Metformin may induce immunologic tolerance at the maternal-foetal interface in early human pregnancy.

Objective: Repeated pregnancy loss has been shown to be related to decidual immune imbalance. Metformin has been found to promote a shift in the Th17/Treg balance towards immune tolerance. Our research aims to evaluate and obtain further information on the role and potential mechanism of metformin on Th17/Treg balance in the early pregnancy decidua.

Methods: Decidual immune cells from normal pregnancy women were treated with metformin, pro-inflammatory cytokines or metformin + cytokines respectively. The mRNA expression levels of STAT3, STAT5, RORC and Foxp3 were detected by qRT-PCR. The proportions of Th17 and Treg cells, the stability of Treg cells, and the STATs phosphorylation levels of T cells were evaluated by flow cytometry. The cytokine concentrations in the culture medium were detected by ELISA.

Results: After treated with metformin, indicators related to immune tolerance, including the mRNA expression and phosphorylation levels of STAT5, mRNA expression level of Foxp3, the proportion of Treg cell, and the IL-10 concentration increased significantly. Indicators related to immune rejection including the mRNA expression level of STAT3, the proportion of Th17 cell, and the IL-17A concentration showed a significant decrease. In inflammatory conditions, the proportion of Th-like Treg cells increased. Metformin promoted CD25 expression to maintain Treg cell stability.

Conclusion: Metformin has beneficial effects on immunological tolerance at the maternal-foetal interface in early pregnancy. The underlying mechanism may be that metformin restores the Th17/Treg balance by changing the expression of STATs, which is conducive to establishing maternal-foetal immune tolerance.