Limosilactobacillus reuteri normalizes gut microbiota dysfunction and social deficits of rat offspring associated with prenatal exposure to stress.

Prenatal stress (PS) is a potential risk factor for social behavior impairment in offspring. Here, we demonstrate that PS induces gut microbiota alterations that are associated with impaired sociability and social novelty preference in rat offspring. In addition, we found that these behavioral deficits could be partially rescued through either cohousing with normal offspring or fecal microbiota transplantation from control donors. Metagenomic analysis identified Limosilactobacillus reuteri (L. reuteri) as a key species based on the considerable difference in its abundance between the PS and control offspring. Subsequent investigations revealed that supplementing L. reuteri during critical neurodevelopmental windows restored oxytocin levels in the paraventricular nucleus (PVN) and rescued dopamine reward pathway function, thereby ameliorating PS-induced social deficits. Notably, these beneficial effects were completely abolished by either treatment with an oxytocin receptor antagonist or subdiaphragmatic vagotomy. Thus, both oxytocin signaling and vagal afferent pathways play essential roles in the observed benefits of L. reuteri. Our findings indicate that social behavior impairments in offspring exposed to prenatal maternal stress can be explained by a novel mechanism involving the gut microbiota-brain axis: whereby PS-induced depletion of specific commensal bacteria (particularly L. reuteri) disrupts vagus nerve-mediated oxytocinergic modulation of PVN-to-VTA dopaminergic circuits, ultimately leading to social behavior impairments in offspring.