Early-life and lifelong exposure to environmentally relevant enrofloxacin reorganizes a proteobacteria-centered gut-lipid-resistome steady state in marine medaka.

Environmental fluoroquinolone residues such as enrofloxacin (ENR) are increasingly detected in coastal waters, yet the persistence of low-dose effects on gut ecosystem organization remains unclear. We compared an early-life window exposure (5 μg/L ENR, 20-35 days post-hatch; depurated to 150 dph) with a lifelong exposure (5 μg/L ENR from fertilization to 150 dph) in marine medaka (Oryzias melastigma), using an environmentally realistic upper-bound concentration reflecting aquaculture-impacted conditions. We integrated intestinal histology and ultrastructure, inflammatory and lipid-metabolic transcriptional programs, intestinal fatty-acid profiles, 16S rRNA and 2bRAD-M characterization of the gut microbiota and antibiotic-resistance genes. Both regimens increased intestinal hypertrophy or densification and rewired communities into more positively connected, Proteobacteria-centered networks. Lifelong exposure produced a pronounced shift in intestinal lipid programming, marked by enhanced lipogenesis and reduced fatty-acid catabolism, together with selective changes in fatty-acid composition and desaturation balance. Early-life window exposure left persistent, albeit weaker, adult signatures in intestinal morphology, microbial network topology, and lipid-related transcription after prolonged withdrawal. Across cohorts, Proteobacteria indicator taxa covaried with inflammatory and lipid gene modules and with coordinated resistance-gene modules, consistent with a Proteobacteria-rich gut-lipid-resistome steady state. These findings indicate that ENR at an environmentally realistic upper-bound concentration reflecting aquaculture-impacted and hotspot contamination scenarios can durably reorganize host-microbe-resistome linkages, supporting re-evaluation of "no-effect" thresholds for antibiotic pollution from a One Health perspective.