Abstract
BACKGROUND: Gastrointestinal dysfunction, including constipation, is a common non-motor feature of Parkinson's disease (PD) and often precedes motor symptoms. The gut microbiome interacts with the host through neural, hormonal, and immune pathways, yet whether constipation represents a cause or consequence of PD remains unclear. Therefore, we aimed to interrogate the associations between microbiome and immune alterations in relation to constipation to provide novel insight into microbiome-gut-brain axis mechanisms in PD. METHODS: We analysed peripheral blood mononuclear cells (PBMCs) for circulating gut-homing T cell populations and used shotgun metagenomics to profile the stool microbiome composition and functional capacity in PD patients (n = 18), healthy controls (n = 21), and individuals with constipation-predominant irritable bowel syndrome (IBS-C; n = 8). Associations between immune markers and microbial taxa were assessed, and functional pathway differences were evaluated. RESULTS: Circulating gut-homing T cell frequencies did not differ significantly between PD and controls, but constipated PD patients showed a trend toward increased circulating gut-homing T cells. Microbiome beta-diversity analyses revealed distinct taxonomic shifts in PD and IBS-C, while functional capacity was largely conserved. Of the differential functional pathways tryptophan biosynthesis, polyamine production, and vitamin B metabolism, processes critical for neurotransmitter synthesis, epithelial integrity, and neuroimmune regulation were reduced in PD compared to IBS-C. CONCLUSION: Our findings highlight unique microbial and immune signatures in PD, partially overlapping with IBS-C, and underscore the importance of microbial metabolic pathways in gut-brain axis disorders. Collectively our findings suggest a contribution to dopaminergic dysfunction, neuroinflammation, and impaired gut motility. Future longitudinal studies are needed to clarify causal relationships and inform targeted interventions for PD-related gastrointestinal dysfunction.