Indole-3-lactic acid derived from tryptophan metabolism promotes trophoblast migration and invasion by activating the AhR/VCAN pathway

Abstract

Background

Preeclampsia (PE) is a life-threatening condition that is unique to human pregnancy, and it is a leading cause of maternal and neonatal morbidity and mortality. Currently, the only definitive treatment for PE is delivery of the placenta. Several studies have suggested that the gut microbiota and its derived metabolites may be associated with PE. Our previous work indicated that the level of indole-3-lactic acid (ILA), which is a metabolite derived from tryptophan (Trp) metabolism in the gut, is increased in PE patients. However, the effects of ILA on trophoblast function and its underlying mechanisms remain largely unknown.

Methods

Transwell assays were conducted to assess the effects of ILA on trophoblast migration and invasion. Moreover, the aryl hydrocarbon receptor (AhR) signaling pathway was examined by qRT-PCR, western blotting and siRNA transfection. Additionally, RNA-seq analysis was performed to explore the mechanism underlying the ILA-mediated effects on trophoblast function. Finally, in vivo trophoblast invasion was evaluated through immunohistochemical analysis.

Results

Our data demonstrated that ILA promoted HTR-8/SVneo cell migration and invasion through AhR signaling pathway activation. Mechanistically, VCAN upregulation played a key role in mediating the effects of ILA on trophoblasts after AhR activation. Notably, ILA supplementation improved spiral artery remodeling and increased trophoblast invasion in PE-like mice, primarily by increasing VCAN levels. Conclusions: These data strongly suggest that elevated ILA in PE serve as a protective mechanism against trophoblast dysfunction. Therefore, we propose that ILA may be a novel and promising therapeutic approach for treating PE by enhancing trophoblast functions.