Postbiotics as a therapeutic frontier in Parkinson's disease: Insights into molecular pathways and neuroprotective effects.

Parkinson's disease (PD) is an aging neurodegenerative disease associated with dopaminergic neuronal impairment, mitochondrial dysfunction, oxidative stress, chronic neuroinflammation, and pathological deposits of misfolded α-synuclein. Gut microbiota (GM) is a general contributing factor in PD pathogenesis via the microbiota-gut-brain bidirectional axis. Gut dysbiosis facilitates intestinal permeability, systemic inflammation, disrupted metabolism of neurotransmitters and amplified α-synuclein aggregation, deteriorates motor and non-motor symptoms. These bioactive metabolites and structural components that beneficial microorganisms generate, known as postbiotics, have been highlighted as having the capacity to regulate neuroinflammation, mitochondrial functionality, synaptic signaling, gut and blood-brain barrier integrity. Short-chain fatty acids (SCFAs), bioactive peptides, bacterial lysates, and exopolysaccharides are compounds with potent neuroprotective and anti-inflammatory properties that are applicable to PD. Preclinical evidence shows that postbiotics, especially butyrate, have the ability to alleviate oxidative stress, inhibit microglial activation, prevent α-synuclein aggregation, and improve behavioral performance in PD models. The emerging clinical evidence also indicates that the optimization of endogenous postbiotic synthesis positively influences gastrointestinal (GI) symptoms and decreases inflammatory biomarkers, and changes GM in PD patients. This review summarizes the mechanistic activities of postbiotics on pathways involved in the pathogenesis of PD and synthesizes recent findings of the therapeutic usefulness of postbiotics. Overall, postbiotics may represent a promising therapeutic strategy for targeting neurodegenerative processes in PD, although their safety, efficacy, optimal dosing, and clinical utility require further investigations. Further studies of specific postbiotic interventions and strategies targeting the microbiota-gut-brain axis are needed to determine their potential to improve the quality of life of patients with PD.