The widespread use of antibiotics has resulted in their frequent occurrence in marine environments, yet their ecological risks remain poorly understood. Enrofloxacin (ENR) is one of the most frequently detected antibiotics in aquatic ecosystems. However, its toxicological mechanisms in marine fish remain unclear. Here, multiomics, Vibrio parahemolyticus infection, short chain fatty acid supplementation and germ-free fish models were integrated to investigate ENR induced neurotoxicity and the role of gut microbiota. The results showed that ENR exposure impaired intestinal function in marine medaka (Oryzias melastigma), accompanied by behavioral abnormalities, neurotoxicity, and liver injury. ENR also induced gut microbiome dysbiosis and altered SCFAs levels. Furthermore, SCFAs supplementation and germ-free fish experiments provided complementary and supportive evidence that gut microbial dysbiosis and altered SCFAs levels may be involved in ENR neurotoxic responses. Moreover, ENR pretreated fish showed increased susceptibility to V. parahemolyticus challenge, which further disrupted the gut microbiome and aggravated neurological dysfunction. Collectively, these findings suggest that ENR induced neurotoxicity is linked to disruption of the microbiome-gut-brain axis and increased susceptibility to subsequent pathogenic stress. This study provides new insights into antibiotic toxicity in marine fish and supports ecological risk assessment of ENR in marine aquaculture.
