) was found in another, albeit small, controlled trial [34]. Furthermore, only 40 percent of patients who received the probiotic became colonized.
ULCERATIVE COLITIS — Various probiotic species have shown promise in the treatment of ulcerative colitis in small studies, although a clear clinical benefit remains to be established [35-45]. Prevention of relapse is more thoroughly documented than treatment of active disease. The following are illustrative controlled trials. E. coli 1917 Nissle was as effective as low dose 5-ASA in preventing relapse of ulcerative colitis in at least two controlled trials [35,36]. The combination of VSL#3 plus balsalazide was slightly more effective than balsalazide or mesalazine alone in a controlled trial of patients with acute mild-to-moderate ulcerative colitis [38]. The combination of a prebiotic and a probiotic (Bifidobacterium longum) was associated with improvement in histologic scores and measures of immune activation in a one-month randomized controlled trial [41]. Lactobacillus GG appeared to be more effective than standard treatment involving mesalazine in prolonging relapse-free time but did not influence relapse rates in patients with quiescent ulcerative colitis [46].
CROHN'S DISEASE — Clinical trials of probiotics in Crohn's disease have shown mixed results [47]. The reasons for the heterogeneity are unclear but could be due to several factors such as the specific probiotics (and doses) used, differences in study duration, characteristics of the included patients (eg, location of disease), and endpoints that were measured. In aggregate, the available data do not clearly demonstrate clinical effectiveness. Whether certain subgroups might benefit remains to be determined. E. coli Nissle was more effective than placebo in preventing relapse of Crohn's disease in remission [48]. Three of four children were successfully tapered off steroids following administration of Lactobacillus GG [49]. Studies evaluating probiotics for prevention of postoperative relapse have produced mixed results with most studies being negative [50]. (See "Medical prophylaxis of postoperative Crohn's disease").
ANTIBIOTIC-ASSOCIATED DIARRHEA — Multiple studies have evaluated a variety of probiotics in the treatment and prevention of antibiotic-associated diarrhea [51,52]. Many were small, used different endpoints, and had serious methodological problems that limited comparisons among them. Nevertheless, several systematic reviews have been conducted [53-63], most of which (although using different sets of primary studies) reached similar conclusions.
One of the largest and most recent meta-analyses (34 placebo-controlled trials) concluded that probiotics were [60]: Associated with a 52 percent reduction in antibiotic-associated diarrhea (95% CI 35-65%) An 8 percent reduction in traveler's diarrhea (95% CI -6 to 21%) A 57 percent reduction in risk of acute diarrhea of various causes in children (95% CI 37-51%) and a 26% reduction in adults (95% CI 7-49%) The protective effects did not vary significantly among the probiotics strains Saccharomyces boulardii, Lactobacillus rhamnosus, GG, Lactobacillus acidophilus, Lactobacillus bulgaricus and other strains used alone or in combination of two or more strains.
A later meta-analysis that focused on studies of children found a protective effect of probiotics on antibiotic associated diarrhea on per-protocol analysis but results were not significant on intention-to-treat analysis [63].
Notably, not all of the included studies used similar definitions of antibiotic-associated diarrhea. In particular, the pooled analysis combined all cases of diarrhea whether or not they were due to the presence of Clostridium difficile (C. difficile) toxin. The degree of overall benefit for primary prevention of C. difficile infection (or prevention of recurrence) was not reported. Similarly, there were insufficient data to describe potential associations with the type of antibiotics used, duration of therapy, or the dose and duration of the probiotic preparation.
Another systematic review that focused on studies in which C. difficile was specifically sought concluded that there was insufficient evidence for routine clinical use of probiotics to prevent or treat C. difficile diarrhea [64].
In summary, the available data are limited with respect to the size and quality of studies from which to draw conclusions. Systematic reviews suggest that probiotics (including various bacterial species and the yeast S. boulardii) are effective in reducing the incidence of diarrhea in patients who are taking antibiotics. However, discordant data have been published and there is little detailed information regarding the optimal dose or timing of supplementation or the effects on subgroups of patients. Whether probiotics can shorten the period of diarrhea in patients who have already developed it is unclear.
Studies focusing specifically on C. difficile diarrhea are inconclusive regarding a benefit on treatment or prevention. While probiotics used in such studies are generally safe, case reports have described Saccharomyces cervisiae fungemia and deaths particularly in immunosuppressed and critically ill patients who received a commercial preparation of S. boulardi (genomically identical to S. cervisiae) for either treatment or prevention of C. difficile diarrhea [65]. Thus, routine use cannot be recommended.
INFECTIOUS DIARRHEA — Several studies have evaluated a variety of probiotics in the treatment of infectious diarrhea. Results have been summarized in at least five systematic reviews all of which found an overall reduction in the duration of diarrhea (by about 17 to 30 hours), although there was heterogeneity among studies [55,66-69]. Probiotics were generally safe, with no serious adverse effects reported. The following illustrate the range of findings. One focused on randomized, placebo-controlled studies in infants and children with acute diarrhea [67]. Probiotics were associated with a significant reduction in the risk of diarrhea lasting for more than three days (RR 0.40, 95% CI 0.28 to 0.57). Only Lactobacillus GG showed a consistent beneficial effect. Probiotics significantly reduced the duration of diarrhea (by about 20 hours) compared with placebo, particularly in gastroenteritis caused by rotavirus. A second meta-analysis included a total of nine studies evaluating several strains of lactobacilli in children [55]. Those who received recent antibiotics were excluded. Probiotics reduced the duration of diarrhea by 0.7 days (95% CI 0.3 to 1.2) and diarrhea frequency on day two by 1.6 stools per day. The authors were able to detect a linear dose-response relationship across studies; a minimum of 10 billion colony-forming units during the first 48 hours was needed to reduce the duration of diarrhea by more than one-half a day. A third meta-analysis that included 23 studies (using several different probiotic preparations) in adults and children found that probiotics reduced the overall risk of having diarrhea at three days by about 35 percent (relative risk 0.66, 95 percent CI 0.55-0.77), and the mean duration of diarrhea by about 30 hours (95 percent CI 19 to 43 hours) [66]. The authors concluded that probiotics were a useful adjunct to rehydration therapy in treating acute, infectious diarrhea in adults and children. A meta analysis of 12 studies examining probiotics for the prevention of traveler's diarrhea concluded that several products, including Saccharomyces boulardii and a combination of Lactobacillus acidophilus and Bifidobacterium bifidum, reduced the risk of travelers diarrhea (RR 0.85, 95% CI 0.79-0.91) with no serious adverse effects [68].