Combined Endoscopic and Oral Fecal Microbiota Transplantation in Patients with Antibiotic-Dependent Pouchitis: Low Clinical Efficacy due to Low Donor Microbial Engraftment

Abstract

Background and objective: A significant number of pouch patients develop antibiotic-dependent pouchitis (ADP). Microbial dysbiosis is thought to be a major driver of clinical symptoms in ADP. The objective of this proof of concept study was to evaluate safety, efficacy, and donor microbial engraftment of an intensified fecal microbiota transplant (FMT) consisting of a single endoscopic FMT followed by daily oral FMT for 2 weeks in patients with ADP.

Methods: We performed a prospective placebo-controlled double-blind FMT trial in patents with established ADP and planned to enroll 20 patients in this proof of concept study. In case of non-response, patients were offered an optional open label active FMT treatment. The endpoints were safety, clinical remission without need for antibiotics during 16 weeks of follow-up, quantitative changes of fecal calprotectin (FCP), and engraftment of donor FMT as determined by metagenomic sequencing of the V4 region of the 16S rRNA gene.

Results: Due to a lower than expected clinical remission rate and low FMT engraftment, enrollment in the study was stopped prematurely after 6 patients were included. All 6 patients enrolled in the placebo-controlled portion failed to respond and needed antibiotic rescue therapy shortly after FMT. FCP increased in the majority of patients in the setting of relapse after FMT. In the active open label FMT extension study 1 out of 5 patients achieved antibiotic-free clinical remission. FMT engraftment after active FMT was observed only in this single patient, whereas engraftment of donor FMT occurred in none of the other patients receiving active FMT, paralleling the lack of clinical response.

Conclusions: Low donor FMT engraftment resulted in low clinical efficacy of FMT in patients with ADP. Before embarking on larger clinical trials with FMT in patients with ADP or other forms of pouchitis, it is mandatory to explore approaches for superior FMT engraftment.

Keywords: Fecal microbiota transplantation; Inflammatory bowel diseases; Microbiome; Pouchitis; Stool transplant.

Fig. 1

Consort diagram of the trial.

Fig. 2

eFMT followed by oFMT in 6 patients. In total, 9 active FMTs were performed in the 6 patients; 3 patients were treated with active FMT in the blinded randomized as well as in the open label part of the study, 1 patient was treated with active FMT in the randomized part only, and 2 patients in the open label part only. The chart shows the number of OTUs that were engrafted from samples of a patient's true donor compared to the number of OTUs that were engrafted from a set of 10 “false donors,” which were randomly selected from the stool bank donor pool (error bars show standard error). Only 1 patient (patient 1,028, who first received placebo FMT and then active FMT in the open label extension) showed strong engraftment specificity, as shown by the significantly higher number of engrafting OTUs inferred from the true donor versus the false donors. This patient also experienced stable clinical symptoms after FMT and did not restart antibiotics during the trial period of 16 weeks.