Shotgun metagenomics of stool from PD patients, controls, and IBS-C showed taxonomic differences but conserved functional deficits in PD—notably reduced microbial tryptophan biosynthesis, polyamine production, and B‑vitamin metabolism—while constipated PD patients trended toward higher circulating…

Identifies specific microbial metabolic pathways linked to neurotransmitter production, epithelial integrity, and neuroimmune regulation that are actionable targets for microbiome‑based, dietary, or supplementation interventions in PD-related GI dysfunction and possibly…

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.