A gut microbial UrdA- axis may drive Parkinson-like pathology through .
Evidence
This mixed patient microbiome and mouse mechanistic study found elevated S. mutans, UrdA, and plasma ImP in patients with Parkinson's disease, then showed UrdA-producing colonization or ImP administration induced dopaminergic loss, gliosis, motor impairment, and alpha-synuclein pathology in mice.
Caveat
The causal evidence comes from colonized or treated mouse models, while the patient data are associative.
Simplified
Parkinson's disease (PD) is characterized by the selective degeneration of midbrain dopaminergic neurons and aggregation of α-synuclein. Emerging evidence implicates the gut microbiome in PD, with microbial metabolites proposed as potential pathological mediators. However, the specific microbes and metabolites involved, and whether gut-derived metabolites can reach the brain to directly induce neurodegeneration, remain unclear. Here we show that elevated levels of Streptococcus mutans (S. mutans) and its enzyme urocanate reductase (UrdA), which produces (ImP), in the gut microbiome of patients with PD, along with increased plasma ImP. Colonization of mice with S. mutans harboring UrdA or Escherichia coli expressing UrdA from S. mutans increases systemic and brain ImP levels, inducing PD-like symptoms including dopaminergic neuronal loss, astrogliosis, microgliosis, and motor impairment. Additionally, S. mutans exacerbates α-synuclein pathology in a mouse model. ImP administration alone recapitulates key PD features, supporting the UrdA-ImP axis as a microbial driver of PD pathology. Mechanistically, activation is crucial for both S. mutans- and ImP-induced PD pathology. Together, these findings identify microbial ImP, produced via UrdA, as a direct pathological mediator of the gut-brain axis in PD.
Key numbers
400 nM
Level Increase
Measured in antibiotic-treated mice colonized with S. mutans.
3-fold
Dopaminergic Neuron Loss
Compared to vehicle-treated controls in the study.
65 of 130
Patient Cohort Size
Patients with PD compared to neurologically healthy controls.
Full Text
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Gut-Brain Axis