Human milk oligosaccharide 2′-fucosyllactose alleviates cognitive impairment <i>via</i> the vagal afferent pathway in Alzheimer's disease mice

Alzheimer's disease (AD) is mainly manifested by cognitive dysfunction, accompanied by excessive β-amyloid (Aβ) deposition and neuroinflammation. The regulation of vagus nerve (VN) signal transmission is crucial for influencing the pathological progression of AD and exploring new therapeutic approaches. Two doses of 2'-fucosyllactose (2'-FL, 500 and 1000 mg kg^-1) were administered orally to AD model mice. 2'-FL rescued spatial and recognition memory deficits in AD mice. Moreover, 2'-FL reduced Aβ deposition and neuroinflammation. 2'-FL enhances c-Fos expression in the solitary tract nucleus (NTS). This suggested that 2'-FL alleviated AD-related cognition by enhancing VN afferent activity. Vagotomy demonstrated that the alleviation of AD-related cognition by 2'-FL depended on the presence of VN. Moreover, 2'-FL enhanced gut barrier function and alleviated gut inflammation. Notably, 2'-FL also reshaped the gut microbiota composition, increasing the relative abundance of <i>Intestinimonas</i>, <i>Muribaculum</i>, and others. Moreover, 2'-FL promoted the production of short-chain fatty acids (SCFAs). Correlation analysis showed that propionate was highly correlated with other related indicators. After vagotomy, although 2'-FL promoted SCFA production, it did not alleviate cognitive impairment. This suggested that the neuroprotective effect of SCFAs could also be partially dependent on the VN. 2'-FL rescued the cognitive deficits in AD mice, which was partly explained by changes in gut microbial composition, production of SCFAs, and the presence of VN.