Sex-specific gut microbiota and metabolite signatures in Parkinson's disease: implications for personalized therapeutics.

Parkinson's disease (PD) is characterized by dopaminergic neuron loss and α-synuclein aggregation in the substantia nigra pars compacta (SNpc). It is a multifactorial disorder with motor and non-motor manifestations and growing evidence suggests that gastrointestinal dysfunction may precede motor onset. Sex differences influence PD risk, onset and clinical features, with men exhibiting higher prevalence and earlier onset, driven by hormonal, genetic, and metabolic factors. The gut microbiota communicates bidirectionally with the central nervous system (CNS) via the gut-brain axis, modulating neural, immune and metabolic processes. Gut dysbiosis and altered microbial metabolites contribute to PD pathogenesis, with distinct sex-specific differences in the microbial composition and functional dynamics of gut microbiota. Despite growing evidence linking the gut-brain axis to PD, sex-specific regulation of microbiota-metabolite interactions remains poorly understood, representing a critical knowledge gap. Further most studies are male-biased, neglecting sex-specific variations in microbial profiles, hormone dynamics, metabolic responses and treatment outcomes. This review addresses current evidence on sex-specific interactions between gut microbiota, metabolites, microbial metabolites and PD mechanisms, highlighting their role in oxidative stress, neuroinflammation, glial dysfunction and genetic predisposition. It further emphasizes the need for sex-tailored, precision therapeutic strategies integrating hormonal, genetic and microbial determinants to improve clinical PD outcomes.