Ellagic acid ameliorates alcohol-induced cognitive and social dysfunction 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. Ellagic acid (EA) is a polyphenolic compound belonging to the ellagitannin family, showing potential as a dietary intervention for alleviating cognitive impairments. Nonetheless, the protective effects and underlying mechanisms of EA on AICSD remain unclear. 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 significantly ameliorated cognitive and social behavioral deficits as well as neuroinflammation induced by alcohol. Moreover, RNA-seq analysis of hippocampi indicates that EA regulated the KEGG pathway of cytokine–cytokine receptor interaction signaling by downregulating the CCL21-CCR7 axis. Furthermore, we observed that EA effectively restored the dysbiosis of gut microbiota and their derived metabolites induced by chronic alcohol consumption. Strong connections were observed between EA-regulated genes, microbiota and metabolites. 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.