The role of indole metabolites derived from gut microbiota in Parkinson's disease: A comprehensive review

Emerging evidence suggests that Parkinson's disease (PD) extends beyond the brain and involves early disturbances along the gut-brain axis. Among the metabolites shaping this communication, bacterial products derived from tryptophan, particularly indole compounds, are gaining attention as key biochemical links between intestinal dysbiosis and neurodegeneration. Multi-omics studies consistently show a reduction in commensal bacteria capable of producing beneficial indoles and an enrichment of Enterobacteriaceae that redirect tryptophan catabolism toward toxic intermediates. This shift disrupts epithelial and blood-brain barrier function and amplifies inflammatory and oxidative stress pathways within the central nervous system. Protective metabolites such as indole-3-propionic acid (IPA), indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indole-3-carbinol (I3C) exert antioxidant, barrier-stabilizing, and anti-inflammatory effects through receptors including the aryl hydrocarbon and pregnane X receptors. Conversely, uremic indoles such as indoxyl sulfate (IS) and p-cresyl sulfate (pCS) activate microglia and astrocytes, promote α-synuclein aggregation, and accelerate dopaminergic neuron loss. Together, these findings support a view of PD as a metabolic imbalance between neuroprotective and neurotoxic indoles. Understanding how microbial and host pathways regulate this balance may open opportunities for early diagnosis and targeted interventions that integrate metabolism, immunity, and neuroprotection.