Emerging evidence implicates the gut microbiome in Parkinson’s disease (PD) pathogenesis and progression. To identify changes in the gut microbiota associated with disease progression in the 3KL model of PD, we utilized individual antibiotics to deplete specific bacterial populations. Metronidazole slowed progression of motor dysfunction, which we link to depletion of Alistipes. Alistipes species have been widely associated with PD, yet the mechanisms underlying their detrimental effects remain unclear.
To investigate the role of Alistipes in PD, Alistipes muris was cultured and administered to 3KL mice from 6–9 months of age. A. muris worsened motor and cognitive function in male 3KL mice. These effects were accompanied by increased IL-17–producing T cells assessed by flow cytometry and increased circulating IL-17 levels assessed by MSD ELISA and NULISA. In the brain, A. muris increased IL-17 levels and microglial bulk transcriptomics revealed an increase in IL-17 signaling pathways. Metabolomic profiling identified Alistipes-derived metabolites that were detected in recipient mouse tissues, supporting a gut-brain mechanistic link. Importantly, peripheral antibody blockade of IL-17A/F mitigated the detrimental behavioral and neuroimmune effects induced by A. muris, reducing inflammatory signaling and partially restoring protective microglial function.
These findings identify Alistipes as a detrimental microbiome component that exacerbates parkinsonian phenotypes through IL-17-mediated neuroimmune mechanisms. IL-17 blockade mitigated these effects, highlighting a microbiome-immune-brain axis driving progression.