Gut microbiota-associated immunomodulation contributes to the protective effects of fluvastatin against endometriosis in a mouse model, accompanied by increased Akkermansia muciniphila abundance

Background Endometriosis (EMs) is a chronic inflammatory disease characterized by tumor-like growth behavior and limited therapeutic options. Increasing evidence suggests that gut microbiota may contribute to EMs progression by promoting chronic inflammation and immune dysregulation. Fluvastatin, a lipid-lowering agent, exhibits anti-inflammatory, anti-tumor, and immunomodulatory effects and has also been reported to influence microbial homeostasis. However, the relationship among fluvastatin treatment, gut microbiota, and EMs progression remains unclear. This study aimed to investigate this relationship. Materials and methods A mouse model of EMs was established by autologous uterine tissue transplantation, followed by oral fluvastatin administration for 3 weeks. Lesion growth, inflammatory responses, and immune characteristics were evaluated by histology, quantitative PCR, flow cytometry, immunofluorescence, and immunohistochemistry. Gut microbiota involvement was assessed using antibiotic-mediated microbiota depletion and fecal microbiota transplantation (FMT). Microbial composition was analyzed by metagenomic sequencing. The role of Akkermansia muciniphila was evaluated by direct oral supplementation. Results Fluvastatin significantly reduced the volume and mass of ectopic lesions and decreased the mRNA expression of pro-inflammatory cytokines. It was also associated with changes in macrophage polarization-related markers and reduced abnormal activation of splenic immune cells. Antibiotic-induced gut microbiota depletion attenuated the protective effects associated with fluvastatin treatment, whereas FMT from fluvastatin-treated mice partially transferred similar protective changes. Metagenomic analysis revealed that fluvastatin reshaped gut microbiota composition and increased the abundance of Akkermansia muciniphila . Moreover, oral supplementation with Akkermansia muciniphila attenuated EMs progression and was associated with anti-inflammatory and immune-related changes similar to those observed after fluvastatin treatment. Conclusion These findings suggest that the protective effects associated with fluvastatin treatment are accompanied by changes in gut microbiota composition, including increased abundance of Akkermansia muciniphila . Gut microbiota may contribute to the beneficial effects of fluvastatin in EMs. These results support the potential value of microbiota-informed therapeutic strategies for EMs.