Chlorogenic Acid Alleviates Heat Stress-Induced Fetal Growth Restriction Through Gut–Placental Crosstalk by Reshaping Gut Microbiota and Mediating Keap1-Nrf2 Antioxidant Signaling

Background: Climate change-driven heat stress (HS) poses a growing threat to pregnancy outcomes; however, the mechanisms linking maternal HS to fetal growth restriction (FGR) remain incompletely understood, and effective nutritional interventions are lacking. The gut–placenta axis critically governs maternal–fetal health, but its role in mediating HS-related FGR has yet to be elucidated. Methods: A murine model of gestational HS (38.5 °C, 2.5 h daily from E0.5 to E12.5) was established to investigate the protective effects of chlorogenic acid (CGA) on HS-induced FGR. Placental efficiency, oxidative status, barrier integrity, and intestinal permeability were assessed. Gut microbiota composition was profiled by 16S rRNA sequencing, while tight junction protein expression in the placenta and intestine was evaluated by Western blot. Additionally, antibiotic-induced microbiota reduction and fecal microbiota transplantation (FMT) were performed to explore the role of gut microbiota in alleviating HS. Results: HS exposure significantly reduced fetal weight without altering litter size, accompanied by reduced placental efficiency and proportion of the labyrinth zone relative to the total placental area. HS triggered oxidative stress and downregulated tight junction proteins (Claudin-1, Occludin) in both the placenta and intestine, indicating compromised barrier integrity. CGA treatment robustly reversed these abnormalities and restored placental structure. In the gut, CGA prevented HS-induced intestinal barrier dysfunction and selectively reshaped the microbiota, enhancing the Firmicutes/Bacteroidetes ratio and promoting beneficial Lactobacillus lineages. Notably, under antibiotic-induced microbial reduction, FMT from CGA-treated donors effectively alleviated HS-induced fetal growth restriction. Conclusions: In summary, our study suggests that gestational HS exposure may trigger FGR through the gut–placenta axis. CGA effectively reverses FGR by restoring placental efficiency and placental barrier integrity, while alleviating maternal gut dysbiosis and intestinal barrier impairment. FMT experiments further confirm that the gut microbiota may play a key role in this protection. Collectively, these findings suggest that targeting the gut–placenta axis with CGA may offer a practical nutritional strategy to mitigate HS-triggered adverse pregnancy outcomes.