Lactobacillus_rhamnosus GG reverses zearalenone-induced pathological macrophage polarization to restore placental angiogenesis and efficiency

Abstract

Zearalenone (ZEN), a widespread mycotoxin exhibiting estrogen-like activity, is known to impair placental function; however, the underlying mechanisms remain elusive, and effective targeted interventions are lacking. In this study, we utilized both porcine and rodent models to investigate the effects of ZEN exposure and evaluate the protective efficacy of Lactobacillus_rhamnosus GG (LGG). In pregnant sows, ZEN exposure significantly compromised placental vascular density and efficiency. Full-length 16S sequencing and bile acid-targeted metabolomics revealed that ZEN induced intestinal microbial dysbiosis and disrupted bile acid metabolism. Mechanistically, ZEN induced a pathological polarization of placental macrophages toward an M2-like phenotype, characterized by the overexpression of arginase-1 (Arg-1) and the suppression of nitric oxide (NO) and vascular endothelial growth factor (VEGF) production. Crucially, LGG supplementation reshaped the gut microbiota by enriching Ruminococcus_gnavus, which subsequently increased the production of isolithocholic acid (isoLCA). This metabolic modulation reversed the ZEN-induced aberrant macrophage polarization. Further validation in rodent models confirmed that ZEN drove aberrant hepatic M2 macrophage polarization, a phenotype that was similarly rectified by LGG administration. In conclusion, this study revealed that ZEN impaired placental function by driving pathological macrophage polarization, and indicated that LGG could mitigate this toxicity through alterations in the gut microbiota and bile acid metabolism. These findings provided a novel perspective and a promising nutritional strategy for combating ZEN-induced reproductive toxicity.