The PROB-PD trial: a pilot, randomised, placebo-controlled study protocol to evaluate the feasibility and potential efficacy of probiotics in modulating peripheral immunity in subjects with Parkinson’s disease

Background: Parkinson’s disease (PD) is a common neurodegenerative disease. No disease-modifying treatment is available, and therapy is symptomatic. The histopathologic hallmark is the loss of dopaminergic neurons and accumulation of alpha-synuclein (alpha-syn) in surviving neurons, but the underlying pathophysiology is unclear. Inflammatory mechanisms seem to play a prominent role, with an imbalance of immune functions and neurotoxicity caused by reactive oxygen species (ROS). Involvement of peripheral adaptive immunity, with an imbalance in T cell subpopulations and in the expression of transcriptional factors in CD4+ T cells, has also been reported. Although clinical presentation is defined by motor symptoms, patients also report non-motor symptoms, often before the onset of a clinically established disease. Etiopathogenesis of PD is unknown, but an initial aggregation ofalpha-syn in the gut, with subsequent propagation along the vagus nerve to the brain has been hypothesised. Interestingly, in an alpha-syn overexpressing murine model, the absence of gut microbiota prevented both microglia activation and motor impairment, thus pointing to a fundamental role of microbiota in the development of PD. Magistrelli et al. showed that in peripheral blood mononuclear cells of PD patients, probiotics modulate the in vitro production of cytokines toward an anti-inflammatory profile and reduce the production of ROS. Methods: This is a pilot randomised placebo-controlled clinical trial protocol for a 12-week treatment with probiotics. At least 80 patients affected by PD will be recruited and randomly allocated to either the treatment or placebo group in a 1:1 ratio. General inclusion criteria will be the onset of PD 2 to 5 years before the trial and absence of autoimmune comorbidities or immunomodulating therapy. Our primary endpoint is the assessment of changes in extracellular cytokine levels (Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10) and ROS production. Secondary outcomes include changes in lymphocyte subpopulations and transcriptional factors mRNA levels. Discussion: This study is designed to highlight the potential beneficial role of probiotics administration on peripheral immunity through the modulation of gut microbiota. Explorative outcomes will be evaluated to assess variations in motor and non-motor symptoms and the possible correlation with probiotics administration. Trial registration: ClinicalTrials.gov ID NCT05173701. Registered 08 November 2021