Metabolic Characteristics of Gut Microbiota and Insomnia: Evidence from a Mendelian Randomization Analysis

Insomnia is a common sleep disorder that significantly impacts individuals' sleep quality and daily life. Recent studies have suggested that gut microbiota may influence sleep through various metabolic pathways. This study aims to explore the causal relationships between the abundance of gut microbiota metabolic pathways and insomnia using Mendelian randomization (MR) analysis. This two-sample MR study used genetic data from the OpenGWAS database (205 gut bacterial pathway abundance) and the FinnGen database (insomnia-related data). We identified single nucleotide polymorphisms (SNPs) associated with gut bacterial pathway abundance as instrumental variables (IVs) and ensured their validity through stringent selection criteria and quality control measures. The primary analysis employed the inverse variance-weighted (IVW) method, supplemented by other MR methods, to estimate causal effects. The MR analysis revealed significant positive causal effects of specific carbohydrate, amino acid, and nucleotide metabolism pathways on insomnia. Key pathways, such as gluconeogenesis pathway (GLUCONEO.PWY) and TCA cycle VII acetate producers (PWY.7254), showed positive associations with insomnia (B > 0, p < 0.05). Conversely, pathways like hexitol fermentation to lactate, formate, ethanol and acetate pathway (P461.PWY) exhibited negative causal effects (B < 0, p < 0.05). Multivariable MR analysis confirmed the independent causal effects of these pathways (p < 0.05). Sensitivity analyses indicated no significant pleiotropy or heterogeneity, ensuring the robustness of the results. This study identifies specific gut microbiota metabolic pathways that play critical roles in the development of insomnia. These findings provide new insights into the biological mechanisms underlying insomnia and suggest potential targets for therapeutic interventions. Future research should further validate these causal relationships and explore how modulating gut microbiota or its metabolic products can effectively improve insomnia symptoms, leading to more personalized and precise treatment strategies.