Gut microbial production of imidazole propionate drives Parkinson's pathologies

Study information

Needs review

study design

case-control
laboratory experiment

Citation

PMID PubMed identifier for scientific articles.

40913049

DOI Digital object identifier for electronic documents.

https://doi.org/10.1038/s41467-025-63473-4

URI Uniform resource identifier for web resources.

Authors

Park H., Cheon J., Kim H., Kim J., Kim J., Shin J.Y., Kim H., Ryu G., Chung I.Y., Kim J.H., Kim D., Zhang Z., Wu H., Beck K.R., Bäckhed F., Kim H.J., Lee Y., Koh A.

Journal

Nature communications

Year

2025

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.

Experiment 1

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Curated date: 2025/10/09

Curator: Yuvashree 1708

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Subjects

Location of subjects: Republic of Korea

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Parkinson's disease IDIOPATHIC PARKINSON DIS,Idiopathic Parkinson Disease,Idiopathic Parkinson's Disease,IDIOPATHIC PARKINSONS DIS,Idiopathic PD,LEWY BODY PARKINSON DIS,Lewy Body Parkinson Disease,Lewy Body Parkinson's Disease,Paralysis agitans,paralysis agitans,PARKINSON DIS,PARKINSON DIS IDIOPATHIC,Parkinson disease,Parkinson Disease, Idiopathic,Parkinson syndrome,Parkinson's,Parkinson's disease,Parkinson's disease (disorder),Parkinson's disease NOS,Parkinson's disease NOS (disorder),Parkinson's Disease, Idiopathic,Parkinson's Disease, Lewy Body,Parkinson's syndrome,Parkinsonian disorder,Parkinsonism, Primary,Parkinsons,PARKINSONS DIS,PARKINSONS DIS IDIOPATHIC,PARKINSONS DIS LEWY BODY,Parkinsons disease,Primary Parkinsonism,parkinson's disease

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Neurologically healthy elderly controls

Group 1 name Corresponds to the case (exposed) group for case-control studies: Individuals with PD (Parkinson's disease patients)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Individuals with Parkinson’s disease (PD) whose gut microbiome was analyzed to identify differential abundances of microbial species associated with PD pathology

Group 0 sample size Number of subjects in the control (unexposed) group: 234

Group 1 sample size Number of subjects in the case (exposed) group: 491

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): NA

Lab analysis

Sequencing type: WMS

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: log transformation

Statistical test: Mann-Whitney (Wilcoxon)

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: No

Matched on Factors on which subjects have been matched on in a case-control study: age, sex, Matched on: "Shared living environment" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.Shared living environment

Signature 1

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Curated date: 2025/10/09

Curator: Yuvashree 1708

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Source: Figure 1a

Description: Taxons showed increased abundance in Group 1.

Abundance in Group 1: increased abundance in Individuals with PD (Parkinson's disease patients)

NCBI	Quality Control	Links
Bifidobacterium dentium
Streptococcus mutans

Revision editor(s): Yuvashree 1708

Experiment 3

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Curated date: 2025/10/11

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Subjects

Host species Species from which microbiome was sampled. Contact us to have more species added.: Mus musculus

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Parkinsonism Parkinsonian disease,Parkinsonism,parkinsonism

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Non-infected or inactivated S. mutans-treated mice

Group 1 name Corresponds to the case (exposed) group for case-control studies: Live S. mutans-infected mice.

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Group 1 consisted of Germ-free (GF) C57BL/6N mice colonized via oral gavage with Live Streptococcus mutans

Group 0 sample size Number of subjects in the control (unexposed) group: 7

Group 1 sample size Number of subjects in the case (exposed) group: 8

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): Not specified

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V3-V4

Statistical Analysis

Statistical test: ANOVA

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Yes

Matched on Factors on which subjects have been matched on in a case-control study: age, Matched on: "gender" is not in the list (abnormal glucose tolerance, acetaldehyde, acute graft vs. host disease, acute lymphoblastic leukemia, acute myeloid leukemia, adenoma, age, AIDS, alcohol consumption measurement, alcohol drinking, ...) of allowed values.gender

Signature 1

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Curated date: 2025/10/11

Curator: Yuvashree 1708

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Source: Figure 1e (Quantification of live S. mutans in feces)

Description: The signature quantified the viable colony formation (CFU) of S. mutans in fecal samples

Abundance in Group 1: increased abundance in Live S. mutans-infected mice.

NCBI	Quality Control	Links
Streptococcus mutans (Strain ATCC 25175)Streptococcus mutans (Strain ATCC 25175)

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Experiment 4

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Curated date: 2025/10/14

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Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Antibiotic-treated mice + Vehicle (Veh)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Antibiotic-treated mice + Live Streptococcus mutans

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Group 1 consisted of C57BL/6N mice whose native gut microbiota was first severely depleted by a seven-day antibiotic cocktail, followed by daily oral gavage of live Streptococcus mutans.