Microbiome signature of Parkinson disease in healthy and genetically at-risk individuals

Parkinson disease (PD) is a major cause of disability with significant personal and system financial implications[1](https://www.medrxiv.org/content/10.1101/2025.05.19.25327907v1#ref-1),[2](https://www.medrxiv.org/content/10.1101/2025.05.19.25327907v1#ref-2). *GBA1* variants are the commonest genetic risk factor for PD and increase the risk up to 30-fold[3](https://www.medrxiv.org/content/10.1101/2025.05.19.25327907v1#ref-3),[4](https://www.medrxiv.org/content/10.1101/2025.05.19.25327907v1#ref-4). Why only ∼20% of *GBA1* variant carriers develop PD remains unknown. Here, by combining clinical and faecal metagenomics data from PD individuals carrying or not *GBA1* variants, carriers of *GBA1* variants not manifesting PD symptoms (GBA-NMC) and healthy controls, and using an innovative microbiome analysis, we show that a large component of the gut microbiome evolves from healthy across GBA-NMC towards PD and is strongly correlated with disease progression in patients, and prodromal symptoms suggestive of future development of PD in GBA-NMC. By using species altered in PD and GBA-NMC, we detect healthy individuals with the strongest prodromal PD clinical profile. These findings indicate that gut microbiome alterations can identify individuals with *GBA1* variants most prone to develop PD and individuals in the general population that may be progressing towards PD. Healthy nutrition mitigates microbiome alterations associated with disease severity, suggesting that it could modify disease progression in PD patients and decrease the risk of disease development in healthy individuals including those with *GBA1* variants.