Introduction:
To identify gut microbiota (GM) with genetic causal effects on insomnia using Mendelian randomization (MR) and predict potential traditional Chinese medicine (TCM) for GM-targeted intervention in insomnia.

Material and methods:
Summary data from genome-wide association studies (GWAS) on GM and insomnia were obtained from the IEU OpenGWAS database. The R 4.4.1 software, particularly the TwoSampleMR package, was utilized to assess the genetic correlation between GM and insomnia, primarily using the inverse-variance weighted (IVW) method. Functional enrichment analysis was conducted on the genes adjacent to the instrumental variables to explore the signaling pathways through which related gut microbiota may mediate insomnia. The CTD and Coremine databases were combined to predict TCM with potential regulatory effects on the genes adjacent to the instrumental variables, and their properties, meridian tropism, and efficacy information were compiled.

Results:
The MR analysis revealed that Ruminococcaceae and Marvinbryantia were associated with an increased risk of insomnia, while Pasteurellaceae, Olsenella, the Ruminococcus gnavus group, Mollicutes RF9, and Pasteurellales were associated with a decreased risk. The genes adjacent to the instrumental variables were mainly enriched in signaling pathways such as neuroactive ligand-receptor interaction and the mTOR.

Conclusions:
The MR analysis identified seven gut microbiota, represented by Ruminococcaceae and Marvinbryantia, that may mediate the occurrence and development of insomnia through signaling pathways such as mTOR and neuroactive ligand-receptor interaction. It predicted potential TCMs that act on gut microbiota to intervene in insomnia. This study provided a reference for exploring TCM prevention and treatment strategies for insomnia from the perspective of gut microbiota.