Nutritional modulation of chenodeoxycholic acid in early pregnancy: Integrating hepatic metabolic reprogramming and uterine transcriptome adaptation

Hepatic-driven metabolic alterations have impacts on both embryo implantation and subsequent fetal development. We previously found that dietary chenodeoxycholic acid (CDCA) improves maternal redox homeostasis and metabolic health to improve embryo implantation. However, a critical knowledge gap remains: how are these systemic metabolic improvements driven by CDCA translated into a uterine microenvironment? This study employed multi-omics integration to elucidate the mechanisms, from the liver-uterine perspective, by which early gestational CDCA supplementation optimizes embryo implantation. Results showed that CDCA improved redox homeostasis and reduced inflammation burden in maternal livers. Hepatic untargeted metabolic analysis and targeted amino acid analysis revealed that CDCA reshaped liver metabolism, especially the amino acid metabolism, as that many amino acid metabolism pathways were enriched and levels of many essential amino acids and branched-chain amino acids were reduced with CDCA intervention. Uterine transcriptome analysis revealed that CDCA induced uterine alterations in substance metabolism (especially amino acid and purine metabolism) and genetic information processing. Notably, the expression of several functional genes involved in adhesion G protein-coupled receptor signaling, cell-cell adhesion, integrins, and development were regulated by CDCA supply. Furtherly, a joint analysis revealed that uterine amino acid metabolism, carbohydrate and energy metabolism, nucleotide metabolism, signaling and endocrine regulation, and others were shaped in response to CDCA-driven metabolic alterations in livers. Our findings indicate that CDCA's role transcends individual organs, potentially establishing a “liver-uterus” functional axis conducive to pregnancy establishment via metabolic regulation. This work provides a novel theoretical framework and potential directions for addressing metabolic-related infertility.