A combined effect of fish-originated collagen peptides and caffeine on the cognitive function of sleep-deprived mice.

Refreshing beverages, consumed worldwide, commonly take advantage of caffeine's impacts on attention and motor performance. However, excessive long-term caffeine intake might disturb sleep/wake rhythms and exacerbate daily anxiety. Fish-originated collagen peptides (FCP) are of high nutrient value with stimulating, calming or relaxing effects, which could reduce the excitotoxicity of caffeine. This study aims to investigate two facets: (1) the combined effect of caffeine and FCP (namely C&F) on the cognitive function of sleep-deprived mice by different administration strategies with dose dependence (low and high dose) or time dependence (intervention in a day and prevention for a week); (2) the potential "microbiota-gut-brain" mechanism by which C&F improves sleep deprivation (SD)-induced cognitive impairments. Here, C57BL/6 mice were administered caffeine (10 or 20 mg per kg per bw) combined with FCP (100 or 200 mg per kg per bw) and were then subjected to 48 h SD. The open-field and Morris water maze tests were performed to evaluate the cognitive function and spatial learning capacities of mice. Our results indicated that the cognitive impairments of SD mice were significantly relieved to a different degree by treating C&F in a dose- and time-dependent manner. The pathological observation of the hippocampus indicated both intervention (time of a day) and prevention (time of a week) of the C&F protected brain tissue from SD-induced injuries. The accumulated pro-inflammatory neurometabolites and factors were significantly inhibited by C&F via the hypothalamus-hippocampal circuit. Furthermore, 16S rDNA analysis of colonic contents showed that the level of Lactobacillus murinus was significantly upregulated and that of Clostridia_UCG-014 was suppressed in the C&F group. The receiver operating characteristic (ROC) curve of Lactobacillus murinus indicated a certain diagnostic utility to distinguish C&F intervention (AUC = 0.52) or prevention (AUC = 0.68). Pathways of ko04622 (immune system) and ko00472 (metabolism processes) were significantly regulated by C&F in a time-dependent manner. Based on PICRUSt2 algorithm analysis, C&F might potentially regulate gut microbial functions through several metabolic pathways, including the RIG-I-like receptor signaling pathway and limonene and pinene degradation. In conclusion, C&F plays a key role in brain function and behavior, which could synergistically relieve cognitive impairments via the microbiota-gut-brain axis.