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BackgroundParkinson's disease is associated with a dysbiotic, proinflammatory gut microbiome, disruptions to intestinal barrier functions, and immunological imbalance. Microbiota-produced short-chain fatty acids, such as propionic and butyric acid promote gut barrier integrity and immune regulation, but their impact on Parkinson's disease pathology remains mostly unknown.MethodsIn a randomized double-blind prospective study, 72 people with Parkinson's disease received propionic and butyric acid and/or the prebiotic fiber 2'-fucosyllactose supplementation over 6 months in combination with existing Parkinson's disease-specific therapy. Patients underwent complete neurological assessment and provided blood and stool samples before as well as 3 and 6 months after supplementation.ResultsWe observed a robust improvement in motor symptoms, with all intervention groups achieving clinically meaningful reductions. These motor benefits were paralleled by clinically relevant reductions in levodopa medication. In contrast, effects on nonmotor symptoms were more heterogeneous. Notably, the interventions also modulated peripheral immune responses and enhanced mitochondrial respiration in immunocytes. Postintervention microbiota remodeled inflammatory and barrier-related gene sets in gut organ cultures and improved in vitro barrier functions. Treatment response was associated with microbiome composition, distinct patterns of colonic transcription and permeability ex vivo. Multiobjective analysis revealed immune parameters associated with an optimal response to supplementation.ConclusionShort-chain fatty acids ameliorate clinical symptoms in Parkinson's disease patients and modulate intestinal and peripheral immunity.RegistrationThis clinical trial was retrospectively registered with the German Clinical Trials Register (DRKS), registration number DRKS00027061 on 11/19/2021.
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