Mechanisms of fetal growth restriction in gestational cholestasis: role of gut microbiota and placental redox.

Abstract

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic liver disorder associated with substantial fetal morbidity, including preterm birth, fetal distress, and even intrauterine demise. Although prior studies have documented structural and transcriptional alterations in the placenta during ICP, the mechanistic underpinnings linking maternal cholestasis to adverse fetal outcomes remain incompletely elucidated. METHODS: In this study, a murine model of ICP was established by feeding pregnant C57BL/6 mice a 0.1% DDC (3,5-dicarboxylic acid-1,4-dihydrocollidine) diet from E0.5 to E18.5. We assessed fetal growth and employed multi-omics approaches, including placental transcriptome sequencing, maternal gut microbiome profiling, and serum/placental metabolome analysis. RESULTS: Placental transcriptome sequencing revealed that ICP significantly downregulated the expression of antioxidant-related genes including, andleading to reduced total antioxidant capacity in placental tissue and elevated levels of malondialdehyde (MDA), a marker of lipid peroxidation. Furthermore, ICP disrupted the maternal gut microbiota, resulting in decreased production of antioxidant microbial metabolites such as valeric acid and erythritol. This deficiency further aggravated oxidative damage in the placenta. DISCUSSION: Collectively, our findings uncover a novel gut microbiota-placenta axis driven by cholestasis, which contributes to fetal IUGR. The maternal cholestasis induces gut dysbiosis, which diminishes the production of valeric acid and erythritol. The deficiency of these metabolites, coupled with a direct suppression of the placental Nrf2/Keap1 antioxidant signaling pathway by cholestasis, leads to placental oxidative stress. This oxidative damage impairs placental function, ultimately resulting in fetal growth restriction. Disrupting this pathogenic cycle may offer a promising therapeutic strategy for preventing or treating ICP-related reproductive disorders.