Molecular mechanisms of YZG-331 ameliorated insomnia based on the gut microbiota-drug interaction.
- 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
- 2Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
- 3Department of Allergy, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment on Allergic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
Abstract
The gut microbiota plays a crucial role in the study of drug efficacy and metabolism. YZG-331 exhibits significant sedative and hypnotic effects. However, the oral bioavailability of YZG-331 in female mice remains low at 27.7%, and it exhibits instability in the gut microbiota, undergoing rapid metabolism, with the intestinal hydrolytic metabolite M2 identified as the characteristic metabolite. Both the underlying mechanisms of YZG-331 therapeutic effects on insomnia and its enzyme-mediated metabolic pathways involving the gut microbiota remain incompletely elucidated. In this study, we found that YZG-331 regulated the tryptophan metabolism and 5-HT production pathways by the gut microbiota. Specifically, YZG-331 increased the abundance of Lactobacillus and Muribaculaceae in the gut, with Lactobacillus reuteri playing a critical role in both the metabolic processes of YZG-331 and the biosynthesis of tryptophan-derived metabolites. YZG-331 enhanced the activation of the tetrahydrobiopterin (BH₄) cofactor system, which subsequently promoted tryptophan hydroxylase (TPH) activity, thereby enhancing 5-HT production. Furthermore, YZG-331 and M2 increased intestinal butyric acid levels, thereby promoting sleep regulation and supporting the restoration of the intestinal barrier. Overall, our study provided the first evidence highlighting the crucial role of the gut microbiota in the therapeutic mechanism and metabolic processing of YZG-331 in the treatment of insomnia.
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BibTeX
@article{zuo2026molecular,
title = {{Molecular mechanisms of YZG-331 ameliorated insomnia based on the gut microbiota-drug interaction.}},
author = {Hengtong Zuo and Qinglan Guo and Bin Zhao and Jinyue Lu and Ru Feng and Jingyue Wang and Jianye Song and Jingyu Jin and Jiachun Hu and Yi Zhao and Hui Xu and Tiefeng Yuan and Wanxia Wang and Yongmei Tu and Lingyu Wei and Yifan Zhao and Xiang Hui and Zhihao Liu and Li Sheng and Yan Li and Jianjun Zhang and Jinlyu Sun and Jiangong Shi and Yan Wang},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = jul,
doi = {10.1016/j.apsb.2026.07.023},
url = {https://europepmc.org/article/MED/42948711},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Molecular mechanisms of YZG-331 ameliorated insomnia based on the gut microbiota-drug interaction.
AU - Hengtong Zuo
AU - Qinglan Guo
AU - Bin Zhao
AU - Jinyue Lu
AU - Ru Feng
AU - Jingyue Wang
AU - Jianye Song
AU - Jingyu Jin
AU - Jiachun Hu
AU - Yi Zhao
AU - Hui Xu
AU - Tiefeng Yuan
AU - Wanxia Wang
AU - Yongmei Tu
AU - Lingyu Wei
AU - Yifan Zhao
AU - Xiang Hui
AU - Zhihao Liu
AU - Li Sheng
AU - Yan Li
AU - Jianjun Zhang
AU - Jinlyu Sun
AU - Jiangong Shi
AU - Yan Wang
PY - 2026
DA - 2026/07/17
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.07.023
UR - https://europepmc.org/article/MED/42948711
AB - The gut microbiota plays a crucial role in the study of drug efficacy and metabolism. YZG-331 exhibits significant sedative and hypnotic effects. However, the oral bioavailability of YZG-331 in female mice remains low at 27.7%, and it exhibits instability in the gut microbiota, undergoing rapid metabolism, with the intestinal hydrolytic metabolite M2 identified as the characteristic metabolite. Both the underlying mechanisms of YZG-331 therapeutic effects on insomnia and its enzyme-mediated metabolic pathways involving the gut microbiota remain incompletely elucidated. In this study, we found that YZG-331 regulated the tryptophan metabolism and 5-HT production pathways by the gut microbiota. Specifically, YZG-331 increased the abundance of Lactobacillus and Muribaculaceae in the gut, with Lactobacillus reuteri playing a critical role in both the metabolic processes of YZG-331 and the biosynthesis of tryptophan-derived metabolites. YZG-331 enhanced the activation of the tetrahydrobiopterin (BH₄) cofactor system, which subsequently promoted tryptophan hydroxylase (TPH) activity, thereby enhancing 5-HT production. Furthermore, YZG-331 and M2 increased intestinal butyric acid levels, thereby promoting sleep regulation and supporting the restoration of the intestinal barrier. Overall, our study provided the first evidence highlighting the crucial role of the gut microbiota in the therapeutic mechanism and metabolic processing of YZG-331 in the treatment of insomnia.
SN - 2211-3835
SN - 2211-3843
ER -