show Abstracthide AbstractParkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. The disorder of gut microbiota is involved in the pathophysiological process of various neurological diseases, and many studies have confirmed that gut microbiota is involved in the progression of PD. As one of the most effective methods to reconstruct gut microbiota, fecal microbiota transplantation (FMT) has been considered as an important treatment for PD. However, the mechanism of FMT treatment for PD is still lacking, which requires further exploration and can facilitate the application of FMT. As a model organism, Drosophila is highly conserved with mammalian system in maintaining intestinal homeostasis. In this study, there were significant differences in the gut microbiota of conventional Drosophila colonized from PD patients compared to those transplanted from normal controls. And we constructed rotenone-induced PD model in Drosophila followed by FMT in different groups, and investigated the impact of gut microbiome on transcriptome of the PD host. Microbial analysis by 16S rDNA sequencing showed that gut microbiota could affect bacterial structure of PD, which was confirmed by bacterial colonization results. In addition, transcriptome data suggested that gut microbiota can influence gene expression pattern of PD. Further experimental validations confirmed that lysosome and neuroactive ligand-receptor interaction are the most significantly influenced functional pathways by PD-derived gut microbiota. In summary, our data reveals the influence of PD-derived gut microbiota on host transcriptome and helps better understanding the interaction between gut microbiota and PD through gut-brain axis. The present study will facilitate the understanding of the mechanism underlying PD treatment with FMT in clinical practice. Overall design: To dissect the relationship between gut microbiota and PD, we first constructed PD model by inducing Drosophila melanogaster with rotenone for 7 days. PD models were validated through phenotypic observation and molecular testing, we then performed cross-colonization experiments (Figure 1A). The PD flies and control flies were subjected with/o FMT for another 7 days. After cross-colonization experiments, we obtained six different groups of flies including control Drosophila (CTRL), Parkinson's Drosophila (PD), control Drosophila with FMT from Parkinson's Drosophila (CWFP), control Drosophila without FMT from Parkinson's Drosophila (CWOFP), Parkinson's Drosophila with FMT from control Drosophila (PWFC) and Parkinson's Drosophila without FMT from control Drosophila (PWOFC).