Maternal oral sodium propionate supplementation restores gut integrity and mitigates stress-induced metabolic and behavioral outcomes in offspring.

Maternal attachment is a critical determinant of offspring's postnatal development, significantly influencing their later-life metabolic and behavioral patterns. We previously showed that stress-vulnerable, socially submissive (Sub) mice exhibit significant disruptions in gut physiology including distorted microbiome composition, lower colonic propionate levels, and increased gut permeability. These alterations exacerbated chronic inflammation, caused metabolic imbalances and reduced maternal care. In this study, we revealed a significant reduction in bacterial diversity and fecal propionate levels in Sub dams. To investigate whether maternal gut integrity could mitigate adverse offspring outcomes, we provided oral sodium propionate (SP) supplementation to Sub dams via drinking water from postpartum day (PD) 0, until weaning (PD21). SP supplementation notably improved maternal care, reflected by faster pup retrieval times and better nesting. Beneficial effects were particularly pronounced in two-month-old male offspring, demonstrating decreased anxiety-like behavior, improved sociability and enhanced short-term memory accompanied by increased abundance of specific gut bacteria (Roseburia, and Shuttleworthia genus). Additionally, male offspring exhibited significant metabolic improvements, including reduced epididymal white adipose tissue (eWAT) mass, decreased adipocyte diameter accompanied by increased eWAT mRNA expression of GPR43 and PPAR-γ. Moreover, SP supplementation increased colon length linked with increased colonic mRNA expression of GPR43, PPAR-γ and Claudin-7, highlighting the importance of propionate in tight junction regulation and inflammation. Importantly, these positive outcomes exhibited notable sex-dependent differences, with male offspring responding robustly, whereas females showed minimal behavioral or metabolic improvements following maternal SP supplementation. Overall, our findings emphasize that innate stress vulnerability-related metabolic and behavioral alterations in offspring can be mitigated by restoring the dams' gut epithelial barrier integrity, highlighting the critical role of the maternal gut environment and demonstrating clear sex-specific responses to gut microbiota-targeted interventions.