Gong_2025_Foods_14_

As the global elderly population is rising, concerns about cognitive decline and memory loss are becoming urgent. This study evaluated the potential of sea cucumber hydrolysates (SCH) from Stichopus japonicus in alleviating cognitive deficits using a D-galactose-induced murine aging model. The effects of SCH on behavior, hippocampal morphology, gut microbiota, hippocampal cholinergic system, brain-derived neurotrophic factor (BDNF) signaling, and neuroinflammatory pathways were investigated. Results showed that SCH ameliorated learning and memory deficits and reduced neuronal damage in aging mice. SCH also modulated gut microbiota, along with increased fecal short-chain fatty acids levels. Functional prediction revealed that alterations in gut microbiota were related to signal transduction. Further, SCH enhanced hippocampal cholinergic function through elevating acetylcholine (ACh) levels and inhibiting acetylcholinesterase (AChE) activity and activated BDNF signaling, consistent with predictions of gut microbiota function. Restoration of cholinergic homeostasis and transmission of the BDNF pathway might contribute to the inhibition of hippocampal neuroinflammation via suppressing microglial activation and the nuclear factor kappa-B (NF-kappaB) pathway. In summary, SCH attenuated cognitive deficits through suppressing neuroinflammation, which might be correlated with the signal transduction caused by regulating gut microbiota. Further validation will be conducted through microbiota depletion and fecal microbiota transplantation. These findings suggest that SCH is a promising functional component for counteracting aging-related cognitive deficits.