Ellagic acid ameliorates alcohol-induced cognitive and social dysfunction by modulating cytokine-cytokine receptor interaction signaling through the gut microbiota-mediated CCL21-CCR7 axis

Chronic alcohol consumption disrupts the balance of the gut microbiome, resulting in alcohol-induced cognitive and social dysfunction (AICSD), and serves as a primary etiological factor for early-onset dementia. Although ellagic acid (EA) has demonstrated beneficial effects on cognitive improvement, its potential for ameliorating cognitive and social function disorders caused by chronic alcohol consumption and the underlying mechanism remain unknown. In our study, we employed a multi-omics approach to elucidate the microbiome-mediated mechanism underlying the beneficial effects of EA on AICSD. Firstly, our findings demonstrate that EA ameliorates AICSD by modulating the cytokine-cytokine receptor interaction signaling pathway. Subsequently, we observed that EA effectively restores the dysbiosis of gut microbiota and their derived metabolites induced by chronic alcohol consumption. Multi-omics analysis revealed a significant positive correlation between EA-enriched beneficial metabolites and beneficial gut microbiota; conversely, there was a negative correlation between EA-enriched beneficial metabolites with cytokine-cytokine receptor interaction signaling-related genes. Finally, the causal relationship between the microbiome and behavioral changes was further confirmed through antibiotic treatment and fecal microbiota transplantation experiments. Overall, our study provides innovative evidence supporting the role of EA in improving AICSD via regulation of the cytokine-cytokine receptor interaction signaling pathway through the microbiota-mediated CCl21-CCR7 axis. These findings offer valuable insights into both EA-based interventions as well as microbial interventions against AICSD.