Methionine regulates maternal-fetal immune tolerance and endometrial receptivity by enhancing embryonic IL-5 secretion

Endometrial receptivity and maternal-fetal immune tolerance are two crucial processes for a successful pregnancy. However, the molecular mechanisms of nutrition involved are largely unexplored. Here, we showed that maternal methionine supply significantly improved pregnancy outcomes, which was closely related to interleukin-5 (IL-5) concentration. Mechanistically, methionine induced embryonic IL-5 secretion, which enhanced the conversion of CD4⁺ T cells to IL-5⁺ Th2 cells in the uterus, thereby improving maternal-fetal immune tolerance. Meanwhile, methionine-mediated IL-5 secretion activated the nuclear factor κB (NF-κB) pathway and enhanced integrin αvβ3 expression in endometrial cells, which improved endometrial receptivity. Further, methionine strongly influenced the DNA methylation and transcription levels of the transcription factor eomesodermin (Eomes), which bound directly to the IL-5 promoter region and inhibited IL-5 transcription. Methionine modulated IL-5 transcription, maternal-fetal immune tolerance, and endometrial receptivity via its effects on Eomes. This study reveals the crucial functions of methionine and IL-5 and offers a potential nutritional strategy for successful pregnancy.