Probiotics

Probiotics are living microorganisms that exert beneficial effects on the host by modulating the intestinal microbiota [91]. Many probiotics have been examined for their efficacy in IBD with the aim of modulating the microbiota and relieving intestinal dysbiosis. It has been demonstrated that some bacteria, such as Lactobacillus, Bifidobacterium and Streptococcus, have a clinical effect on gastrointestinal inflammation. A large clinical trial was conducted to investigate the efficacy of E. coli Nissle 1917, a nonpathogenic strain, on maintaining remission of UC. E. coli Nissle 1917 achieved comparable efficacy and safety outcomes to salicylate in the maintenance of remission in UC patients [92]. Studies using VSL#3, a probiotic mixed with 4 Lactobacilli (L.) (L. casei, L. acidophilus, L. delbrueckii subsp., Bulgaricus), 3 Bifidobacteria (B.) (B. longum, B. breve, B. infantis) and a Streptococcus (Streptococcussalivarius subsp. thermophilus), have yielded the most available evidence in IBD patients. A clinical study found that VSL#3 was effective in inducing remission in patients with mild-to-moderately active UC [93, 94]. In addition, in a small cohort study, VSL#3 was found to be effective in maintenance of remission [93]. A meta-analysis has recently shown that VSL#3 with standard treatment achieved better outcomes when compared to standard treatment alone in the induction of remission and response [95]. A randomized study to investigate the efficacy of Lactobacillus GG was conducted in quiescent UC. Lactobacillus GG was safe and more effective than standard treatment with mesalazine for maintaining remission in UC patients [96]. Several systematic reviews and meta-analyses have addressed the role of probiotics in UC without conclusive outcomes, and a Cochrane review showed that probiotics were no more effective than placebo or standard treatment in inducing the remission of UC [97].

In contrast, there is limited evidence available for the efficacy of probiotics in CD patients. A randomized, double-blind, placebo-controlled study investigated the efficacy of L. johnsonii in CD patients who underwent surgical resection of the intestine; however, L. johnsonii did not have a sufficient effect on the suppression of recurrence rate [98]. Other probiotics, such as E. coli Nissle 1917 [99] and Saccharomyces boulardi [100], did not have a significant effect on remission rate in CD patients. A Cochrane review reported that probiotics have no advantage over placebo in the maintenance and induction of CD, and suggested that well-designed randomized clinical trials (RCTs) should be conducted to address the efficacy of probiotics in the treatment of CD [101].

Fecal microbiota transplantation

Fecal microbiota transplantation (FMT) aims to restore the intestinal microbiota in diseased individuals by transferring intestinal microbiota of healthy donors. FMT has been clinically adapted to recurrent Clostridium difficile infection (CDI), and the efficacy of FMT for CDI has been established with a high cure rate of >90% in clinical trials [102, 103]. The success of FMT in treating CDI has raised the possibility that FMT may be beneficial in other diseases associated with dysbiosis. Therefore, FMT has recently attracted attention as a new therapeutic strategy in IBD.

The number of clinical studies on the efficacy and safety of FMT for IBD has increased, and the evidence for the effect of FMT on IBD has accumulated accordingly. Initial data to support the role of FMT in treating IBD came from case reports. Recent reports of the use of FMT in adult patients with UC yielded mostly no or limited effects. Subsequently, two randomized placebo-controlled clinical trials in patients with active UC were recently published in 2015 (Table 1) [104, 105]. Moayyedi et al. [104] reported that 75 subjects received FMT or placebo (water) by retention enema for 6 weeks and that the remission rate (Mayo Score of <3 with an endoscopic subscore of 0 at week 7) of the FMT group was significantly higher than the placebo group (9/38 [24%] vs 2/37 [5%]; P = 0.03). On the other hand, in the clinical trial reported by Rossen et al., 50 patients with mild-to-moderately active UC were treated with either donor stool (FMT group) or autologous FMT (placebo group) delivered via nasoduodenal tube at day 0 and 3 weeks later, and there was no significant difference in the remission rate (clinical remission combined with a ≥1-point decrease in the Mayo endoscopic score at week 12) between the two groups [105]. Notably, the two above-mentioned clinical trials were stopped early for futility by the Data Monitoring and Safety Committee. More recently, another two RCTs in patients with mild-to-moderately active UC were reported in 2017 (Table 1). Paramsothy et al. [106] reported that 85 patients were randomly assigned FMT or placebo, and that the primary outcome was defined as steroid-free clinical remission with endoscopic remission or response (Mayo score of ≤2, all subscores ≤1, and ≥1-point reduction in endoscopy subscore) at week 8. The rate of the primary outcome of the FMT group was significantly higher than the placebo group (11/41 [27%] vs 3/40 [8%], P = 0.02). Costello et al. [107] reported that 73 patients with active UC were enrolled and randomly allocated to FMT or autologous FMT (placebo). Prepared donor stool was administered via colonoscopy on day 0 followed by two enemas by day 7. The remission rate (steroid-free remission, Mayo score ≤2 and endoscopic subscore ≤1) of FMT was significantly higher than that of the placebo group (12/38 [32%] vs 3/35 [9%]; P = 0.02). Paramsothy et al. [108] recently published a systematic review and meta-analysis of 53 studies that included 661 IBD patients who were treated by FMT. They found that the clinical remission rate of UC patients was 36%. They also found a significant benefit in clinical remission in UC for four above-mentioned RCTs (pooled odds ratios = 2.89, 95% CI = 1.36–6.13, P = 0.006).

Table 1 Randomized controlled trials of FMT in ulcerative colitis Full size table

FMT has also been applied to CD patients. All reports of FMT for CD patients published to date are case reports or cohort studies. A recent systematic review and meta-analysis of 11 studies (four case reports and seven prospective uncontrolled cohort studies) on FMT for CD that included 83 CD patients demonstrated an overall clinical remission rate of 50.5% (42/83) [108]. The authors indicated that publication bias was observed in this meta-analysis. In the future, RCTs should be conducted to evaluate the efficacy of FMT on CD patients.

It is obvious that FMT is not as effective in IBD as it is in CDI. CDI develops because of the disruption of gut microbiota using antibiotics followed by an overgrowth of Clostridium difficile. Therefore, the treatment with FMT shows high cure rates for recurrent CDI, regardless of donor, recipient, and delivery method [102]. On the other hand, various factors such as microbial, genetic, immunologic, and environmental factors are involved in the pathogenesis of IBD. The interplay between the host and gut microbiota in IBD is more complicated than that in CDI. In addition, the protocol of FMT, including the criteria of donor selection, patient pretreatment and administration route, is different in each clinical trial, which results in different effects. Finally, the most important issue is that dysbiosis is associated with the pathogenesis of IBD, but it is not clear whether this is a cause or a result of the inflammatory process. It is possible that all of these factors might contribute to the low clinical efficacy of FMT for IBD compared to that of FMT for CDI.

The factors involved in the response to FMT in UC patients remain unclear. An RCT conducted by Moayyedi et al. [104] found that early diagnosis of UC in patients might result in better outcomes with FMT. This suggests the possibility that there is a window of opportunity for FMT after diagnosis of UC. Paramsothy et al. [106] suggested that less severe endoscopic inflammation may be a potential predictor of FMT response. Moreover, the increase of Clostridium clusters IV and XVIII and the high microbial diversity in patients were identified as predictors of FMT response [106]. Conversely, the presence of Fusobacterium spp. and Sutterella spp. in patients were associated with non-response to FMT [106].

Based on the clinical data, FMT may remain in clinical trials but not in clinical practice. More high-quality clinical studies are necessary to optimize the protocol for FMT and determine the efficacy of FMT in IBD and long-term safety in the future.