Ulcerative Colitis and Fecal Transplantation: Where are We Now?

gut microbiome
gut microbiome
It is thought that dysregulation of the gut microbiome could cause increased production of pro-inflammatory toxins that can predispose patients to the development of UC.

The precise pathophysiology of ulcerative colitis (UC) is not yet fully understood. However, one prevailing theory is that dysregulation of the gut microbiome causes the condition. Dysbiosis in the gut could lead to altered regulation of oxidative stress and metabolism of short chain fatty acids, causing increased production of pro-inflammatory toxins that can predispose patients to the development of UC..

There are extensive treatment options for patients with UC, which range from what may be perceived as “benign” agents such as 5-ASAs to what may be considered “stronger” medications such as anti-tumor necrosis factor (TNF) agents. Based on the proposed role of the gut microbiome in the development and progression of UC, there has been increasing interest in the role of fecal microbiota transplantation (FMT) as a potential therapeutic option. Recently, Lopetuso et al published a review of FMT use in UC in the journal Expert Opinion on Biological Therapy.2

The majority of published data on FMT has been obtained from patients with recurrent Clostridium difficile infection (rCDI). Patients with IBD have been found to have decreased diversity of gut microbiota, including decreased numbers of Firmicutes and Bacteriodetes and increased numbers of Actinobacteria, Proteobacteria and Escherichia coli.3 In addition to aberrant amounts of certain types of bacteria in the gut, cellular components of the gastrointestinal (GI) tract can also directly contribute to microbiome dysregulation. A disruption in the epithelial cell barrier within the GI tract can lead to increased susceptibility to infection as well as decreased production of antimicrobial peptides, which could lead to a decreased immune response.2 These disruptions can facilitate a proinflammatory state as well as contribute to the pathogenesis of UC.  In addition to disrupting the epithelial cell barrier, gut microbiota can influence the pathogenesis of UC via toll-like receptors (TLRs) and cytokines.2 

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The authors included 4 randomized controlled trials (RCTs) in their review. Moayyedi et al found that in 70 patients with UC, those who had undergone FMT displayed a 24% clinical remission rate compared with the 5% clinical remission rate in those who were given placebo (P =.03). Patients in former group also showed increased gut microbiome diversity.4 Rossen et al found no difference between administration of placebo and FMT in 37 patients with mild to moderate UC.5 Paramsothy et al evaluated an intensive frozen FMT protocol that used 1 colonoscopy and 5 enemas per week for 8 weeks in 85 patients with mild to moderate UC.6  The clinical remission rate in the donor FMT group was 27% compared with the 8% clinical remission rate in the autologous FMT group (P =.021).  Costello et al found greater clinical remission in a donor FMT group, which showed a 32% clinical remission rate compared with a 9% rate in an autologous FMT group (P =.03).7 This study used frozen FMT prepared under anaerobic conditions in hopes of preserving “healthy” microbes. While this procedure did lead to increased microbial diversity in the gut, the ensuing gains in clinical remission rate were modest.  The authors also reviewed other randomized controlled trials evaluating FMT in UC and found clinical remission rates varying from 28% to 37% and endoscopic remission rates varying from 14% to 30%.2

When evaluating studies using FMT to treat UC, it is important to consider several factors including study size, blinding, study protocol (especially the number of FMTs required), FMT route and both current and past UC medications. Many of the studies include a heterogeneous patient population and varying FMT protocols, which can make direct comparison between studies challenging.  Depending on the protocol used by researchers, the feasibility of undergoing multiple FMTs (either via colonoscopy or enemas) in the “real world” may preclude its routine use, especially when considering a relatively modest improvement in clinical and endoscopic remission compared with placebo.  The recent incorporation of FMT into capsule formulation may prove helpful in reducing the administration barrier in the future.

There has also been heightened scrutiny of FMT use due to side effects of the procedure experienced by some patients, particularly when they develop infection-related complications8.  These types of warnings could limit both research in clinical trials and in real-world settings because many patients with UC are concerned about baseline infectious risks.  Interestingly, the review provided by Lopetuso et al did not include significant safety data. It is also unclear whether a given patient’s gut microbiome can be significantly altered by prior treatments such as anti-TNFs and if this would impact their response to FMT. 

Although there is some promising data supporting the use of FMT in patients with UC, further study is needed to optimize administration of the procedure as well as achieve an acceptable safety and efficacy profiles. 

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1. Cammarota G, Ianiro G, Cianci R, et al. The involvement of gut microbiota in inflammatory bowel disease pathogenesis: potential for therapy. Pharmacol Ther. 2015;149:191-212.

2. Lopetuso LR. et al.  Fecal transplantation for ulcerative colitis: current evidence and future applications.  Expert Opin Biol Ther. 2020 Apr;20(4):343-351.

3. Sartor RB. Microbial influences in inflammatory bowel diseases.  Gastroenterology. 2008 Feb;134(2):577–594.

4. Moayyedi P, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015 Jul;149(1):102–109 e6.

5.     Rossen NG, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. 2015 Jul;149(1):110–118 e4.

6.     Paramsothy S, et al.  Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017 Mar 25;389(10075):1218–1228.

7.     Costello SP, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA. 2019 Jan 15;321(2):156–164.

8.     Fecal Microbiota for Transplantation:  Safety Alert-Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms.  https://www.fda.gov/safety/medical-product-safety-information/fecal-microbiota-transplantation-safety-alert-risk-serious-adverse-events-likely-due-transmission.