Gut Microbiota, Immune Phenotypes, and Insomnia: A Two-Sample Mendelian Randomization Study

The microbiota-gut-brain axis offers a novel framework for understanding insomnia; however, the hypothesis that specific immune pathways mediate the causal effects of gut microbial taxa on insomnia requires supporting genetic evidence. This study aimed to explore the genetic evidence supporting the causal interplay between the gut microbiota, immune phenotypes, and insomnia using large-scale genetic data.

We employed two-sample bidirectional Mendelian Randomization (MR) using large-scale genome-wide association study (GWAS) summary statistics for gut microbiota, 731 immune cell phenotypes, and insomnia (FinnGen R12). Mediation analysis was conducted to quantify the specific indirect effects of immune cells.

We found suggestive genetic evidence linking 13 gut microbial taxa to insomnia risk. Notably, a directional divergence was observed within the Blautia genus at the species level, where Blautia A sp900066355 showed a robust protective association (surviving FDR correction), whereas other species within the genus increased risk at a nominal significance level (uncorrected P < 0.05). Furthermore, 17 immune phenotypes were found to be associated with insomnia. Exploratory mediation analysis suggested that monocytic myeloid-derived suppressor cells (M-MDSCs) may mediate the pathway linking the uncultured bacterium CAG-177 to insomnia, accounting for 10.7% of the total effect.

This study provides preliminary genetic evidence linking specific gut microbial taxa and immune phenotypes to insomnia risk, with Blautia A sp900066355 demonstrating robust protective effects. As a secondary hypothesis-generating observation, we propose a preliminary hypothesis that the depletion of protective M-MDSCs, rather than solely pro-inflammatory activation, may contribute to insomnia pathogenesis. Given the borderline statistical significance of this mediation finding, drawing direct therapeutic implications is currently premature.