Faecalibacterium prausnitzii, depleted in the Parkinson's disease microbiome, improves motor deficits in α-synuclein overexpressing mice
Anastasiya MoiseyenkoiD, Giacomo AntonelloiD, Aubrey M SchonhoffiD, Joseph C. BoktoriD, Kaelyn LongiD, Blake DirksiD, Anastasiya D. OguienkoiD, Alexander Viloria WinnettiD, Patrick Simpson, Dorsa Daeizadeh, Rustem F. IsmagiloviD, Rosa Krajmalnik‐BrowniD, N Segata, Levi WaldroniD, Sarkis K. MazmanianiD
Abstract
Gut microbiome composition is altered in Parkinsons disease (PD), a neurodegenerative disorder characterized by motor dysfunction and frequently accompanied by gastrointestinal (GI) symptoms. Notably, microbial taxa with anti-inflammatory properties are consistently depleted in PD patients compared to controls. To explore whether specific gut bacteria may be disease-protective, we assembled a microbial consortium of 8 human-associated taxa that are reduced in individuals with PD across multiple cohorts and geographies. Treatment of -synuclein overexpressing (Thy1-ASO) mice, an animal model of PD, with this consortium improved motor and GI deficits. A single bacterial species from this consortium, Faecalibacterium prausnitzii, was sufficient to correct gut microbiome deviations in Thy1-ASO mice, induce anti-inflammatory immune responses, and promote protective colonic gene expression profiles. Accordingly, oral treatment with F. prausnitzii robustly ameliorated motor and GI symptoms and reduced -synuclein aggregates in the brain. These findings support the emerging hypothesis of functional contributions by the microbiome to PD and embolden development of potential probiotic therapies.
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Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 1 (21 Sept 2025) · CC BY 4.0
Oral Faecalibacterium prausnitzii, the taxon most consistently depleted in PD stool, improved motor and GI deficits and lowered α-synuclein aggregates in male Thy1-ASO mice.
No disease-modifying PD drugs exist, and some probiotic treatments use Lactobacilli and Bifidobacteria, which are among the most enriched taxa in patients. This work instead replenishes depleted commensals, first an 8-taxon consortium and then F. prausnitzii, which BugSigDB lists as decreased in 16 PD studies and never increased.
Key results
ShownF. prausnitzii monoculture improved motor and GI function in Thy1-ASO mice, with more outcomes affected than the consortium (adding beam traversal).
Significant improvements vs vehicle Thy1-ASO in adhesive removal, hindlimb clasping, beam crossing time and errors per step, bead expulsion time and Bristol score; N = 23-29 pooled from two cohorts; Kruskal-Wallis with Conover-Iman, BH FDR (exact p-values not in text). · F. prausnitzii has robust therapeutic effects on…; Motor and gastrointestinal function testing; Figure legends
SuggestedThe 8-taxon benCom-PD consortium gave modest benefits on select motor and GI tests and lowered striatal pS129-αSyn, but not in the substantia nigra.
Improved adhesive removal latency, hindlimb clasping, bead expulsion and Bristol score vs vehicle (N = 11-15); no effect on beam, pole descent or wire hang; pS129-αSyn reduced in striatum by Western blot (N = 3-6). · A human gut microbial consortium ameliorates…; Figure legends
ShownF. prausnitzii reduced aggregated αSyn in the substantia nigra but not the striatum, and pS129-αSyn was unchanged in brain tissue.
Dot blot for aggregated αSyn in substantia nigra lower than vehicle Thy1-ASO (N = 11-15, two cohorts; one-way ANOVA with Tukey); no difference in striatum or in pS129-αSyn. · F. prausnitzii has robust therapeutic effects on…; Figure legends
SuggestedF. prausnitzii partly shifted the fecal microbiome toward WT, and mediation analysis suggested its effects on beam errors per step and bead expulsion were direct rather than microbiome-mediated.
Pairwise PERMANOVA FDR 0.011 (WT vs control Thy1-ASO), 0.020 (treated vs control Thy1-ASO), 0.250 (WT vs treated); richness, Shannon and Firmicutes/Bacteroidetes ratio unchanged; mediation ACME near zero for beam errors/step and bead expulsion. · F. prausnitzii treatment aligns the Thy1-ASO…; Fecal microbiome analysis with shotgun…; Figure legends
SuggestedTreatment raised intestinal anti-inflammatory readouts and moved colonic gene expression toward the WT profile without changing short-chain fatty acids.
Colon RNA-seq group difference p = 2.00E-04; log fold-change correlation (WT vs control against treated vs control) ρ = 0.37, p < 2.2E−16; MLN TREG increased (N = 3-5); colon IL-10 increased (N = 14-17); fecal, cecal and serum SCFAs unchanged. · F. prausnitzii alters the immune landscape in…; F. prausnitzii supplementation remodels the gene…; Figure legends
Methods, data and reproducibility
Male Thy1-ASO mice received twice-weekly intragastric benCom-PD or F. prausnitzii for about 15 weeks, followed by behavioral testing at 20 weeks, blot assays, flow cytometry, colonic bulk RNA-seq, fecal shotgun metagenomics and mediation analysis.
- benCom-PD cohort: WT, vehicle Thy1-ASO and benCom-PD-treated Thy1-ASO male mice, behavior at 20 weeks · mouse · n = N = 11-15 (behavior); N = 3-6 (Western blot)
- F. prausnitzii cohorts: WT, vehicle and treated Thy1-ASO male mice from two independent cohorts, behavior and brain aggregates · mouse · n = N = 23-29 (behavior); N = 11-15 (dot blot) · 10.5281/zenodo.17137678
- Fecal shotgun metagenomes collected at 18 weeks of age · mouse · PRJNA1259538
- Bulk RNA-seq of proximal large intestine · mouse · PRJNA1308739
- Flow cytometry of mesenteric lymph node TREG cells · mouse · n = N = 3-5 · 10.5281/zenodo.16929959
- Colon IL-10 multiplex bead assay, two cohorts · mouse · n = N = 14-17
- BugSigDB-curated PD patient microbiome studies used to select F. prausnitzii · human · n = 16 independent studies reporting decrease
- Methods & tools
- STAR v2.7.1, featureCounts, DESeq2, clusterProfiler, MetaPhlAn v4.1.1, HUMAnN v3.9, KneadData, mia (R package), MaAsLin3, mediation (R package), pairwiseAdonis, curatedMetagenomicsNextflow
- Code
- https://doi.org/10.5281/zenodo.17128213https://github.com/jboktor/fprausnitzii-treatment-rnaseqhttps://github.com/seandavi/curatedMetagenomicsNextflowhttps://github.com/ASAP-MAC/parkinsonsMetagenomicData
- Software & environment
- R 4.5.1 for microbiome analyses (sessionInfo in scripts); R v4.3.0 for DESeq2; MetaPhlAn v4.1.1; HUMAnN v3.9; STAR v2.7.1; curatedMetagenomicsNextflow commit 4cde6fb.
- Reproducibility gaps
- Behavior-analysis GitHub repository is referenced only via the Key Resources Table (Supplementary Table 2), not given as a URL in the main text; no compute resources reported.
Limitations (5)
- Only one preclinical model (Thy1-ASO) was tested; it lacks overt dopaminergic neuron loss at the ages studied, and only male mice were used because the X-linked transgene is expressed inconsistently in females. · stated by the authors
- Treatment was prophylactic, given before symptom onset, so translation would require identifying at-risk or prodromal PD populations, which is not yet reliably achievable. · stated by the authors
- Mechanisms remain untested: SCFAs did not change, and peripheral immune modulation, vagal signaling, secreted metabolites and microbiome restoration are not distinguished. · stated by the authors
- F. prausnitzii was not detected in the mouse metagenomes, so engraftment or persistence of the dosed strain was not verified. · noted in this summary
- Some mechanistic readouts rest on small groups (flow cytometry N = 3-5, Western blot N = 3-6), and the consortium members other than F. prausnitzii were not tested individually. · noted in this summary
Who should read:Read this if you study gut-brain mechanisms in PD and want mouse evidence for replenishing depleted commensals, with microbiome, immune and colonic transcript data.
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