Feng Cuiping, Wu Yujun, Zhang Xiangyu, Wang Shuxian, Wang Junjun, Yang Huixia
Department of Obstetrics and Gynecology and Reproductive Medicine, Peking University First Hospital, Beijing, China.
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China.
Gut Microbes. 2025 Dec;17(1):2449095. doi: 10.1080/19490976.2024.2449095. Epub 2025 Jan 6.
Intrauterine growth restriction (IUGR) caused by placental dysfunctions leads to fetal growth defects. Maternal microbiome and its metabolites have been reported to promote placental development. Milk fat globule membrane (MFGM) is known for its diverse bioactive functions, while the effects of gestational MFGM supplementation on the maternal gut microbiota, placental efficiency, and fetal development remained unclear. In this study, low protein diet-induced IUGR decreased the litter birth weight, fetal birth weight, and the fetal/placental ratio in pregnant mice, while gestational MFGM supplementation restored these impairments. Meanwhile, MFGM supplementation during gestation enriched intestinal () and increased luminal and circulating short chain fatty acids (SCFAs) in IUGR pregnant mice, which improved placental efficiency and fetal development due to an enhanced antioxidant capacity and a decreased inflammation. In addition, fecal microbiota transplantation (FMT) with MFGM-derived microbiota reprinted the promoted phenotypes of maternal litter characteristics, gut enrichment, placental efficiency, and fetal gut development in MFGM-fed pregnant mice, which were also recapitulated by exogenous administration with or SCFAs cocktail. Mechanically, MFGM, MFGM-derived microbiota, , or SCFAs cocktail activated IUGR-induced depressive phosphorylation of PI3K-Akt signaling in the placenta. Moreover, placental cells cultivation under amino acid shortage model (AAS) or oxygen-glucose shortage model (OGS) was used to validate that MFGM-derived key microbial and circulating SCFAs cocktails can alleviate placental oxidative stress and inflammation via activating PI3K/Akt signaling. Taken together, gestational MFGM supplementation enriched intestinal and circulating SCFAs of IUGR pregnant mice, thereby improving placental efficiency, fetal growth, and intestinal functions of IUGR fetus. Our findings will provide theoretical support for the application of MFGM in the maternal-placental-fetal nutrition to address pregnancy malnutrition-induced IUGR.
胎盘功能障碍引起的宫内生长受限（IUGR）会导致胎儿生长缺陷。据报道，母体微生物群及其代谢产物可促进胎盘发育。乳脂肪球膜（MFGM）以其多样的生物活性功能而闻名，而孕期补充MFGM对母体肠道微生物群、胎盘效率和胎儿发育的影响尚不清楚。在本研究中，低蛋白饮食诱导的IUGR降低了妊娠小鼠的窝产仔体重、胎儿出生体重和胎儿/胎盘比值，而孕期补充MFGM可恢复这些损伤。同时，孕期补充MFGM可使IUGR妊娠小鼠肠道（此处原文缺失具体内容）丰富，并增加肠腔和循环中的短链脂肪酸（SCFAs），由于抗氧化能力增强和炎症减少，从而改善了胎盘效率和胎儿发育。此外，用源自MFGM的微生物群进行粪便微生物群移植（FMT）重现了MFGM喂养的妊娠小鼠母体窝仔特征、肠道（此处原文缺失具体内容）丰富、胎盘效率和胎儿肠道发育的促进表型，用（此处原文缺失具体物质）或SCFAs混合物进行外源给药也可重现这些表型。从机制上讲，MFGM、源自MFGM的微生物群、（此处原文缺失具体物质）或SCFAs混合物激活了IUGR诱导的胎盘中PI3K-Akt信号通路的抑制性磷酸化。此外，在氨基酸缺乏模型（AAS）或氧-葡萄糖缺乏模型（OGS）下进行胎盘细胞培养，以验证源自MFGM的关键微生物和循环SCFAs混合物可通过激活PI3K/Akt信号通路减轻胎盘氧化应激和炎症。综上所述，孕期补充MFGM可使IUGR妊娠小鼠肠道和循环中的SCFAs丰富，从而改善IUGR胎盘效率、胎儿生长和IUGR胎儿的肠道功能。我们的研究结果将为MFGM在母-胎-胎盘营养中的应用提供理论支持，以解决妊娠营养不良引起的IUGR。
