Unveiling the Gut-Brain Axis: Fusobacteriaceae Promotes Parkinson's Disease Development via CA9 Suppression-Induced Ferroptosis.

The conceptual framework of the ‘gut-brain axis’ proposes that an imbalance in the gut microbiota plays a contributory role in the etiology of Parkinson’s disease (PD). However, the specific molecular mechanisms, particularly those involving ferroptosis, remain largely unknown. We adopted a robust two-sample Mendelian randomization (MR) strategy, analyzing extensive summary-level GWAS data to unravel the causal connections tying the gut microbiota and ferroptosis-associated proteins to the risk of PD. Our analysis pinpointed 22 distinct gut microbial taxa and five proteins involved in ferroptosis that are genetically predicted to influence PD susceptibility. Notably, the family Fusobacteriaceae was identified as a robust risk factor. Further mediation analysis suggested that the ferroptosis-related protein carbonic anhydrase 9 (CA9) mediates the genetically predicted effect of Fusobacteriaceae on PD. Specifically, an elevated genetic predisposition to Fusobacteriaceae is associated with a downregulation of plasma CA9, a molecular shift that is genetically predicted to heighten the risk of developing PD. The calculated mediation proportion was 11.7%, and the robustness of this result was upheld by comprehensive sensitivity assessments. This study provides novel genetic evidence supporting a potential “gut microbiota–ferroptosis–PD” axis. We propose that Fusobacteriaceae may aggravate PD progression by downregulating CA9, thereby compromising CA9-dependent anti-ferroptotic defense mechanisms. Collectively, our results provide fresh perspectives on the molecular mechanisms underpinning the gut-brain axis, highlighting promising avenues for therapeutic intervention in PD.