Inadequate and poor-quality sleep is increasingly recognized as a risk factor for coronary artery disease (CAD). Gut microbiota may play a role in sleep regulation. However, the associations between gut microbiota, sleep, and CAD risk, and the causal nature of these associations, remain unclear. We performed a 2-step Mendelian randomization analysis using summary-level data to assess the association between gut microbiota and CAD and the potential mediating roles of sleep-related traits (i.e., chronotype, insomnia, sleep duration, short sleep, and long sleep) herein. The inverse-variance weighted method served as the primary analysis, with several other complementary methods as sensitivity analyses. Our findings revealed that 2 gut microbial taxa were negatively associated with genetically predicted CAD risk, while 4 taxa, including species Veillonella unclassified (odds ratio: 1.054, 95% confidence interval: 1.010-1.101), showed positive associations. Regarding sleep-related traits, we found that insomnia (odds ratio: 1.553, 95% confidence interval: 1.081-2.230) and short sleep duration causally increased CAD risk, whereas longer sleep duration causally reduced CAD risk. The mediation Mendelian randomization analysis demonstrated that insomnia partially mediated the causal, predisposing effect of species Veillonella unclassified on increased CAD risk, with a proportion mediated of 5.7%. This study provides evidence for a causal relationship between specific gut microbial taxa and CAD risk, as well as the mediating role of insomnia in this relationship. These findings offer novel insights into potential strategies for CAD prevention through modulation of the gut microbiome and improvement of sleep quality.
