Comparison of Neuroprotection and Regulating Properties on Gut Microbiota between Selenopeptide Val-Pro-Arg-Lys-Leu-SeMet and Its Native Peptide Val-Pro-Arg-Lys-Leu-Met In Vitro and In Vivo

Selenopeptides are promising candidates for intervening in neuroinflammation; however, the key role of selenium (Se) in selenopeptides remains poorly understood. To address this gap, we compared the neuroprotective effects of selenopeptide Val-Pro-Arg-Lys-Leu-SeMet (namely, Se–P1) and its native peptide Val-Pro-Arg-Lys-Leu-Met (namely, P1). Our results demonstrate that Se–P1 treatment exhibits superior antioxidant and antineuroinflammatory effects in PC12 cells and lipopolysaccharide (LPS)-injured mice compared to P1. Moreover, the administration of Se–P1 and P1 resulted in a shift in the gut microbiota composition. Notably, during LPS-induced injury, Se–P1 treatment demonstrated greater stability in maintaining gut microbiota composition compared to P1 treatment. Specifically, Se–P1 may have a positive impact on gut microbiota dysbiosis by modulating inflammatory-related bacteria such as enhancing Lactobacillus abundance while reducing that of Lachnospiraceae_NK4A136_group. Furthermore, the alteration of metabolites induced by Se–P1 treatment exhibited a significant correlation with gut microbiota, subsequently modulating the inflammatory-related metabolic pathways including histidine metabolism, lysine degradation, and purine metabolism. These findings suggest that organic Se contributes to the bioactivities of Se–P1 in mitigating neuroinflammation in LPS-injured mice compared to P1. These findings hold significant value for the development of potential preventive or therapeutic strategies against neurodegenerative diseases and introduce novel concepts in selenopeptide nutrition and supplementation recommendations.