Is Crohn’s Disease Ready for Fecal Microbiota Transplantation? (2014)

Fecal microbiota transplantation (FMT), in which homogenized stool from a healthy donor is infused into the gastrointestinal (GI) tract of a patient, has come to the fore in recent years and is being investigated as a treatment method for a number of GI and indeed non-GI disorders. The use of FMT in inflammatory bowel disease (IBD) has attracted increasing attention since the first reports in the late 1980s. Bennet and Brinkman’s1 initial report documented the complete clinical remission of a case of ulcerative colitis (UC) for at least 6 months following FMT through retention enema. Our Sydney group treated its first colitis patient in 1988 and has repeatedly reported cases of prolonged remission in IBD patients following FMT,2–4 with remission persisting up to 13 years in some cases. Unlike its application in recurrent Clostridium difficile infection (CDI), however, the success of FMT in IBD remains variable. In 2012, a systematic review of FMT for IBD5 found that the majority (albeit not an overwhelming majority) of patients experienced symptom improvement, disease remission, and cessation of medication following FMT treatment. This review was limited to the 9 small case series/reports available at the time. A number of randomized controlled trials of FMT for IBD, at least 4 of which are for Crohn’s disease (CD), are now underway to further characterize treatment efficacy and safety. In this issue, Kao et al6 have reported marked clinical and histologic improvement following colonoscopic FMT in a 26-year-old man with Crohn’s colitis. Four weeks after FMT, the patient’s modified Harvey-Bradshaw Index had reduced to 0, fecal calprotectin levels had normalized, and complete mucosal healing was evident upon colonoscopy. This observation provides evidence of the untapped power of the normal luminal flora to inhibit even the most severe inflammation of Crohn’s colitis, in contrast to the previous theory of IBD being the result of “inappropriate and ongoing activation of the mucosal immune system driven by the presence of normal luminal flora.”7 In the case presented by Kao and colleagues, clinical response was not sustained. Indeed, such a marked effect with clinical and endoscopic remission after a single infusion is certainly not the norm, with several other published reports yielding disappointing results.8 In our experience, CD is overall less responsive to FMT compared with UC, and, although a few exceptional cases may demonstrate striking results after a single infusion, in the vast majority of those who do respond, multiple infusions are required. Nonetheless, an additional 2 recent case reports9,10 have described similar responses in 2 patients with CD following a single FMT treatment, while we have reported prolonged CD remission following repeated FMT.11 As such, these case reports raise important questions, none more so than why some patients with IBD respond so impressively after a single or several FMT infusions and others fail to do so. It may be that FMT is more effective in cases of short disease duration, before colonic dysbiosis becomes deeply established. Alternatively, perhaps FMT is more effective in IBD cases in which antibiotic use is potentially associated with disease onset. It may also be that some manifestations of IBD-associated dysbiosis are more susceptible than others to rapid reversal after FMT, as occurs with CDI. Donor characteristics may be equally important in determining interpatient variability in FMT efficacy, in particular the donor’s microbial profile. Anecdotally, we have noticed that FMT response rates are better with certain donors than with others. This is likely because donor selection is at present a very basic and imprecise process that works on the principle of exclusion rather than inclusion. People are excluded if they have a transmissible disease, comorbidities, or risk factors for GI dysbiosis, such as recent antibiotic use. However, the future lies in identifying and selecting specific donors who have been shown to effect good clinical outcomes, based on their particular microbial profile. As suggested in the report of Kao and colleagues, there may not be 1 standard definition for a “good donor,” with a need to match donors to particular recipient enterotypes, and the definition may vary based on the underlying condition to be treated. In the case of Kao and colleagues, the patient elected to continue with FMT, ultimately receiving a total of 4 FMT infusions at increasing intervals of 4, 6, and 8 weeks. The authors speculate that IBD patients may require FMT maintenance therapy to prevent relapse, as the subject experienced a disease flare 6 weeks after his last FMT infusion. Such an observation is in line with the current authors’ extensive clinical experience, as well as published literature. In 2013, Kump et al12 documented the treatment of 6 cases of UC with a single colonoscopic infusion of FMT. Despite initial short-term improvement, only 2 patients achieved sustained improvement over the 90-day follow-up period and none achieved remission. Later that year, however, the same group13 presented the preliminary results of repeated colonoscopic FMT infusions (n=5) following a 10-day antibiotic regime in 9 UC patients. After 90 days of follow-up, 5/9 patients displayed sustained clinical improvement, with sustained mucosal healing in 1 patient. The establishment and maintenance of stable donor microbiota may be crucial for remission, and deep metagenomic analysis of recipient flora at a number of time points following FMT may enable a greater understanding of this. A key feature of the work in this issue is the microbial pyrosequencing analysis of the donor and comparison with that of the patient before and after FMT. GI microbiota metagenomic sequencing by Qin et al14 revealed 25% fewer genes (suggestive of reduced diversity) in the IBD microbiota and a significant difference in bacterial abundance between CD samples and control (P=0.031). Detailed analysis by Gevers et al15 of the treatment-naive microbiome in new-onset CD found a strong association between disease status and an overall decrease in species richness and altered taxa abundance. Their work identified a distinct, disease-state microbial signature characterized by an increased abundance of Enterobacteriaceae and Fusobacteriaceae, and decreased abundance in Bacteroidales and Clostridiales, among others. Interestingly, mucosa-associated dysbiosis (identified from colonic biopsies) was only weakly reflected in the accompanying fecal samples, a concept that may have important implications in reverse when contemplating the potential for FMT to correct mucosal dysbiosis. In the case presented here, the authors noted marked differences between the patient and donor fecal microbial compositions before FMT, whereas after FMT the patient microbiota approached that of the healthy donor. These changes were seen to correlate with clinical response. A similar phenomenon is well established in CDI, in which the “implantation” of the healthy donor microbiota is thought to play a key role in the durable eradication of the infection. In the initial work of Kump et al,12 however, such a distinct correlation between clinical improvement or remission and the reversal of dysbiosis was not observed, with no patients achieving remission despite compositional changes toward the donor microbiota in 3/6 patients. Additional analysis of microbial changes on a mucosal level with colonic biopsies, along with the luminal information provided by deeper analysis of fecal samples, may shed further light on the success or failure of implantation and the likely durability of any response achieved. That said, it appears likely that the mechanism of action of FMT in IBD involves more than simply the implantation of the introduced donor microbiota. The work by Kao and colleagues represents an important contribution to the IBD/FMT knowledge base. It is clear that in some cases FMT can profoundly reverse inflammation and induce remission in IBD. Despite this case report, evidence suggests that, unlike CDI, the vast majority of IBD cases require repeat FMT administration for successful treatment. We now await the outcomes of current clinical trials to provide further information as to the overall safety, efficacy, and durability of FMT in both UC and CD. Associated metagenomic studies will undoubtedly prove vital in further understanding and optimizing FMT as a therapeutic strategy in IBD, and in helping to identify patient and donor factors predictive of response.