Gut Microbiome Composition Changes During Insomnia Treatment with Lemborexant

Abstract

Seiko Miyata,1,&ast; Kunihiro Iwamoto,1,&ast; Mikako Ito,2 Ippei Okada,3 Nao Matsuyama,1,3 Akihiro Fujimoto,4 Yuki Kogo,4 Hiroshi Nishiwaki,2,5 Jun Ueyama,6 Kinji Ohno,2,7 Norio Ozaki1,8 1Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 2Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 3PharmaLex Japan, Inc., Shibuya, Tokyo, Japan; 4Medical Headquarters, Eisai Co., Ltd., Bunkyo, Tokyo, Japan; 5Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; 6Department of Biomolecular Sciences, Field of Omics Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 7Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin, Aichi, Japan; 8Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan&ast;These authors contributed equally to this workCorrespondence: Seiko Miyata, Department of Psychiatry, Nagoya University Graduate School of Medicine 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan, Email [email protected]: 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.Participants and Methods: 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).Results: 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.Conclusion: 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. Keywords: insomnia intervention, gut microbiota, lemborexant, short-chain fatty acids, elderly, home sleep monitoring

Keywords

• insomnia intervention
• gut microbiota
• lemborexant
• short-chain fatty acids
• elderly
• home sleep monitoring