Fecal microbiota transplantation in Parkinson's disease-A randomized repeat-dose, placebo-controlled clinical pilot study

Abstract

Background and purpose: The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease.

Methods: This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months).

Results: Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks (p = 0.008) and 13 weeks (p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index (p = 0.0374) were improved in the FMT group.

Conclusions: Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms.

Clinical trial registration: ClinicalTrial.gov, identifier: NCT03671785.

Keywords: Parkinson's disease; constipation; dysbiosis; fecal microbiota transplantation; microbiome.

Figure 1

CONSORT flow diagram describing the study population, number screened, excluded, and enrolled into active treatment or placebo study arms.

Figure 2

Alpha diversity [observed operational taxonomic units (OTUs)] and Shannon index at baseline (pre-treatment), at 6 weeks (mid-treatment), 13 weeks (1 week post-treatment), 4, 6, and 9 months.

Figure 3

Beta diversity (taxa) differences comparing FMT- and placebo-treated subjects, comparisons of Jaccard distances between FMT and placebo recipients were compared using box plots. Over time, subjects in the placebo group had bacterial community compositions more similar to each other than those in the FMT group at baseline (p < 0.629), at 6 weeks p < 0.008, and at 13 weeks (p < 0.0008) post FMT. P-values were determined using the Mann-Whitney U-test.

Figure 4

Comparison of the 10 most abundant genera in the group receiving FMT, at baseline, at 6 weeks (med-therapy), at 13 weeks (1 week after completing therapy), and at 4 and 9 months (1–6 months after completing therapy).

Figure 5

LEfSE analysis of preferentially abundant bacterial families at 13 weeks (1 week after completing treatment with either FMT or placebo) in treatment groups after eliminating families found in <30% of subjects in the treatment groups. All differences shown here at 13 weeks were statistically significant (see Results). No families were preferentially abundant in one of the treatment groups but not the other for baseline (pre-treatment) or at 6 weeks (mid-treatment).