Coffee intervention alleviates anxiety-like behavior and metabolic dysfunction induced by a high-fat diet combined with sleep deprivation in mice: a multi-omics analysis of alterations associated with the gut-liver-brain axis.

A high-fat diet (HFD) combined with sleep deprivation (SD) (collectively termed HSD) is a common modern lifestyle stressor that induces metabolic dysfunction and neurobehavioral alterations. Here, we investigated whether daily coffee (5 g of coffee powder per kg body weight) could alleviate the above-mentioned alterations induced by HSD in male C57BL/6 mice subjected to 20 h day-1 SD for 9 weeks, and explored the underlying mechanisms using multi-omics approaches. Our results showed that the coffee intervention ameliorated HSD-induced anxiety-like behavior, hippocampal synaptic damage, and hepatic steatosis. These improvements may be associated with alterations in the gut microbiota composition (enrichment of Adlercreutzia, Eubacterium, and Kineothrix; reduction of Turicibacter), enhanced hepatic bile acid and lipid metabolism (e.g., upregulation of Cyp7a1, Cyp4a32), suppression of profibrotic and proinflammatory signaling, and altered brain transcriptome profiles, including the upregulation of synaptic and neurotransmitter release related genes. Integrated multi-omics network analysis showed that the HSD network was dominated by a single microbial hub with brain inflammatory and hepatic lipid metabolism genes as core features, whereas the coffee treatment group exhibited a more distributed network architecture featuring multiple microbial genera, coffee metabolism related genes (Cyp1a2/Cyp2a5), and the synaptic gene Rab3a. Collectively, these findings suggest that moderate coffee consumption may alleviate HSD-induced neurobehavioral and metabolic disturbances, an effect accompanied by coordinated multi-organ adaptation.