Integrated plasma metabolomics, proteomics, and gut metagenomics reveal that RBD-associated PD and idiopathic RBD show a shift from TCA toward glycolysis, dysregulated urea cycle, lipid remodeling, activation of PI3K‑Akt/IL‑17/NF‑κB/MAPK/TNF inflammatory pathways, and accumulation of gut…

Provides actionable, translationally relevant evidence linking gut microbiome-driven metabolic reprogramming and inflammation to prodromal and aggressive PD subtypes, pointing to microbiome modulation, metabolic and anti‑inflammatory interventions, and biomarker development for early therapeutic…

Rapid eye movement sleep behavior disorder (RBD) is the most specific prodromal marker of Parkinson's disease (PD), affecting 40-50% of PD patients. PD with RBD (RBD-PD) represents a clinically aggressive subtype characterized by more severe motor and nonmotor symptoms, prominent autonomic dysfunction, and accelerated disease progression; however, its underlying pathogenesis remains poorly understood. Here, we integrated multiplatform metabolomics and proteomics with precise clinical phenotyping to delineate molecular signatures in plasma across different PD subtypes. Our analyses demonstrated that PD patients exhibit significant metabolic reprogramming, characterized by a shift in energy metabolism from the tricarboxylic acid cycle toward glycolysis, a dysregulated urea cycle, and lipid remodeling, as well as extensive activation of inflammatory and immune responses involving the PI3K-Akt, IL-17, NF-kappaB, MAPK and TNF signaling pathways. Notably, the RBD-PD subgroup exhibited distinctive metabolic disturbances characterized by the accumulation of gut microbiota-derived toxic aromatic amino acid catabolites. Importantly, these alterations were also observed in idiopathic RBD (iRBD) patients, representing the prodromal stage of PD. By integrating metagenomic profiles, we further revealed that gut microbial dysbiosis in RBD-PD and iRBD drives a functional shift away from dietary fiber fermentation and toward enhanced degradation of protein, aromatic amino acids, glycine, and intestinal mucin glycans. This metabolic reprogramming is associated with exacerbated oxidative stress, neuroinflammation, and accelerated pathological progression. These findings provide multiomic evidence that clarifies the molecular heterogeneity in PD and highlights gut microbiota-driven dysfunction as a key contributor to both the iRBD and RBD-PD subtypes.