{"title":"Cognitive and behavioral benefits of 2'-fucosyllactose in growing mice: the roles of 5-hydroxytryptophan and gut microbiota.","authors":"Liuying Zhu, Zhiyi Zhang, Ting Luo, Hongyan Li, Zeyuan Deng, Jing Li, Liufeng Zheng, Jinqiang Liao, Minghui Wang, Bing Zhang","doi":"10.1186/s40168-025-02094-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":18447,"journal":{"name":"Microbiome","volume":"13 1","pages":"97"},"PeriodicalIF":13.8000,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992797/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Microbiome","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s40168-025-02094-x","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: 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.
Results: 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.
Conclusion: 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.
期刊介绍：
Microbiome is a journal that focuses on studies of microbiomes in humans, animals, plants, and the environment. It covers both natural and manipulated microbiomes, such as those in agriculture. The journal is interested in research that uses meta-omics approaches or novel bioinformatics tools and emphasizes the community/host interaction and structure-function relationship within the microbiome. Studies that go beyond descriptive omics surveys and include experimental or theoretical approaches will be considered for publication. The journal also encourages research that establishes cause and effect relationships and supports proposed microbiome functions. However, studies of individual microbial isolates/species without exploring their impact on the host or the complex microbiome structures and functions will not be considered for publication. Microbiome is indexed in BIOSIS, Current Contents, DOAJ, Embase, MEDLINE, PubMed, PubMed Central, and Science Citations Index Expanded.
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