Parkinson’s disease (PD), the fastest growing and second most common neurodegenerative disorder, affects up to 2-3% of the population aged >65 years. It is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra, resulting in bradykinesia, rigidity, resting tremor and postural instability. To date, PD can only be treated symptomatically, and pharmacological treatments are primarily based on the replacement of dopamine, via e.g. levodopa administration. In recent years, it became increasingly clear that non-motor symptoms, particularly gastrointestinal dysfunction, precede the onset of the typical PD motor symptoms by several years. Notably, approximately 80% of de novo untreated patients exhibit prolonged colon transit time, indicative of constipation. Moreover, emerging evidence suggests that at least in a subset of PD patients the gut microbiome may play a pivotal role in PD pathogenesis and progression as the aggregation of α-synuclein starts in the gut before spreading to the brain. Additionally, recent microbiome studies consistently showed microbiota differences between PD patients and healthy controls. Notably, the alterations in the gut microbiome observed in PD patients have additional far-reaching consequences as they e.g. also affect the pharmacokinetics of levodopa, the most important pharmacotherapy used for PD management. This is due to the activity of various microbial enzymes that metabolize the drug, consequently influencing its availability at the target site in the brain.   

The current project stems from ground breaking faecal microbiota transplantation (FMT) trials performed by partners of this project, more specifically a double-blind, placebo-controlled, randomised, phase 2 trial (GUT-PARFECT; results submitted to The Lancet Neurology) and a self-controlled interventional donor-FMT pilot study trial (FMT4PD) to assess the feasibility, safety and efficacy of FMT in patients with early mild to moderate PD. The GUT-PARFECT study is the first of its kind with larger sample sizes compared to previously reported trials and revealed that the healthy donor FMT group demonstrated significant improvements in motor symptom severity compared to the placebo group. The largest divergence in the evolution of MDS-UPDRS III scores between the placebo and the treatment group occurred between 6 and 12 months post-intervention. In addition, objective assessments of gastrointestinal transit indicated improvements in the group receiving FMT from healthy donors, starting from the 3 to 6 months post-transplantation interval. The FMT4PD trial is currently analysing several clinical motor and non-motor outcomes, medication-related motor complications and changes in microbiota composition of recipients up until 12 months post-FMT, as well as the differential effect of two randomized healthy donors. No severe adverse events were reported in neither of the trials, further supporting the safety profile of FMT in PD. Together, these results open radically novel and exciting treatment perspectives for PD, serving as proof-of-principle upon on which this grand challenge project is based.  

Building on these promising results, our project aims to conduct a detailed analysis of the clinical trial data and collected samples, paving the way for an optimized multicentre FMT trial. We seek to identify the specific conditions under which FMT positively impacts PD patients, exploring patient/donor stratification and potential biomarkers of FMT treatment success. The key objectives include determining optimal procedures, considering safety aspects, and addressing potential side effects. The ultimate goal is to translate these findings into practical guidelines for widespread adoption of FMT for PD alleviation in clinical practice, offering innovative and transformative treatment perspectives for patients with PD.