Société des Produits Nestlé SA, Nestlé Research, Lausanne, Switzerland.
Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.
Mol Psychiatry. 2021 Jul;26(7):2854-2871. doi: 10.1038/s41380-021-01054-9. Epub 2021 Mar 4.
Breastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129-St6gal1/J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6'SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6'SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6'SL-deficient milk. To test whether lactational 6'SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6'SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6'SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.
母乳中含有对大脑和认知发育至关重要的生物活性分子。虽然唾液酸化人乳寡糖（HMO）与表型编程有关，但它们的选择性作用和潜在机制仍不清楚。在这里，我们研究了选择性剥夺特定唾液酸化 HMO 对小鼠的长期影响。我们利用敲除（KO）小鼠模型（B6.129-St6gal1/J），该模型缺乏负责合成唾液酸（Neu5Ac）的基因之一的基因，即乳糖的两个唾液酸（Neu5Ac）来源之一（6'SL），对哺乳期后代。Neu5Ac 参与了维持认知的大脑结构的形成。为了剥夺哺乳期后代的 6'SL，我们将新生野生型（WT）幼鼠交叉寄养给 KO 母鼠，这些母鼠提供缺乏 6'SL 的乳汁。为了测试哺乳期 6'SL 剥夺是否会影响成年后的认知能力，我们评估了注意力、坚持性和记忆力。为了详细描述相关的表型，我们研究了海马电生理学、血浆代谢组学和肠道微生物群组成。为了研究潜在的分子机制，我们评估了两个介导执行功能和记忆的大脑区域（海马体和前额叶皮层，PFC）中的基因表达（在睁眼和成年时）。与对照小鼠相比，在哺乳期被剥夺 6'SL 的 WT 后代在所有测试的认知功能、海马电生理学以及调节 5-羟色胺能系统的途径（通过肠道微生物群和血浆代谢组学鉴定）中均表现出一致的改变。这些改变与前额叶皮层（PFC）中的基因表达（时空特异性）降低有关，这些基因参与中枢神经系统发育。我们的数据表明，母乳中的 6'SL 通过短期上调调节 PFC 中神经元模式的基因来调节认知发育。
