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The host microbiome plays an important role in regulating physiology through microbiota-derived metabolites during host-microbiome interactions. However, molecular mechanism underly host-microbiome interactions remains to be explored. In this study, we used <i>Drosophila</i> as the model to investigate the influence of microbiome and microbiota-derived metabolite sodium butyrate on host transcriptome and metabolome. We established both a sterile <i>Drosophila</i> model and a conventional <i>Drosophila</i> model to demonstrate the role of sodium butyrate. Using multi-omics analysis, we found that microbiome and sodium butyrate could impact host gene expression patterns in both the sterile <i>Drosophila</i> model and the conventional <i>Drosophila</i> model. The analysis of gut microbial using 16S rRNA sequencing showed sodium butyrate treatment also influenced <i>Drosophila</i> bacterial structures. In addition, <i>Drosophila</i> metabolites identified by ultra-high performance liquid chromatography-MS/MS were shown to be affected by sodium butyrate treatment with lipids as the dominant changed components. Our integrative analysis of the transcriptome, the microbiome, and the metabolome data identified candidate transcripts that are coregulated by sodium butyrate. Taken together, our results reveal the impact of the microbiome and microbiota-derived sodium butyrate on host transcriptome and metabolome, and our work provides a better understanding of host-microbiome interactions at the molecular level with multi-omics data.