Dietary L-malic acid supplementation during early pregnancy improves reproductive performance through modulation of...

Embryo loss during early pregnancy is a major constraint on mammalian reproductive efficiency. We previously revealed that dietary L-malic acid (L-MA) supplementation benefits maternal health in sows during late pregnancy. However, the effect of L-MA on sows during early pregnancy is largely unexplored. In the present study, in vitro assays confirmed that L-MA directly promoted the adhesion of embryonic trophoblast (JAR) cells to endometrial epithelial (Ishikawa) cells, and alleviated H₂O₂-induced reactive oxygen species (ROS) accumulation in the endometrial cells. In vivo, L-MA supply during early pregnancy optimized the physiological environment in sows, thereby improving pregnancy outcomes, without altering circulating estradiol or progesterone levels on GD 28. L-MA significantly enhanced maternal antioxidant capacity and alleviated inflammatory responses. Metabolomics analysis showed that L-MA reshaped the maternal metabolic profile, modulated amino acid, lipid and nucleotide metabolism, and activated the NOD-like receptor signaling pathway and the cGMP-PKG signaling pathway. L-MA enriched beneficial bacteria, including short-chain fatty acid (SCFA)-producing, anti-inflammatory, and antioxidant taxa, while repressing inflammation-associated bacteria, and these specific taxa were significantly correlated with differential metabolites, antioxidant/anti-inflammatory markers, and reproductive outcomes. Overall, our data revealed that dietary L-MA supplementation during early pregnancy enhanced reproductive performance in sows. These benefits might be associated with shifts in the maternal gut microbiota-metabolite axis and enhanced antioxidant and anti-inflammatory capacities. Therefore, L-MA supplementation may be a potential strategy for ameliorating embryo loss and improving reproductive performance in mammals.