Lindsey Russell, MD, MSc and Paul Moayyedi, MD, PhD, MPH
IBD is thought to arise from a dysregulated immune system reacting to an environmental agent in a genetically susceptible individual. Most therapies currently focus on dampening the immune response, with very little attention paid to possible environmental stimulus driving the inflammation that characterizes IBD.1 Our ability to study the microbiome has increased exponentially over the past decade, and this has allowed us to understand differences in the microbiome in patients with IBD compared with those who are healthy.2 Indeed, it is likely that the microbiome is driving the immune response in IBD, and if the gut microbiota were altered in a favorable direction, this could ameliorate the disease. Researchers have attempted to do this with antibiotics3 and probiotics but with limited success. This is not surprising because we have a limited understanding of what constitutes a healthy microbiome so cannot engineer this with antibiotics or probiotics.
Altering the gut microbiota in IBD patients with microbiota from a healthy donor by FMT is an intuitive approach to this problem. Even if we cannot define a healthy gut microbiota, we may able to restore homeostasis through FMT and thus treat IBD patients. This section will review the evidence for FMT in the 2 diseases that constitute IBD—ulcerative colitis (UC) and Crohn’s disease (CD)—as well as give future directions for study.
Fecal Microbiota Transplantation in Ulcerative Colitis
There is more evidence for the efficacy of FMT in UC than any other disease except CDI. There are 4 randomized clinical trials that have evaluated FMT in 277 active UC patients,4–7 and 3 trials have been positive.5–7 A systematic review suggested that FMT induces remission in approximately 25% of patients with active UC compared with 5% of those given placebo after 6 to 8 weeks.8 This translates to a number needed to treat (NNT) of 5 (95% confidence interval,4–10; Figure 10.2.1-1), which is similar to the NNT seen for biologic therapy.9 The evidence has been assessed according to Grading of Recommendations, Assessment, Development and Evaluations criteria9 and is low-quality evidence because there is imprecision in the estimate and there is heterogeneity between studies in terms of type of donor, mode of administration, and type of active UC patient included in the trial. Interestingly, 1 trial suggested there may be a donor effect, with 1 donor being effective in 40% of cases while another donor was not successful in any patient.5 This trial also suggested that FMT may be more effective in those who had been diagnosed with UC within 1 year and those who were taking concomitant immunosuppressive therapy but had flared despite taking these drugs.5 These observations are based on small numbers of patients and need evaluation in further trials. The longest follow-up for FMT in the context of a randomized trial was 1 year; therefore, further follow-up is needed to establish the long-term benefit of this approach. In our experience, most patients flare over time but usually respond to further courses of FMT. Currently, we offer UC patients who are in remission with FMT repeated enemas every 2 to 4 weeks as maintenance therapy, although this is still investigational (Figure 10.2.1-2).
Fecal Microbiota Transplantation in Crohn’s Disease
There is less evidence for the role of FMT in CD than there is for UC. There is only 1 randomized clinical trial, and it compared administering FMT via gastroscopy or colonoscopy with no placebo arm.10 One study found that FMT increased microbial diversity in CD patients, and this was more apparent in patients who responded to therapy.11 A systematic review of case series of active CD patients treated with FMT identified 11 studies that reported that 52% (95% confidence interval, 31%-72%) achieved clinical remission.12 There was significant clinical and statistical heterogeneity between studies, and most studies did not perform a colonoscopy at the end of treatment, so the impact on mucosal healing is less certain. The choice of donor and mode of delivery was also different between studies, with some using colonoscopy, others using nasogastric tubes (NGTs), and yet others using capsules to deliver FMT. Open-label studies where there is no control arm almost always overestimate treatment effect, so it is unclear whether FMT is effective in active CD. Case series data are promising, and there are a number of randomized trials of FMT in active CD currently being conducted.