Li Xuguang, Shiraki Nobuaki, Watanabe Takami, Fukui Rikako, Furukawa Kyohei, Kato Yusuke, Nakahara Yuri, Kume Shoen, Taguchi Akashi, Wada Youichiro, Warman Dwina Juliana, Saito Kenji, Nakajima-Adachi Haruyo, Hachimura Satoshi, Kato Hisanori, Jia Huijuan
Health Nutrition, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan; Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan.
School of Life Science and Technology, Institute of Science Tokyo, Tokyo, Japan; School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
EBioMedicine. 2025 Jun 26;118:105817. doi: 10.1016/j.ebiom.2025.105817.
Maternal nutrition during critical developmental windows is crucial for offspring metabolic programming. Methionine, an essential amino acid, is crucial in pancreatic differentiation. However, the impact of a maternal methionine-deficiency (MD) diet on offspring during the critical stage of embryonic pancreatic differentiation remains unclear.
We used an in vitro human induced pluripotent stem cell (hiPSC) differentiation model and in vivo mouse and rat models to assess the impact of short-term maternal MD during pancreatic development. Offspring metabolic outcomes were evaluated under control or high-fat diet conditions. Multi-omics analyses were performed to explore mechanistic pathways, and Ruminococcus flavefaciens supplementation was used to assess microbiota-metabolite-host interactions.
During foetal pancreatic development in mice, a two-day maternal MD diet induced long-term metabolic perturbations in offspring. MD disrupted pancreatic progenitor differentiation in vitro and altered offspring glucose homeostasis, pancreatic function, and gut microbiota composition in vivo. Male offspring showed impaired glucose tolerance, enhanced pancreatic differentiation, and increased susceptibility to diet-induced obesity in adulthood. These metabolic impairments were evident early in life, with MD neonates displaying altered metabolic profiles and pancreatic gene expression. We identified an association between maternal MD diet, gut microbiota-dependent R. flavefaciens abundance, and elevated creatine levels in both mothers and offspring. R. flavefaciens supplementation in mice recapitulates the observed metabolic dysregulation.
Short-term maternal MD during foetal pancreatic development can induce lasting metabolic reprogramming in offspring. Gut microbiota-dependent creatine dysregulation may serve as a key mediator linking maternal diet to offspring metabolic susceptibility. These findings highlight the developmental impact of transient maternal nutrient imbalance and role of the microbiota-metabolite axis in shaping offspring health.
See Acknowledgements.
关键发育窗口期的母体营养对后代的代谢编程至关重要。蛋氨酸作为一种必需氨基酸，在胰腺分化中起着关键作用。然而，母体蛋氨酸缺乏（MD）饮食在胚胎胰腺分化关键阶段对后代的影响仍不清楚。
我们使用体外人诱导多能干细胞（hiPSC）分化模型以及体内小鼠和大鼠模型，来评估胰腺发育过程中短期母体MD的影响。在对照或高脂饮食条件下评估后代的代谢结果。进行多组学分析以探索作用机制途径，并使用补充黄化瘤胃球菌来评估微生物群 - 代谢物 - 宿主相互作用。
在小鼠胎儿胰腺发育期间，为期两天的母体MD饮食会在后代中诱发长期的代谢紊乱。MD在体外破坏胰腺祖细胞分化，并在体内改变后代的葡萄糖稳态、胰腺功能和肠道微生物群组成。雄性后代表现出葡萄糖耐量受损、胰腺分化增强以及成年后对饮食诱导肥胖的易感性增加。这些代谢损伤在生命早期就很明显，MD新生儿表现出代谢谱和胰腺基因表达的改变。我们发现母体MD饮食、肠道微生物群依赖性黄化瘤胃球菌丰度与母亲和后代中肌酸水平升高之间存在关联。在小鼠中补充黄化瘤胃球菌可重现观察到的代谢失调。
胎儿胰腺发育期间短期母体MD可在后代中诱导持久的代谢重编程。肠道微生物群依赖性肌酸失调可能是将母体饮食与后代代谢易感性联系起来的关键介质。这些发现突出了短暂母体营养失衡的发育影响以及微生物群 - 代谢物轴在塑造后代健康中的作用。
见致谢部分。
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