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 () and Ara Koh ()
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Hyunji Park: Pohang University of Science and Technology
Jiwon Cheon: Sungkyunkwan University School of Medicine
Hyojung Kim: Sungkyunkwan University School of Medicine
Jihye Kim: Pohang University of Science and Technology
Jihyun Kim: Pohang University of Science and Technology
Jeong-Yong Shin: Sungkyunkwan University School of Medicine
Hyojin Kim: Pohang University of Science and Technology
Gaeun Ryu: Pohang University of Science and Technology
In Young Chung: Pohang University of Science and Technology
Ji Hun Kim: Sungkyunkwan University School of Medicine
Doeun Kim: Sungkyunkwan University School of Medicine
Zhidong Zhang: Inner Mongolia University
Hao Wu: Fudan University
Katharina R. Beck: University of Gothenburg and Sahlgrenska University Hospital
Fredrik Bäckhed: University of Gothenburg and Sahlgrenska University Hospital
Han-Joon Kim: Seoul National University College of Medicine
Yunjong Lee: Sungkyunkwan University School of Medicine
Ara Koh: Pohang University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63473-4

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