Caffeic Acid Phenethyl Ester Alleviates Alcohol-Induced Inflammation Associated with Pancreatic Secretion and Gut Microbiota in Zebrafish

Caffeic acid phenethyl ester (CAPE) is identified to be an efficacious bioactive polyphenol in propolis for ameliorating glucose and lipid metabolism disorders and inflammation. In this study, an alcohol-induced zebrafish inflammation model was established. CAPE treatments at different concentrations (0.04, 0.2, and 1.0 μg/mL) were administered to alcohol-exposed zebrafish to investigate the underlying mechanisms of alleviating alcohol-induced liver inflammation using transcriptomic analysis and 16S rRNA gene sequencing methods. The results indicated that CAPE decreased the expressions of TNF-α and IL-1β and significantly increased the expression of IL-10 (<i>p</i> < 0.0001). Based on the KEGG enrichment analysis of transcriptomic sequencing, CAPE effectively alleviated the inflammation in zebrafish mainly through pancreatic secretion, complement and coagulation cascades, and protein digestion and absorption. Molecular docking supported the potential of CAPE in targeting cholecystokinin (CCK) A Receptor (CCKAR) and mediating the regulation of pancreatic secretion and related inflammation pathways. Moreover, intestinal microbiota analysis demonstrated that CAPE could improve the alcohol-induced microbiota disorder. Additionally, there was a significant correlation between the key genes related to lipid and sterol metabolism among the KEGG-enriched pathways and the specific intestinal microbial communities in zebrafish. Flavobacterium from Bacteroidota was significantly positively correlated with <i>CEL1</i>, <i>CEL2</i>, and <i>LPIN</i> (<i>p</i> < 0.01), which suggested that the anti-inflammatory function of CAPE was closely associated with the intestinal microbiota improvement. In conclusion, our findings demonstrated that CAPE could ameliorate liver inflammation in alcohol-induced zebrafish, which was mainly associated with the regulation of pancreatic secretion and intestinal microbiota disorder. This study emphasized the anti-inflammatory mechanisms of CAPE based on targeting the pancreatic secretion pathway, which will broaden the application of natural antioxidants in improving metabolic and inflammatory problems.