After 4 weeks of supplementation, (2'-FL) enhanced cognitive memory function in growing mice.
Cognitive improvements were assessed using Y-maze, novel object recognition, and water maze tests.
2'-FL supplementation significantly altered diversity, increasing Bacteroides and Lactobacillus genera.
Elevated levels of 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP) were observed in the hippocampal tissue.
Antibiotic treatment eliminated the cognitive benefits of 2'-FL, indicating the importance of gut microbiota.
Short-term supplementation for 7 days led to rapid changes in gut microbiota prior to cognitive improvements.
In vitro experiments suggested that 2'-FL may influence enzymes involved in 5-HTP production in the gut.
Simplified
BACKGROUND: (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 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.
Key numbers
5 days
Increase in cognitive performance
Duration of the Morris water-maze training phase showing improved escape latency in the 2'-FL group.
78%
78% reduction in fecal bacterial load
Observed after antibiotic treatment in the 2'-FL group.
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Declarations. Ethics approval and consent to participate: All the experimental protocols were in accordance with the Chinese Council on Animal Care Guidelines and approved by Institutional Animal Care Committee of Nanchang University (MDL2023-06–09-02). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
