Gut Microbiome Composition Changes During Insomnia Treatment with Lemborexant

Insomnia is a common disorder worldwide. Growing evidence has revealed that the microbiota-gut-brain axis contributes to the regulation of sleep continuity and duration, both directly and indirectly. Although lemborexant is effective in treating insomnia, its effect on the gut microbiota remains unclear. Here, we investigated the relationship between the gut microbiota and hypnotic use in insomnia. We enrolled 29 adults with insomnia and performed sleep electroencephalography and stool analyses at baseline and after 4 and 12 weeks of open-label lemborexant treatment. Changes in gut microbiota were analyzed using 16S rRNA sequencing and metabolite analysis was performed to assess short-chain fatty acids (SCFAs). Beta diversity (Jaccard dissimilarity) and Firmicutes/Bacteroidetes ratio significantly increased after administration of lemborexant for 12 weeks (p < 0.05). Seven genera were significantly different (p < 0.05). Among these, Tannerellaceae Parabacteroides decreased significantly after 12 weeks of lemborexant treatment (p = 0.013), even after correcting for false discovery rates. Akkermansia was strongly negatively correlated with sleep efficiency (r = -0.754, p = 0.0003). Allisonella showed opposite correlations with latency to persistent sleep and sleep efficiency after 12 weeks of lemborexant treatment (r = 0.523, p = 0.018, r = -0.516, p = 0.020, respectively). There were no significant differences in SCFAs during the treatment period. Our findings suggest that prolonged lemborexant treatment in individuals with insomnia may induce notable shifts in gut microbiota composition, including a significant reduction in Parabacteroides underscoring the potential interaction between hypnotic use and gut microbial balance.