Zhu Liuying, Zhang Zhiyi, Luo Ting, Li Hongyan, Deng Zeyuan, Li Jing, Zheng Liufeng, Liao Jinqiang, Wang Minghui, Zhang Bing
State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China.
International Institute of Food Innovation, Nanchang University, Nanchang , Jiangxi, 330051, China.
Microbiome. 2025 Apr 12;13(1):97. doi: 10.1186/s40168-025-02094-x.
2'-Fucosyllactose (2'-FL) is one of the major oligosaccharides found in human breast milk, with several recognized beneficial effects on the host. Extensive research has indicated positive effects of 2'-FL on cognitive development in the brain, yet its molecular mechanisms have remained elusive. This study aimed to assess the impact of 2'-FL on the gut-brain axis microbiota and cognitive function in growing mice, along with its potential mechanisms of action.
Following long-term supplementation for 4 weeks, 2'-FL was found to enhance cognitive memory function in growing mice (3 weeks old) as assessed through Y-maze, novel object recognition, and water maze tests. Analysis via 16S rRNA sequencing revealed significant alterations in gut microbiota diversity and composition induced by 2'-FL, notably increasing the relative abundance of Bacteroides and Lactobacillus genera. Additionally, 2'-FL significantly elevated levels of 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP) in the hippocampal tissue. However, antibiotic intervention abolished the cognitive advantage conferred by 2'-FL, highlighting the critical role of gut microbiota in mediating its effects. Similarly, short-term supplementation with 2'-FL for 7 days indicated rapid changes in gut microbiota composition preceding cognitive improvements, further suggesting a potential causal relationship between gut microbiota characteristics and cognition. Further, in vitro experiments with mouse feces suggested that 2'-FL may influence tryptophan hydroxylase levels in the gut microbiota and inhibit the activity of 5-hydroxytryptophan decarboxylase, potentially leading to increased accumulation of 5-HTP. Additionally, 2'-FL may indirectly impact tryptophan hydroxylase levels in enterochromaffin cells by promoting short-chain fatty acid production, which could support 5-HTP synthesis. Elevated 5-HTP produced by the gut system enters the bloodstream, crosses the blood-brain barrier, and may potentially enhance brain 5-HT levels.
This study offers preliminary evidence that the cognitive-promoting effects of 2'-FL in mice may be closely associated with gut microbiota and 5-HT. The findings suggest that 2'-FL contribute to cognitive development in growing mice, potentially by modulating gut microbiota and enhancing 5-HT levels in the brain. Video Abstract.
2'-岩藻糖基乳糖（2'-FL）是母乳中发现的主要低聚糖之一，对宿主有多种公认的有益作用。广泛的研究表明2'-FL对大脑认知发育有积极影响，但其分子机制仍不清楚。本研究旨在评估2'-FL对生长中小鼠肠道-脑轴微生物群和认知功能的影响及其潜在作用机制。
经过4周的长期补充后，通过Y迷宫、新物体识别和水迷宫测试评估发现，2'-FL可增强生长中小鼠（3周龄）的认知记忆功能。通过16S rRNA测序分析显示，2'-FL可诱导肠道微生物群多样性和组成发生显著变化，特别是增加拟杆菌属和乳杆菌属的相对丰度。此外，2'-FL显著提高了海马组织中5-羟色胺（5-HT）和5-羟色氨酸（5-HTP）的水平。然而，抗生素干预消除了2'-FL赋予的认知优势，突出了肠道微生物群在介导其作用中的关键作用。同样，短期补充2'-FL 7天表明，在认知改善之前肠道微生物群组成迅速变化，进一步表明肠道微生物群特征与认知之间可能存在因果关系。此外，对小鼠粪便的体外实验表明，2'-FL可能影响肠道微生物群中色氨酸羟化酶的水平，并抑制5-羟色氨酸脱羧酶的活性，可能导致5-HTP积累增加。此外，2'-FL可能通过促进短链脂肪酸的产生间接影响肠嗜铬细胞中色氨酸羟化酶的水平，这可能支持5-HTP的合成。肠道系统产生的5-HTP升高进入血液，穿过血脑屏障，并可能潜在地提高大脑5-HT水平。
本研究提供了初步证据，表明2'-FL对小鼠的认知促进作用可能与肠道微生物群和5-HT密切相关。研究结果表明，2'-FL可能通过调节肠道微生物群和提高大脑5-HT水平，促进生长中小鼠的认知发育。视频摘要。
