<p>Parkinson’s disease (PD) is increasingly recognized as a multisystem disorder in which pathogenic processes may originate in the gastrointestinal tract. Converging clinical, experimental, and multi-omics evidence implicates gut microbial dysbiosis as a key contributor of mucosal immune disruption, epithelial barrier dysfunction, and systemic inflammation that ultimately enhances vulnerability of the nigrostriatal pathway. PD-associated microbiome profiles consistently demonstrate a marked reduction in short-chain fatty acid (SCFA) producing commensals and an expansion of pro-inflammatory, endotoxin-enriched taxa. The consequent decline in SCFA availability weakens tight junction integrity, impairs intestinal immune regulation, and diminishes microglial maturation and anti-inflammatory signaling. Increased LPS activates TLR4-dependent inflammatory pathways. This peripheral inflammatory state is characterized by elevated circulating IL-1β, IL-6, TNF-α, and chemotactic mediators that prime microglia, facilitate immune cell infiltration into the central nervous system, and potentiate oxidative and mitochondrial stress within the substantia nigra. Accumulating findings further suggest that intestinal inflammation may trigger misfolding of α-synuclein within enteric neurons, enabling its propagation to the brainstem via vagal pathways and providing a mechanistic link between gut pathology and dopaminergic neurodegeneration. The immune–microbiome interface therefore represents a critical axis connecting peripheral immune dysregulation with central neuroinflammation. Therapeutic strategies aimed at restoring microbial homeostasis, reinforcing gut barrier integrity, or modulating innate immune activation such as probiotics, prebiotics, dietary interventions, fecal microbiota transplantation, and TLR-targeted agents hold promise for disease modification. Understanding these interconnected pathways may accelerate biomarker development and inform microbiome-based immunomodulatory therapies for PD.</p>