背景:生命早期的肠道发育受到母乳中多种生物成分的深刻影响,其中乳源细胞外囊泡(mEV)含有大量来自母亲的垂直传输信号。然而,关于母体富含纤维的饮食如何通过影响mEV来调节后代肠道发育,人们知之甚少。
结果:在这项研究中,我们发现,在妊娠后期和哺乳期,母体抗性淀粉(RS)的消耗改善了子代的生长和肠道健康。母乳中的电动汽车是驱动这些有益效果的主要因素,尤其是增强肠道细胞的增殖和迁移。具体而言,母体RS摄入后施用mEV可增强体内肠细胞增殖和迁移(在小鼠模型中进行,并通过肠组织学观察表明,EdU分析,和细胞周期蛋白的定量)和体外(由CCK8,MTT表示,EdU,和伤口愈合实验)。值得注意的是,发现miR-146a-5p在母体RS组的mEV中高度表达,这也促进了细胞和小鼠模型中的肠细胞增殖。机械上,miR-146a-5p靶向沉默泛素连接酶3基因NEDD4L的表达,从而抑制DVL2泛素化,激活Wnt通路,促进肠道发育。
结论:这些发现证明了mEV在母体富含纤维的饮食与后代肠道生长之间的联系中的有益作用。此外,我们发现了一个新的miRNA-146a-5p-NEDD4L-β-catenin/Wnt信号轴在调节早期肠道发育中的作用。本研究为研究母体饮食对子代发育的影响提供了新的视角。
BACKGROUND: The intestinal development in early life is profoundly influenced by multiple biological components of breast milk, in which milk-derived extracellular vesicles (mEVs) contain a large amount of vertically transmitted signal from the mother. However, little is known about how maternal fiber-rich diet regulates offspring intestinal development by influencing the mEVs.
RESULTS: In this study, we found that maternal resistant starch (RS) consumption during late gestation and lactation improved the growth and intestinal health of offspring. The mEVs in breast milk are the primary factor driving these beneficial effects, especially enhancing intestinal cell proliferation and migration. To be specific, administration of mEVs after maternal RS intake enhanced intestinal cell proliferation and migration in vivo (performed in mice model and indicated by intestinal histological observation, EdU assay, and the quantification of cyclin proteins) and in vitro (indicated by CCK8, MTT, EdU, and wound healing experiments). Noteworthily, miR-146a-5p was found to be highly expressed in the mEVs from maternal RS group, which also promotes intestinal cell proliferation in cells and mice models. Mechanically, miR-146a-5p target to silence the expression of ubiquitin ligase 3 gene NEDD4L, thereby inhibiting DVL2 ubiquitination, activating the Wnt pathway, and promoting intestinal development.
CONCLUSIONS: These findings demonstrated the beneficial role of mEVs in the connection between maternal fiber rich diet and offspring intestinal growth. In addition, we identified a novel miRNA-146a-5p-NEDD4L-β-catenin/Wnt signaling axis in regulating early intestinal development. This work provided a new perspective for studying the influence of maternal diet on offspring development.