Human milk oligosaccharide 2'-fucosyllactose alleviates Alzheimer's disease cognitive impairment via the SCFAs/vagal afferent pathway
Description
Alzheimer's disease (AD) is mainly manifested by cognitive dysfunction, accompanied by excessive β-amyloid (Aβ) deposition and neuroinflammatory reactions. Recent studies have shown that dietary nutrition intervention strategies based on gut brain signal communication are beneficial for delaying the pathological development of AD. 2'-Fucosyllactose (2'-FL), a human milk oligosaccharide, can remodel the gut microbiota composition and affect brain cognition. In addition, the vagus nerve (VN) partially mediates the neuroprotective effect of 2'-FL. In this study, it was found that 8-week 2'-FL (500 mg/kg &1000 mg/kg, gavage) intervention significantly rescued spatial memory impairment and recognition memory deficits in AD model (APP/PS1) mice. Moreover, 2'-FL significantly reduced Aβ deposition and neuroinflammatory response in hippocampal dentate gyrus (DG) and cortex. It is worth noting that 2'-FL enhances the expression of c-Fos protein in the solitary tract nucleus (NTS). This suggests that 2'-FL may improve AD related cognitive impairment by enhancing VN afferent activity. Unilateral cervical vagotomy demonstrates that the improvement of AD related cognition by 2'-FL depends on the presence of VN. In addition, 2'-FL enhanced gut barrier function, alleviated gut inflammatory responses, and prevents lipopolysaccharide (LPS) leakage. Notably, 2'-FL also reshaped the composition of the gut microbiota, increasing the relative abundance of Intestinimonas, Muribaculum, and others. Moreover, 2'-FL promoted the production of neuroprotective metabolites short-chain fatty acids (propionate and butyrate). Correlation analysis showed that propionate was highly correlated with behavioral and other related indicators. After unilateral cervical vagotomy, although 2'-FL still promoted the production of SCFAs, it did not improve cognitive impairment in AD mice. This suggests that the neuroprotective effect of SCFAs may also be partially dependent on the VN. In conclusion, this study showed thaaddt 2'-FL significantly rescued the associated cognitive deficits in AD mice, which was partly explained by changes in gut microbial composition, production of SCFAs, and the presence of VN. Consequently, 2'-FL can be used as a prebiotic to play a potential regulatory role in gut and brain cognition-related dysfunction.