Akkermansia muciniphila protects against endometritis through a tyrosol-mediated gut-uterus axis.

Endometritis is a common reproductive disorder in humans and domestic animals that causes infertility and livestock losses. However, few specific bacteria and related metabolites involved in its pathogenesis have been identified. Here, we find that endometritis cows (EC) exhibit gut dysbiosis, with depletion of Akkermansia muciniphila (AKK). Gut microbiota transplantation from EC (E-GMT) induces endometritis in mice, whereas gut microbiota transplantation from healthy cows (H-GMT) does not. Supplementation with live AKK or its culture supernatant, but not heat-inactivated AKK, alleviates Escherichia coli-induced endometritis and protects E-GMT mice. Metabolomic profiling shows that live AKK increases tyrosol levels. Genomic and functional analyses support a role for AKK-derived alcohol dehydrogenase (ADH)1/ADH2 in tyrosol production. Engineered bacteria overexpressing this enzyme reproduce the anti-endometritis effects, whereas enzyme inhibition abolishes AKK-mediated protection. Mechanistically, tyrosol exerts protective effects by activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway via upregulation of SIRT1 expression, highlighting the gut-uterine axis as a target for endometritis and uterine diseases.