Gut microbiota-derived Tryptophanol driven by N-Carbamylglutamate alleviates premature ovarian failure through inhibiting oxidative stress.

BACKGROUND

Premature ovarian failure (POF) affects 1-5% of women under 40 years old and is characterized by granulosa cells (GCs) apoptosis and follicular atresia. However, the pathogenesis of POF is complex and lacks effective prevention and treatment strategies. N-carbamylglutamate (NCG), a bioactive substance known for its antioxidant properties; however, whether it can alleviate POF remains unclear.

METHODS

This study using the cyclophosphamide (Cy)-induced POF mouse model, and demonstrated that NCG, has beneficial effects in alleviating POF symptoms and restoring the intestinal mucosal barrier through gut microbiota-metabolite crosstalk. Integrated 16 S rRNA sequencing, untargeted metabolomics, and fecal bacteria transplantation (FMT) experiments revealed that NCG induced restructuring of gut microbial communities, with enrichment of Muribaculum intestinale and concomitant elevation of its associated Tryptophan-derived metabolite, Tryptophanol.

RESULTS

Mechanistically, Tryptophanol, supplementation alleviated POF by reducing mouse GCs apoptosis and oxidative stress via inhibiting Phosphatidylinositol 3-kinase/ Protein Kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways, thereby restoring ovarian function and fertility, and the efficacy of NCG in alleviating POF relies on promoting Tryptophanol-mediated anti-oxidative stress.

CONCLUSIONS

Our findings, highlight the "gut microbiota-Tryptophanol-ovary" axis in POF pathogenesis, and propose a potential therapy for NCG to regulate gut microbiota to restore ovarian redox homeostasis to alleviate POF.