Trials for treating mild/moderate pouchitis are few with small numbers of adult participants. Kuisma et al. [44] recruited 20 patients (ten intervention arm) for a DBRPC trial of Lactobacillus rhamnosus GG 2  ×  10¹⁰ CFU/day for 3 months. Those patients with chronic, active pouchitis were excluded. The Pouchitis Disease Activity Index [45] was utilized for evaluation of clinical effect and prior to study entry, the mean PDAI was in the mild range (8.0  ±  0.8). There was no difference following the intervention period with clinical response (defined as a PDAI score reduction of ≥3) occurring in one of ten (10 %) patients in the probiotic group and zero of ten (0 %) patients in the placebo group (10 % vs. 0 %, p  =  0.32).

In an open-label trial of 51 UC patients postileal pouch-anal anastomosis using a fermented milk product with a blend of probiotic strains (L. acidophilus strain La5  +  Bifidobacterium lactis strain Bb12) containing 5  ×  10¹⁰ CFU/day [46] however, there was a reported improvement in endoscopic evaluation. In another open-label trial, 23 consecutive patients with mild pouchitis as defined using Pouchitis Disease Activity Index (scores 7–12) were treated with 3.6  ×  10¹² CFU/day of VSL#3™ for 4 weeks [47]. Sixteen of 23 patients (69 %) with mild pouchitis were in remission after treatment and the median total Pouchitis Disease Activity Index scores reported before therapy improved following therapy (ten vs. four, p  <  0.01).

Thus, there is limited evidence for a role of probiotics as monotherapy for mild/moderate pouchitis at the present time. Limiting access of microbiota to the mucosa of the pouch and subsequent development of inflammation may be a mechanism whereby probiotics provide benefit. Alternatively, changing the composition of the pouch microbiota may be important; although it is interesting that no long-term colonization of probiotic strains is achieved [48]. Thus it may not be surprising that once the deleterious microbiota have colonized within the pouch there is little a probiotic as monotherapy can do to alter the situation. A somewhat analogous situation exists for use of probiotics as monotherapy in treating Helicobacter pylori gastritis. The eradication rate of probiotic monotherapy was poor compared to standard triple therapy (a proton pump inhibitor  +  two antibiotics) in children colonized with H. pylori [49] but a number of studies have reported reduced H. pylori colonization with probiotic monotherapy even though eradication rate is poor [50]. In addition, one study suggested reduced gastritis on biopsy [51]. The increased eradication rates of H. pylori using combined probiotic and antibiotic may take advantage of lower levels of pathogen in the stomach and/or decreased adverse effects of the antibiotics. Thus, if there is an analogy to be drawn for it would be to treat patients with pouchitis requiring continuous antibiotics or very frequent use of antibiotics with probiotics as adjuvant to shorter antibiotic courses of therapy.

Two trials have studied whether there is an advantage to initiate probiotics immediately following ileal pouch-anal anastomosis and both found there to be benefit to the delay in onset of development of pouchitis. In a placebo-controlled trial [52] at the end of 1 year (see Table 29.3), only 2 of 20 (10 %) of those in the intervention probiotic arm had developed colitis as compared to 8 of 20 (40 %; no episodes 80 % vs. 60 %, p  =  0.03) of the control arm participants as determined using the PDAI with endoscopy. The Peto odds ratio for prevention of pouchitis by the probiotic (VSL#3™) compared with placebo was 4.76, 95 % CI: 1.16–19.56.

The initial controlled trial for this indication was in the year 2000 using the blend probiotic product, VSL#3™ and reported an outstanding effect in prevention of the recurrence of pouchitis in patients with antibiotic-dependent pouchitis. Prior to the administration of the blend probiotic, participants in his trial were successfully treated with a combination of antibiotics (ciprofloxacin  +  rifaximin). At the end of the study period of 9 months, only 3 of 20 (15 %) had developed pouchitis in the probiotic intervention group whereas all 20 participants in the control group had a recurrence of pouchitis and occurred by 4 months following antibiotics cessation [53]. A similar result was noted in another European trial of VSL#3™ (see Table 29.3) also evaluating prevention of recurrence of pouchitis in relapsing or chronic pouchitis patients [48]. Remission of the pouchitis was induced in these participants by administering 4 weeks of a combination of antibiotics (metronidazole  +  ciprofloxacin) that was followed by either VSL#3™ or a placebo to then evaluate the preventative effects of the probiotics. In the probiotic treatment group remission was maintained in 17 of 20 (85 %) but only 1 of 16 (6 %, p  <  0.0001) on placebo. The pooled Peto odds ratio for these two studies for the combined rate of maintenance of remission with probiotic bacteria compared to placebo (97 % vs. 3 %, p  <  0.0001) was 25.39 (95 % CI: 10.37–62.17). The number needed to treat with oral probiotic therapy to prevent one additional relapse was 2 [54].

In contrast, an open-label trial by Shen and colleagues [55] reported less responses in prevention of pouchitis recurrence using the same probiotic. In their trial, 31 subjects were prescribed a 2-week treatment of a single antibiotic (ciprofloxacin) followed by VSL#3™. Also in contrast to the other studies, the VSL#3™ was bought by patients rather than be supplied through the study. Probiotic therapy was stopped by 9 of 31 (29 %) 7 weeks into therapy and 25 of 31 (81 %) by 8 months had discontinued the probiotic because of failure to prevent pouchitis (n  =  23) or side effects of the probiotic administration (n  =  2). Only 6 of 31 (19 %) did not develop clinical evidence of pouchitis by the end of the 8-month trial period. Even among these six subjects, endoscopy revealed some level of pouch inflammation. In this trial [55], there was a single antibiotic administered and endoscopy was not performed prior to probiotic administration to ensure pouch inflammation had completely resolved.

Out of all of this is a recent clinical practice guideline on management of pouchitis [43] suggesting that for those patients with prompt recurrence of pouchitis following antibiotic usage or having multiple recurrences of pouchitis despite antibiotics either VSL#3™ or chronic use of antibiotics is a strategy to consider. Probiotics alone were not ­recommended for acute treatment of pouchitis.

There is a paucity of studies investigating use of probiotics to settle active inflammation. In two open-label studies [56,57], probiotics (using combination of Bifidobacterium breve  +  Lactobacillus casei  +  B. longum  +  prebiotics or L. rhamnosus GG, respectively) were added as adjuvant therapy to immunomodulators and corticosteroids. In the former study [56], seven of ten patients were reported to respond as determined by Crohn Disease Activity Index scores with most noticeable improvement in the diarrhea. However, there was no improvement in inflammation as measured by erythrocyte sedimentation rate (ESR) and CRP. In an open-label trial using L. rhamnosus GG [57], three of the four children were reported to have improved Pediatric Crohn Disease Index (PCDAI) scores or serial determinations over the 6 months of the trial. Specifics with regards to ESR or CRP are not reported although the ESR is a component of the PCDAI [58].

A placebo-controlled trial using L. rhamnosus GG was the sole study included in a Cochrane review of efficacy of probiotic supplementation for the induction of remission in CD [59]. There were a total of 11 participants in the study and subjects received antibiotics and concurrent therapy of corticosteroids and some methodological concerns were raised. Four of five patients in the probiotic group achieved remission compared to five of six in the placebo group (OR 0.80; 95 % CI: 0.04–17.20). Thus, this one small study did not show that probiotics had any effect in treating active Crohn disease. At best, one could say there is insufficient evidence to make any conclusions about the effectiveness of probiotics for treatment of active Crohn disease.

Initial randomized trials (see Table 29.4) in Crohn disease were reported with probiotics used as sole maintenance ­therapy following corticosteroid therapy or in combination with 5-aminosalicylate therapy for maintenance therapy in those already in remission as adjuvant therapy [60–63]. Among these studies [60–62], there were no differences in the number of relapses in patients receiving E. coli Nissle compared to the placebo (p  =  0.11), S. boulardii (1 g/day) plus mesalazine (2 g/day) compared to mesalazine alone (3 g/day) (p  =  0.08), or patients with remission induced medically and then receiving L. rhamnosus GG (p  =  0.77).

In the largest maintenance trial to date, Bousvaros et al. [63] also reported no difference in relapse rate for subjects receiving L. rhamnosus strain GG 2  ×  10¹⁰ CFU/day (31 %; 12 of 39) or placebo (17 %; 6 of 36, p  =  0.18). The time to relapse is shown in Figure 29.1, and although there was a trend in those receiving probiotics to a shorter time to relapse, comparison between it and the placebo control group was not statistically different (p  =  0.10) in this study.