Bagaev Anastasia, Sur Debpali, Agranyoni Oryan, Pe'er Naamah, Savita Brajesh Kumar, Rocha Beatriz Gonçalves Silva, Thanos Panayotis K, Navon-Venezia Shiri, Pinhasov Albert
Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, Israel.
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Transl Psychiatry. 2025 Jul 9;15(1):235. doi: 10.1038/s41398-025-03436-x.
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.
母体依恋是后代出生后发育的关键决定因素，对其后期的代谢和行为模式有重大影响。我们之前发现，应激易感性、社会顺从型（Sub）小鼠的肠道生理功能存在显著紊乱，包括微生物群组成扭曲、结肠丙酸水平降低以及肠道通透性增加。这些改变加剧了慢性炎症，导致代谢失衡并减少了母性关怀。在本研究中，我们发现Sub母鼠的细菌多样性和粪便丙酸水平显著降低。为了研究母体肠道完整性是否可以减轻后代的不良后果，我们从产后第0天开始，通过饮用水向Sub母鼠补充口服丙酸钠（SP），直至断奶（第21天）。补充SP显著改善了母性关怀，表现为更快的幼崽找回时间和更好的筑巢行为。有益效果在两个月大的雄性后代中尤为明显，表现为焦虑样行为减少、社交能力提高、短期记忆增强，同时特定肠道细菌（罗氏菌属和舒氏菌属）的丰度增加。此外，雄性后代在代谢方面有显著改善，包括附睾白色脂肪组织（eWAT）质量减少、脂肪细胞直径减小，同时eWAT中GPR43和PPAR-γ的mRNA表达增加。此外，补充SP增加了结肠长度，这与结肠中GPR43、PPAR-γ和Claudin-7的mRNA表达增加有关，突出了丙酸在紧密连接调节和炎症中的重要性。重要的是，这些积极结果表现出明显的性别差异，雄性后代反应强烈，而母体补充SP后，雌性后代在行为或代谢方面的改善最小。总体而言，我们的研究结果强调，通过恢复母鼠的肠道上皮屏障完整性，可以减轻后代与先天应激易感性相关的代谢和行为改变，突出了母体肠道环境的关键作用，并证明了对针对肠道微生物群的干预措施存在明显的性别特异性反应。
