BackgroundGut dysbiosis and gut‐brain‐axis involvement in people with Parkinson's disease (PwP) support the use of gut‐microbiota‐modulating interventions. Probiotics may help manage constipation in PwP; however, mechanisms underpinning additional beneficial properties are unknown.ObjectiveThe aim was evaluating the effects of a probiotic (Lacticaseibacillus rhamnosus, Lactobacillus acidophilus, Lactiplantibacillus plantarum and Enterococcus faecium) on gut microbiota, inflammation, motor and non‐motor symptoms (NMS) in PwP and constipation.MethodsIn this multicenter, randomized, double‐blind, placebo‐controlled trial (NCT05146921), PwP and constipation were randomized (1:1) to receive either the probiotic (4.08 × 108 CFU/mL) or placebo orally (70 mL/day) for 12 weeks. The primary endpoint was the differential abundance of gut microbiota taxa between baseline and end‐of‐treatment in the active versus placebo group. Secondary/exploratory endpoints included changes in inflammatory cytokines plasma levels, short‐chain fatty acids (SCFAs) plasma and fecal levels, motor and NMS outcomes after 12 weeks. A per‐protocol analysis was performed.ResultsBetween July 17, 2019 and February 6, 2022, 74 participants were randomized. Data from 35 (probiotic) and 33 (placebo) participants were analyzed. Enrichments of bacteria with beneficial health‐related properties (Odoribacteraceae, Enterococcaceae, and Blautia faecicola) were observed in the active group compared to placebo (P ≤ 0.05). Proinflammatory cytokine TNF‐α plasma levels decreased with probiotic treatment and increased with placebo (P < 0.05). No changes in SCFAs levels were observed. Reductions in time‐to‐on and NMS scale scores (P < 0.05) were observed only in the active group.ConclusionsThis probiotic was effective in beneficially enriching the gut microbiota with potential to reduce systemic inflammation, shortening time‐to‐on following levodopa administration, and alleviating NMS burden in PwP experiencing constipation. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.