Neuroprotective Attributes of Gut-derived Urolithins in Parkinson's Disease

Urolithins, a class of gut microbiota-derived metabolites, are produced from dietary ellagitannins and ellagic acid. Their pleiotropic activities, including antioxidant, anti-inflammatory, and mitophagy-enhancing effects, position them as promising candidates for Parkinson's disease (PD), a disorder increasingly understood through the lens of gut-brain axis dysfunction. Mounting evidence implicates gastrointestinal disturbances, including dysbiosis, increased intestinal permeability, and aberrant microbial signaling, as early events that may initiate or exacerbate neuropathological cascades in PD. In this context, urolithins represent a unique class of neuromodulatory agents operating at the intersection of host-microbiota co-metabolism and neuroprotection. This review synthesizes mechanistic insights into urolithin biosynthesis and interindividual variability in bioavailability, followed by a critical appraisal of their efficacy in preclinical PD models. We outline their relevance across key pathogenic dimensions, including preservation of dopaminergic neurons, inhibition of pathological α-synuclein aggregation and propagation, suppression of oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activation and enhancement of endogenous antioxidant defenses, attenuation of neuroinflammation through downregulation of pro-inflammatory cytokines and glial reactivity, rescue of mitochondrial dysfunction, and promotion of autophagy-lysosomal pathways to mitigate proteostatic failure. By translating mechanistic insights into a coherent therapeutic framework, this review highlights the promise of urolithins as microbiota-derived interventions capable of modifying the course of PD.