Effect of oral and intraperitoneal administration of walnut-derived pentapeptide PW5 on cognitive impairments in APP/PS1 mice.

Food-derived bioactive peptides, encrypted in native protein sequence, have attracted enormous research attention due to its potential in the prevention and/or treatment of a broad range of diseases. However, administration route poses a great challenge to their development and commercial applications. Patient-friendly delivery of bioactive peptides which also enhances its efficacy urgently remain to be addressed. Here we compared the effects of oral administration (PO) to intraperitoneal injection (IP) of a walnut-derived bioactive pentapeptide PW5 (Pro-Pro-Lys-Asn-Trp) in cognitive improvement capacity in APP/PS1 transgenic mice. Strikingly, we found that only PO administration of PW5 could effectively ameliorate cognitive impairments and reduce the β-amyloid deposits in the brain compared to the IP administration. This may be attributable to alterations in the gut microbiota communities, including alterations in microbial α- and β-diversities after PO treatment, leading to the reversal of the relative abundances of ten differential genera (e.g. Acinetobacter, Lactobacillus, Akkermansia, Allobaculum, Adlercreutzia, Coriobacteriaceae, unclassified_p_ Firmicutes, Desulfovibrionaceae, Oscillospira and Anaeroplasma) which are highly correlated with disease progression. Thus, this study has leveraged on PW5 to proof the superior efficacy of oral delivery to injection delivery in improving cognitive impairments in vivo, suggesting that oral delivery might be highly recommended as a prioritized delivery route in the development of food-derived peptides.