Objectives:  Emerging evidence implicates the gut microbiome in the pathogenesis and progression of Parkinson’s disease and related synucleinopathies. Notably, butyrate-producing bacteria are consistently reduced in these disorders. This study aimed to investigate the role of two key butyrate-producing commensals, Faecalibacterium prausnitzii and Blautia faecis, in synucleinopathy.

Methods: To assess the impact of these commensal microbes on disease phenotypes, Faecalibacterium prausnitzii and Blautia faecis were cultured and administered to 3KL synucleinopathy mice from 6 to 9 months of age. Motor and cognitive performance were evaluated longitudinally, and peripheral immune responses were assessed using flow cytometry. Microglial responses were characterized by bulk RNA sequencing. In addition, metabolomic profiling was performed on bacterial supernatants and mouse cecum, serum, and brain samples.

Results: Oral administration of F. prausnitzii and B. faecis improved motor and cognitive function in male 3KL mice. These effects occurred in the absence of a strong peripheral immune response, with only modest alterations observed in T cell populations and cytokine profiles. Microglial pathway analysis demonstrated that F. prausnitzii upregulated pathways related to epigenetic regulation and cognitive function while suppressing inflammatory signaling. Similarly, B. faecis enhanced autophagy and protein clearance pathways and reduced inflammatory signaling. Metabolomic analysis of bacterial supernatants revealed that F. prausnitzii produced several key metabolites, including betaine, which was detected in recipient mouse brains and has been associated with neuroprotective effects in Parkinson’s disease. In contrast, B. faecis increased brain levels of metabolites involved in unsaturated fatty acid biosynthesis, a pathway linked to reduced Parkinson’s disease risk.

Conclusion: These findings demonstrate that F. prausnitzii and B. faecis improve motor and cognitive function in a model of synucleinopathy through microglial and metabolic reprogramming. Distinct microbial metabolites, including betaine and unsaturated fatty acid–related compounds, were detected in recipient mouse brains, supporting a gut–brain mechanistic link. Together, these results highlight beneficial commensal microbes as modulators of neuroinflammation and metabolism and suggest that targeting the gut microbiome may represent a promising therapeutic strategy for synucleinopathies.