Fisetin regulates gut microbiota to decrease CCR9+/CXCR3+/CD4+ T-lymphocyte count and IL-12 secretion to alleviate premature ovarian failure in mice.

Currently, there are no studies reporting the efficacy of fisetin in premature ovarian failure (POF). In this study, using mouse and Caenorhabditis elegans models, we found that fisetin not only significantly reversed ovarian damage in POF mice, but also effectively increased C. elegans lifespan and fertility. Subsequently, we carried out 16S rRNA v3+v4 sequencing using fresh feces samples from each group of mice. Results showed that although there was no significant difference in the number of gut microbiomes between the different groups of mice, fisetin affected the diversity and distribution of gut microbiota in POF mice. Alpha and beta diversity analyses showed that in the gut of POF mice in the fisetin group, the bacterial count of uncultured_bacterium_f_Lachnospiraceae was significantly increased, while that of Akkermansia was significantly decreased. Finally, flow cytometry analysis showed that the numbers of CCR9+/CXCR3+/CD4+ T lymphocytes in the peripheral blood of POF mice in the fisetin group were significantly reduced, along with the number of CD4+/interleukin (IL)-12+ cells. Therefore, our data suggested that fisetin regulates the distribution and bacterial counts of Akkermansia and uncultured_bacterium_f_Lachnospiracea in POF mice, and reduces peripheral blood CCR9+/CXCR3+/CD4+ T-lymphocyte count and IL-12 secretion to regulate the ovarian microenvironment and reduce inflammation, thus exerting therapeutic effects against POF. AJTR