Comparative assessment of various protein isolates underpinning cognitive modulation: An interplay of neurobiological markers and gut-brain axis

Dietary composition significantly influences gut microbiota, which modulates neurodevelopment and cognitive functions via the gut-brain axis. While various protein sources have demonstrated neuroprotective effects, their impact during early developmental stages remains underexplored. This study evaluated the effects of fish protein isolate (FPI), soy protein isolate (SPI), and egg white isolate (EPI) on cognitive functions in juvenile mice. Behavioral evaluations, including the Morris water maze, Y-maze, and novel object recognition tests, were completed during the feeding trial. FPI supplementation significantly enhanced cognitive performance compared to SPI and EPI groups. Biochemical analyses revealed that FPI normalized cholinergic activity and oxidative stress markers in the mice brains. The FPI group exhibited higher levels of synaptophysin and postsynaptic density proteins in the hippocampus, along with increased antioxidant enzyme levels and lower amounts of malondialdehyde, compared to the SPI and EPI groups, respectively. Synaptic plasticity was enhanced by FPI supplementation. Moreover, the same FPI diet upregulated the levels of brain-derived neurotrophic factor and doublecortin, while downregulating the activation of astrocytes and microglia, when compared to SPI and EPI groups. Additionally, <i>Lactobacillus</i> abundance in the gut microbiota was significantly greater in the FPI group, correlating positively with improved cognitive behaviors relative to SPI and EPI groups. These findings indicated that fish protein supplementation during early development may improve cognitive functions through modulation of the gut-brain axis.