Oral administration of cranberry-derived exosomes attenuates murine premature ovarian failure in association with changes in the specific gut microbiota and diminution in ovarian granulosa cell PANoptosis

Background: Although a high-fat and high-sugar diet (HFHS) can induce ovarian insufficiency and premature ovarian failure (POF)-making the treatment difficult-plant-derived exosome-like nanovesicles manifest numerous therapeutic effects on various diseases. Purpose: To explore the therapeutic effects and the molecular biology mechanism of exosomes derived from Vaccinium macrocarpon Ait (cranberry) (Va-exos) in the treatment of murine HFHS-POF. Methods: The exosomes from cranberry (Va-exos) were isolated, purified and fed to HFHS-POF model mice. The pathological changes in ovaries, livers, intestines were detected by H&E and Masson staining. The 16s rRNA-seq technique was used to investigate the changes in the gut microbiota and microecology. The mRNA and protein expressions of PANoptosis and their phosphorylation levels in ovarian granulosa cells were detected by qPCR and western blot. Results: Pathological examination showed that Va-exos not only significantly alleviated the symptoms of POF in model mice but also improved the intestinal barrier function and inhibited the production of inflammatory factors. The high-throughput sequencing results of 16s rRNA indicated that the relative abundances of Akkermansia and Allobaculum microorganisms in the intestines of the Va-exos group of mice significantly increased, while the relative abundances of uncultured-bacterium_f-Muribaculaceae, Dubosiella, and uncultured-bacterium_f-Lachnospiraceae microorganisms were significantly reduced. The FCM test results indicated that Va-exos significantly reduced necrosis, apoptosis, and accumulation of reactive oxygen species in ovarian granulosa cells (OGCs) of the HFHS POF mice. Finally, both qPCR and western-blot analyses indicated that Va-exos significantly attenuated the expression levels of key regulatory factors in the PANoptosis of OGCs in HFHS POF mice. Conclusion: We confirmed that oral administration of cranberry-derived exosomes attenuated murine POF by modulating the gut microbiota and decreasing ovarian granulosa cell PANoptosis.