Functional food intervention alleviates cognitive impairment by reshaping the gut microbiota and restoring propionate levels: evidence from edible bird’s nest supplementation

Introduction Aging-related cognitive decline is closely associated with synaptic dysfunction, neuroinflammation, and alterations in gut microbial homeostasis. Edible bird’s nest (EBN), a glycoprotein-rich functional food, has attracted attention for its potential neuroprotective effects. However, whether EBN has an ameliorative effect on aging-related cognitive impairment remains unclear. This study evaluated the effects of EBN supplementation on memory impairment in a D-galactose (D-gal) -induced aging model and explored the potential mechanisms. Methods Mice were subjected to chronic D-gal administration and treated with low or high-dose EBN or sialic acid (SA). Spatial learning and memory were assessed using the Morris water maze. Hippocampal neuronal morphology, dendritic spine density, synaptic marker expression, glial activation, and inflammatory cytokines were evaluated. Gut microbial composition was analyzed using 16S rRNA gene sequencing, while fecal short-chain fatty acids (SCFAs) were quantified by gas chromatography–mass spectrometry (GC–MS). Correlation analysis was performed to examine the association between gut microbial taxa and SCFA levels. Results D-gal treatment induced marked cognitive impairment in mice, as reflected by reduced spatial memory performance, decreased hippocampal dendritic spine density, and diminished expression of synaptic markers including Bdnf (brain-derived neurotrophic factor), Dlg4 (postsynaptic density protein 95), and Syp (synaptophysin). In contrast, EBN supplementation, particularly at the higher dose, significantly improved spatial learning and memory, preserved dendritic spine integrity, and upregulated the synaptic genes. Moreover, EBN effectively attenuated D-gal-induced glial activation and lowered the elevated pro-inflammatory cytokine levels in both serum and brain tissue. Analysis of the gut microbiota revealed that EBN supplementation was associated with a partial reversal of D-gal-induced shifts in microbial community structure, with a pronounced increase in the relative abundance of Lactobacillus . Concurrently, fecal propionate levels, which were reduced by D-gal treatment, were restored following EBN supplementation, and propionate abundance correlated positively with Lactobacillus . SA supplementation also showed beneficial changes in several measured outcomes, suggesting that SA may contribute to some of the responses observed following EBN supplementation. Conclusion In summary, EBN supplementation ameliorated cognitive impairment in D-gal-induced aging mice, and this effect may be associated with restoration of gut microbial homeostasis and increased fecal propionate levels. Given that aging is a major risk factor for metabolic syndrome and related cognitive decline, these findings highlight the potential of EBN as a functional food for combating age-associated metabolic and neurological disorders, possibly through modulation of the microbiota-gut-brain axis.