Faecalibacterium prausnitzii: A microbial ally against preeclampsia via extracellular vesicle-mediated ferroptosis inhibition.

Abstract

Mounting evidence highlights preeclampsia (PE) pathogenesis involves gut microbiota dysregulation and trophoblast ferroptosis. However, the mechanistic nexus bridging intestinal homeostasis and placental ferroptosis remains elusive. Here, we found that Faecalibacterium prausnitzii (F. prausnitzii) reduced blood pressure (SBP/DBP), proteinuria, and levels of anti-angiogenic (sFlt-1) and pro-inflammatory (IL-6, TNF-α) mediators in PE rats established using reduced uterine perfusion pressure (RUPP) surgery. Critically, F. prausnitzii elevated fetal survival rate, increased fetal length and weight, and restored placental length and weight. Moreover, F. prausnitzii restored intestinal barrier function (upregulated claudin-1, occludin, ZO-1/2). In both PE rats' placentas and hypoxia-induced HTR-8/SVneo cells, F. prausnitzii reduced ferroptosis markers (MDA, Fe, 8-OHdG, lipid ROS), while increasing GSH, GPX4, and SLC7A11 levels. Mechanistically, F. prausnitzii facilitated the transfer of intestinal-epithelial cell-derived extracellular vesicles (EVs) to the placenta and alleviated PE symptoms, by delivering NRP1 to inhibit trophoblast cell ferroptosis. Molecularly, NRP1 activates SLC7A11 both by directly binding to it and by stabilizing its mRNA via NSUN2-mediated mC methylation. These findings demonstrate that F. prausnitzii alleviates PE by transporting EVs-encapsulated NRP1 through the gut-placenta axis, which in turn modulates the NSUN2/SLC7A11 pathway to suppress trophoblast ferroptosis. Our findings identify NRP1 as a core mediator of EV-dependent ferroptosis inhibition and highlight the therapeutic potential of targeting the gut microbiota or the NRP1/NSUN2/SLC7A11 axis for PE treatment.