Integrated multi-omics highlights alterations of gut microbiome functions in prodromal and idiopathic Parkinson’s disease

•Background: Parkinson’s disease (PD) is associated with gut microbiome shifts. These shifts are mainly described at taxonomic level, but the functional consequences remain unclear. To obtain insight into the functional disruptions of the gut microbiome in PD, we used an integrated multi-omics approach, comparing gut microbiomes of individuals with PD, prodromal PD, and healthy controls. •Results: Meta-metabolomics, the most discriminatory and robust omics level, was selected to Guide the analysis. We identified 11 metabolites that were differentially abundant between the groups, among which β-glutamate was increased in PD and prodromal PD, and correlated with the transcriptional activities of Methanobrevibacter smithii and Clostridium spp. We identified decreases in transcripts, but not in gene abundances, related to glutamate metabolism, bile acids biosynthesis, chemotaxis, and flagellar assembly in PD, particularly in keystone genera such as Roseburia , Agathobacter , and Blautia . Our findings, integrated into the Expobiome map, reveal multifactorial microbiome alterations which converge with PD pathways. •Conclusion: Our study highlights the apparent disruption of microbial gene expression in PD, particularly in genes associated to mobility. Moreover, we showcase the importance of investigating the gut microbiome’s functional dimensions to better resolve microbiome-host interactions in health and disease.