Gut microbiota modulation via repeated donor fecal transplantation improves motor and gastrointestinal symptoms in drug-naïve Parkinson's disease: a randomized phase 2 trial.

Donor FMT significantly improved motor symptoms compared to autologous FMT in drug-naïve Parkinson's disease patients at 35 weeks.

• Mean change in UPDRS III score: -3.8 in the dFMT group vs. +0.1 in the aFMT group (p = 0.0001)
• 72 patients were randomized 1:1 to dFMT or aFMT; 66 completed the trial
• The trial was randomized, double-blind, and placebo-controlled (phase 2)
• Patients were de novo (drug-naïve) PD patients

Donor FMT produced a substantially greater reduction in constipation severity compared to autologous FMT.

• Mean reduction in constipation severity: -6.5 in the dFMT group vs. -0.7 in the aFMT group (p < 0.0001)
• Assessment was conducted at 35 weeks post-treatment initiation
• Improved quality-of-life scores were also observed in the dFMT group

Microbiome profiling after dFMT showed greater similarity to donor composition and a marked reduction in Escherichia-Shigella abundance.

• Reduction in Escherichia-Shigella correlated with decreased colonic α-synuclein aggregation (r = 0.3775, p = 0.0277)
• This correlation supports a gut-brain mechanistic link in PD pathogenesis
• The dFMT group showed greater overall compositional similarity to the donor microbiome compared to the aFMT group

Biochemical analyses revealed elevated fecal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels following dFMT.

• Both fecal dopamine and DOPAC levels were increased in the dFMT group
• These findings suggest microbiota modulation may influence dopaminergic metabolic pathways in the gut
• Results were part of mechanistic assessments alongside microbiome profiling

Histological assessments demonstrated strengthened epithelial barrier integrity with increased E-cadherin expression following dFMT.

• Increased E-cadherin expression was observed in the dFMT group, indicating enhanced intestinal epithelial barrier function
• This finding provides a potential mechanistic pathway linking gut barrier integrity to PD symptom improvement
• Histological assessments were conducted as part of the mechanistic evaluation of dFMT effects

The FMT protocol used repeated administration cycles, with all adverse events being mild and self-limited.

• FMT was administered for seven days per 4-week cycle (200 mL on days 1–3; 50 mL on days 4–7)
• No serious treatment-related adverse events were observed
• All adverse events were categorized as mild and self-limited
• The safety and tolerability profile supports feasibility of repeated dFMT in PD patients

The gut-brain axis is increasingly recognized as a critical contributor to Parkinson's disease pathogenesis, yet therapeutic impact of microbiota modulation had remained unclear due to lack of clinical trials in drug-naïve patients.

• This trial addresses a gap in evidence by specifically enrolling de novo, drug-naïve PD patients
• Prior to this trial, the therapeutic impact of microbiota modulation in PD was unclear
• The trial is registered in the Chinese Clinical Trial Registry as ChiCTR2200064151