The maternal microbiome modifies adverse effects of protein undernutrition on offspring neurobehavioral impairment in mice.

Protein undernutrition is a global risk factor for impaired growth and neurobehavioral development in children. However, the critical periods, environmental interactions, and maternal versus neonatal influences on programming lasting behavioral abnormalities are poorly understood. In a mouse model of fetal growth restriction, limiting maternal protein intake particularly during pregnancy leads to cognitive and anxiety-like behavioral abnormalities in adult offspring, indicating a critical role for the gestational period. By cross-fostering newborn mice to dams previously exposed to either low protein or standard diet, we find that the adult behavioral impairments require diet-induced conditioning of both fetal development and maternal physiology, rather than either alone. This suggests that protein undernutrition during pregnancy directly disrupts fetal neurodevelopment and indirectly alters maternal state in ways that interact postnatally to precipitate behavioral deficits. Consistent with this, maternal protein restriction during pregnancy reduces the diversity of the maternal gut microbiome, modulates maternal serum metabolomic profiles, and yields widespread alterations in fetal brain transcriptomic and metabolomic profiles, including subsets of microbiome-dependent metabolites. Further depletion of the maternal microbiome in protein-restricted dams exacerbates alterations in fetal brain gene expression and neurocognitive behavior in adult offspring, suggesting that the maternal microbiome modifies the impact of gestational protein undernutrition on risk for neurobehavioral impairment in the offspring. To explore the potential for microbiome-targeted interventions, we find that maternal treatment with short chain fatty acids, a cocktail of 10 diet- and microbiome-dependent metabolites, or a consortium of gut bacteria reduced by protein undernutrition each yield differential effects on fetal development and/or postnatal behavior. Results from this study highlight impactful prenatal influences of maternal protein undernutrition on fetal neurodevelopment and adverse neurobehavioral trajectories in offspring, which are mitigated by microbiome-targeted interventions during pregnancy.蛋白质营养不良（protein undernutrition）是导致儿童生长受损与神经行为发育异常的全球性风险因素。然而，其关键易感窗口期、环境交互作用，以及母体与新生子代对长期行为异常发育程序化的影响机制仍未被充分阐明。本研究通过构建胎儿生长受限（fetal growth restriction）小鼠模型，发现仅在妊娠期间限制母体蛋白质摄入，即可导致成年子代出现认知功能异常与焦虑样行为障碍，这提示妊娠期在该过程中发挥关键调控作用。通过将新生小鼠交叉寄养至此前分别暴露于低蛋白饮食与标准饮食的母鼠体内，本研究发现成年子代的行为损伤需要同时满足胎儿发育阶段的饮食诱导编程与母体生理状态的饮食重塑，而非任一单一因素即可介导。该结果表明，妊娠期间的蛋白质营养不良可直接干扰胎儿神经发育，并间接改变母体生理状态，二者在产后产生交互作用，最终引发子代行为缺陷。与此一致的是，妊娠期间母体蛋白质限制会降低母体肠道微生物组（gut microbiome）的多样性，调节母体血清代谢组谱，并在胎儿脑转录组与代谢组谱中引发广泛改变，其中包含部分依赖于微生物组的代谢产物。在蛋白质限制的母鼠中进一步耗竭母体微生物组，会加剧胎儿脑基因表达异常与成年子代的神经认知行为缺陷，这提示母体微生物组可修饰妊娠期蛋白质营养不良对子代神经行为损伤风险的影响程度。为探索靶向微生物组的干预策略潜力，本研究发现，对母鼠给予短链脂肪酸（short chain fatty acids）、10种饮食与微生物组依赖性代谢产物的组合制剂，或蛋白质营养不良所耗减的肠道细菌联合体，均可对胎儿发育与/或产后行为产生差异化调控效果。本研究结果凸显了妊娠期间母体蛋白质营养不良对子代胎儿神经发育与不良神经行为发育轨迹的显著影响，而妊娠期实施靶向微生物组的干预措施可有效缓解该类不良结局。