Effect of Human Milk Oligosaccharides on Learning and Memory in Mice with Alzheimer’s Disease

Alzheimer's disease (AD) is distinguished by cognitive dysfunction and neuroinflammation in the brain. 2′-Fucosyllactose (2′-FL) is a major human milk oligosaccharide (HMO) that is abundantly present in breast milk and has been demonstrated to exhibit immunomodulatory effects. However, the role of 2′-FL and HMO in gut microbiota modulation in relation to AD remains insufficiently investigated. This study aimed to elucidate the preventive effect of the 2′-FL and HMO impact of AD and the relevant mechanism involved. Here, the behavioral results showed that 2′-FL and HMO intervention decreased the expression of Tau phosphorylation and amyloid-β (Aβ), inhibited neuroinflammation, and restored cognitive impairment in AD mice. The metagenomic analysis proved that 2′-FL and HMO intervention restored the dysbiosis of the gut microbiota in AD. Notably, 2′-FL and HMO intervention significantly enhanced the relative abundance of Clostridium and Akkermansia. The metabolomics results showed that 2′-FL and HMO enhanced the oleoyl-l-carnitine metabolism as potential drivers. More importantly, the levels of oleoyl-l-carnitine were positively correlated with the abundances of Clostridium and Akkermansia. These results indicated that 2′-FL and HMO had therapeutic potential to prevent AD-induced cognitive impairment, which is of great significance for the treatment of AD.