Gut microbial production of imidazole propionate drives Parkinson’s pathologies
Hyunji Park, Jiwon Cheon, Hyojung Kim, Jihye Kim, Jihyun Kim, Jeong‐Yong Shin, Hyojin Kim, Gaeun Ryu, In Young Chung, Ji Hun Kim, Doeun Kim, Zhidong Zhang, Hao Wu, Katharina R. Beck, Fredrik Bäckhed, Han‐Joon Kim, Yunjong Lee, Ara Koh
Abstract
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 imidazole propionate (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, mTORC1 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. Here, the authors show that the oral microbe Streptococcus mutans, elevated in the gut microbiome of Parkinson’s patients, produces imidazole propionate via UrdA that in mice reaches the brain and triggers Parkinson’s-like pathology, suggesting a causal gut–brain axis disease link.