Maternal intestinal and placental mitochondrial dysfunction, autophagy, and ferroptosis involving intestinal microbiota by gut microbiota transplantation from sheep to mice

Exposure to testosterone (T) in pregnant ewes resulted in placental dysfunction and fetal growth restriction (FGR). However, the impact of T on gut microbiota and its contribution to exacerbating intestinal and placental pathologies remains uncharacterized. Pregnant sheep received intramuscular injections of 100 mg T propionate or a control vehicle. To examine the gut microbiota' s role in T-induced FGR, gut microbiota transplantation (GMT) was conducted from T-exposed and control ewes into antibiotic-treated pregnant mice. The findings demonstrated that T exposure exacerbated mitochondrial impairment, autophagy, and ferroptosis in placental and intestinal tissues, alongside inducing gut microbial dysbiosis. GMT further revealed that pathological alterations were mechanistically linked to gut microbiota imbalance. The findings demonstrated that gut-placental axis play a central role in mediating T-induced mitochondrial dysfunction, autophagy, and ferroptosis in maternal intestinal and placental tissues. These results underscore novel therapeutic opportunities, which operate via the gut-placental axis to mitigate FGR.