Molecular mechanisms of YZG-331 ameliorated insomnia based on the gut microbiota-drug interaction

29/10/2026

AI Summary

YZG-331 modulates gut microbiota, increasing Lactobacillus and Muribaculaceae; Lactobacillus reuteri crucial for YZG-331 metabolism and tryptophan-derived metabolite biosynthesis.
YZG-331 activates the tetrahydrobiopterin cofactor system, enhancing tryptophan hydroxylase activity and increasing central and peripheral 5-HT production.
Oral bioavailability is low (27.7%) with rapid gut microbial metabolism to M2; YZG-331 and M2 raise intestinal butyric acid, improving sleep regulation and barrier.

TL;DR (AI Generated)

Both the underlying mechanisms of YZG-331 therapeutic effects on insomnia and its enzyme-mediated metabolic pathways involving the gut microbiota remain incompletely elucidated.

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.

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.

Basic summary

Acta Pharm Sin B. 2026 Oct;16(10):6705-6730. doi: 10.1016/j.apsb.2026.07.023. Epub 2026 Jul 17.

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.

PMID:42948711 | PMC:PMC13712296 | DOI:10.1016/j.apsb.2026.07.023

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