The gut microbiome and brain inflammation in Parkinson’s disease: mechanisms and therapies

Parkinson’s disease (PD) is the second most common chronic progressive neurodegenerative disorder affecting over 10 million people worldwide. PD is increasingly understood to have peripheral origins in a substantial subset of patients, in whom microbiota dysbiosis precedes and facilitates central neurodegeneration via the gut-brain axis. Dysbiosis-associated depletion of short-chain fatty acid (SCFA)-producing bacteria, enrichment of lipopolysaccharide-producing taxa, and loss of gut barrier integrity activate toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling, prime microglia towards a disease-linked phenotype, and promote the misfolding of α-synuclein and its propagation from the enteric to the central nervous system. Complement, activated by α-synuclein and shaped by the gut microbiota, further links dysbiosis to neurodegeneration. Beyond neuroinflammation, the gut microbiome modulates levodopa pharmacokinetics through bacterial tyrosine decarboxylase activity and interacts with catechol-O-methyltransferase inhibitors to alter drug bioavailability. Certain microbial metabolites, including the trimethylamine N-oxide to butyrate ratio and secondary bile acids, have emerged as candidate biomarkers. Cutaneous phosphorylated α-synuclein deposition and seeding amplification assays (SAA) are evaluated as minimally invasive peripheral biomarkers, along with epidemiological evidence linking prior antibiotic exposure and inflammatory bowel disease to PD risk. Emerging therapeutic strategies include SCFA supplementation, fecal microbiota transplantation, glucagon-like peptide-1 receptor (GLP-1R) agonists, and targeted probiotics. Microbiome-direct strategies may benefit patients with a gut-first PD subtype, suggested by prodromal constipation, rapid eye movement (REM) sleep behavior disorder, or cardiac sympathetic denervation, underscoring the need for subtype-stratified trial designs. In this review article, we highlight recent evidence linking the gut microbiome with neuroinflammation in Parkinson’s disease through α-synuclein pathology, complement activation, and LPS/TLR4/NF-κB signaling, and discuss the implications for biomarkers, pharmacological interactions, and therapies. In conclusion, the convergence of mechanisms, biomarkers, and clinical evidence indicates the gut microbiome may be a significant diagnostic and modifiable therapeutic target in PD.