Discussion
gastrointestinal symptoms, intestinal barrier dysfunction, levodopa-treated PD, PD, dysbiosis, intestinal inflammation, heterogeneous disease, LBP
NEURODEGENERATION, INFLAMMATION, INTESTINAL INFLAMMATION, SECONDARY, INTESTINAL BARRIER DYSFUNCTION
This proof-of-concept study found that 10 days of prebiotic intervention was both well-tolerated and safe in PD patients (primary and secondary outcomes) and decreased total GI symptom severity score in treated PD participants. The prebiotic intervention was also associated with anti-inflammatory shifts in the intestinal microbiota, increased SCFA, reduced calprotectin (intestinal inflammation), reduced zonulin (a putative marker of intestinal barrier dysfunction/inflammation), and a subtle, but statistically significant, reduction in NfL (a marker of neurodegeneration). No changes in LBP, cytokines, CRP, HMGB-1, or BDNF were noted which may reflect the short, 10-day duration of this proof-of-concept study. In addition, exploratory analyses show the prebiotic intervention may be associated with improved clinical outcomes (i.e., gastrointestinal symptoms and UPDRS).Recent studies highlight the importance of the microbiota-brain axis in PDStudies suggest that microbiota-directed interventions (diet, probiotics, microbiota transplant) may beneficially impact symptoms and/or PD pathogenesisAs hypothesized based on the fermentation experiment, consumption of the prebiotic mixture altered the stool microbiota community in PD participants including reduced relative abundance of putative pro-inflammatory bacteria (e.g., Proteobacteria) and increased relative abundance of putative anti-inflammatory bacteria including SCFA-producing bacteria (e.g., Microbiota dysbiosis and intestinal barrier dysfunction are often associated with intestinal inflammation. In this study, stool calprotectin (a reliable and specific marker of inflammation) was used to assess intestinal inflammation. Prior studies demonstrate that calprotectin is increased in PD patientsThe prebiotic intervention modestly but significantly reduced NfL, a putative systemic marker of neurodegenerationLastly, differences were observed between newly diagnosed, non-medicated and treated PD participants. Because PD is a highly heterogeneous disease, future studies are needed to begin to understand which populations can benefit most from a prebiotic intervention. For example, levodopa-treated PD patients may particularly benefit from a prebiotic intervention. The PD-associated microbiota is characterized by a high abundance of bacteria that contain the levodopa metabolizing enzyme, tyrosine decarboxylase (TDC)A strength of this study is the within-subject design, but there are also limitations including small sample size and an open-label, non-placebo design. The prebiotic mixture was administered in the form of a healthy bar containing additional non-prebiotic fiber with potential antioxidant effects. Thus, the observed biological changes might not be due to prebiotic fibers alone but could instead be related to the consumption of another healthy component in the bar. In addition, while participants were instructed to maintain their usual diet throughout the study, consumption of the prebiotic bar may have influenced diet. The non-blinded design of the study could have impacted the results of clinical outcomes like the UPDRS and gastrointestinal symptom severity score reported by participants (i.e., placebo effect). However, the non-blinded design should not have impacted biological-based outcomes which were analyzed by staff blinded to time (baseline, after prebiotic intervention) and PD group (newly diagnosed, non-medicated vs treated).This proof-of-concept study demonstrates that a SCFA-promoting prebiotic fiber mixture can be used to modulate the intestinal microbiota in PD patients (i.e., the approach is feasible) and that the prebiotic mixture is well-accepted, tolerated, and safe for use in PD patients. Moreover, the prebiotic fiber mixture may have a clinical impact leading to reduced severity of motor and non-motor PD symptoms and improved gastrointestinal function. This proof-of-concept study provides the scientific rationale for future studies evaluating the potential of a microbiota-directed prebiotic intervention as a disease-modifying therapeutic approach in PD patients.