Gut Microbiota‐Derived Acetate Ameliorates Endometriosis via JAK1/STAT3‐Mediated M1 Macrophage Polarisation

ABSTRACT Endometriosis (EMs) is a common inflammatory disorder in women of reproductive age, severely impacting patients' quality of life and fertility. Current hormonal therapies offer limited efficacy, and surgical interventions often fail to prevent recurrence. Recent studies suggest a close association between gut microbiota and the pathophysiology of EMs, though the precise mechanisms remain unclear. To investigate the influence of gut microbiota on EMs, this study established an EMs mouse model and performed faecal microbiota transplantation (FMT) using samples from healthy donors (AH group) and EMs patients (AE group) into the model mice. Results demonstrated that compared to the model group (M group), FMT from healthy donors (AH group) significantly reduced ectopic lesion volume (658.3 ± 116.1 vs. 167.2 ± 112.8 mm 3 , p < 0.01) and weight (0.7420 ± 0.1233 vs. 0.1885 ± 0.1239 mg, p < 0.01). Conversely, FMT from EMs patients exacerbated disease progression. Mechanistic studies revealed that healthy donor FMT attenuated EMs by remodelling the gut microbial composition (enhancing α‐diversity and Lactobacillus abundance while suppressing Bacteroidetes), significantly elevating acetate levels in faeces and ectopic lesions, activating the JAK1/STAT3 signalling pathway within lesions, and thereby driving macrophage polarisation toward the M1 phenotype (by increased iNOS/CD86 expression and decreased Arg1/CD206 expression). Simultaneously, healthy donor FMT enhanced intestinal barrier integrity by upregulating tight junction proteins (ZO‐1, Occludin, Claudin‐1/5) and reducing levels of intestinal permeability markers (DAO, IFABP). In contrast, AE group FMT disrupted gut microbial ecology, reduced acetate production, failed to activate the JAK1/STAT3 pathway, promoted M2 macrophage polarisation and impaired intestinal barrier function. Collectively, this study elucidates for the first time that acetate, as a key gut microbiota metabolite, exerts anti‐EMs effects by activating the JAK1/STAT3 signalling pathway to drive macrophage reprogramming toward the M1 phenotype, thereby positioning gut microbiota reconstruction as a novel therapeutic strategy for endometriosis.