As the global population ages, cognitive decline in older adults has gained significant attention in public health, underscoring the urgent need for effective intervention strategies. This study investigates the impact of salmon protein hydrolysate (SPH) on gut microbiota and cognitive decline in aged rats. Over 8 weeks, aged Sprague-Dawley rats were treated with SPH, resulting in significant enhancements in cognitive function as evidenced by operant-based attentional set-shifting and Morris water maze tasks. SPH modulated microglial activation in the hippocampus, reducing M1 polarization and promoting M2 polarization. RT-PCR analysis indicated a decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines, suggesting a reduction in neuroinflammation. Additionally, 16S rRNA gene sequencing revealed that SPH transformed gut microbiota, increasing Bacteroidetes and decreasing Proteobacteria. The bacterial genera Prevotella, Bacteroidetes and Ruminococcus showed notable increases. Furthermore, SPH intervention can also increase the concentrations of certain short-chain fatty acids (SCFAs) in aged rats. Additionally, SPH also restored the Th17/Treg balance and decreased peripheral inflammation. This study offers compelling evidence for SPH as a functional food that may mitigate cognitive decline due to aging.

Cognitive decline is a critical hallmark of brain aging. Although aging is a natural process, there is significant heterogeneity in cognition levels among individuals; however, the underlying mechanisms remain uncertain. In our study, we classified aged male Sprague‒Dawley rats into aged cognition-unimpaired (AU) group and aged cognition-impaired (AI) group by using an attentional set-shifting task. The transcriptome sequencing results of medial prefrontal cortex (mPFC) demonstrated significant differences in microglial activation and inflammatory response pathways between the two groups. Specifically, compared to AU rats, AI rats exhibited a greater presence of CD86-positive microglia and major histocompatibility complex class II (MHC-II)-positive microglia, along with elevated inflammatory molecules, in mPFC. Conversely, AI rats exhibited a reduction in the percentage of microglia expressing CD200R and the anti-inflammatory molecules Arg-1 and TGF-β. Additionally, peripheral blood analysis of AI rats demonstrated elevated levels of Th17 and Th1 cells, along with proinflammatory molecules; however, decreased levels of Treg cells, along with anti-inflammatory molecules, were observed in AI rats. Our research suggested that peripheral Th17/Treg cells and central microglial activation were associated with cognitive heterogeneity in aged rats. These findings may provide a new target for healthy aging.

While transplanting the fecal microbiota from young to aged rodents has been extensively studied (that is, young FMT [yFMT]), its mechanism of alleviating working memory decline has not been fully elucidated. In this report, we aimed to investigate the effect of yFMT on the working memory of aged recipient rats performing delayed match-to-position (DMTP) tasks and the associated cellular and molecular mechanisms. The results revealed that yFMT mitigated the decline in DMTP task performance of aged recipients. This improvement was associated with a reshaped gut microbiota and increased levels of brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunit 1, and synaptophysin, enhancing synaptic formation and transmission. The remodeling of the gut microbiome influenced peripheral circulation and the hippocampus and medial prefrontal cortex by regulating the Th17/Treg ratio and microglial polarization. Ultimately, interleukin-4 and interleukin-17 emerged as potential key molecules driving the beneficial effects of FMT. These observations provide new insights into the gutbrain axis, emphasizing the connection between the gut and brain through the circulation system, and suggest an immunological mechanism that may help reverse age-related declines in the gut microbiota.