Prenatal exposure to low-dose ciprofloxacin antibiotic increased male offspring’s defensive aggressive behaviors via a gut–phosphatidylcholine–α7 nAChR axis

Prenatal adversities disrupt the development of the gut microbiota and thereby increase the risk of neuropsychiatric disorders in later life. However, the effects of prenatal antibiotic exposure on aggressive behavior in adulthood and the underlying gut–brain mechanisms remain poorly defined. Here, we showed that low-dose exposure to the fluoroquinolone ciprofloxacin during late gestation increased defensive aggressive behavior in adult male offspring. Prenatal ciprofloxacin exposure thinned the colonic mucus layer, reduced MUC2 secretion, and depleted mucosa-associated Lactobacillus species, thereby reshaping the microbial ecosystem and disturbing systemic phosphatidylcholine (PC) homeostasis. This microbiota–lipid dysregulation is accompanied by reduced hippocampal α7 nicotinic acetylcholine receptor (α7 nAChR) expression, increased microglial activation and a pro-inflammatory cytokine profile, as well as increased neuronal activity in the hippocampus. Correlation analyses further linked altered PC species to bacterial taxa, supporting a microbiota-associated PC–α7 nAChR axis in the regulation of defensive aggression. Importantly, post-weaning supplementation with either phosphatidylcholine or Lactobacillus reuteri ( L. reuteri) attenuated defensive aggression in adult offspring prenatally exposed to ciprofloxacin. Altogether, these findings provide new insights into the gut–lipid–brain mechanisms by which prenatal antibiotics program aggressive behavior in adulthood and highlight phosphatidylcholine or L. reuteri supplementation as promising interventions for alleviating aggression abnormalities induced by prenatal antibiotic exposure.