The Gut–Brain Axis in Parkinson's Disease: From Clinical Observation toward Mechanism‐Based Precision Medicine

Gastrointestinal dysfunction is increasingly recognized as a core feature of Parkinson's disease (PD), affecting quality of life, nutrition, medication response, and potentially the earliest stages of pathogenesis. This perspective traces the evolution of the gut from a neglected source of non-motor symptoms to a central component of biological models of PD. Gastrointestinal manifestations are physiologically heterogeneous and require objective phenotyping to distinguish dysphagia, gastroparesis, slow transit, defecatory dysfunction, and overlapping mechanisms. The body-first/brain-first framework further suggests that Lewy pathology may follow distinct anatomical trajectories, with early enteric and autonomic involvement defining a subgroup in which gut-directed biomarkers and therapies may be especially relevant. Alterations of the gut microbiome are reproducibly associated with PD, although geography, constipation, medication, diet, disease stage, and reverse causation complicate interpretation. Emerging work is shifting from taxonomy toward microbial functions and host pathways, including barrier integrity, immune and enteroendocrine signaling, short-chain fatty acids, glucagon-like peptide-1 (GLP-1), host genetic susceptibility, α-synuclein aggregation and propagation, and microbial levodopa metabolism. Trials of probiotics, fecal microbiota transplantation, and dietary interventions remain heterogeneous and have not established disease-modifying efficacy. Progress will require longitudinal studies in prodromal and subtype-defined populations, objective gastrointestinal measurements, integrated microbial, host-genetic and other multi-omics, mechanistic human and animal models, and clinical trials combining target-engagement markers with meaningful outcomes. Such an approach may enable precision gut-brain medicine for appropriately selected patients with PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.