Environmental Enrofloxacin Exposure as a Modifiable Driver of Mitochondria‐Mediated Intestinal Aging and Barrier Dysfunction

Environmental antibiotic pollution is an underexplored contributor to gut aging and chronic intestinal diseases. We provide evidence that chronic exposure to enrofloxacin (ENR), a commonly detected veterinary antibiotic, accelerates gut aging and disease progression through a mitochondria-centered mechanism. In a population-based cross-sectional analysis, recent antibiotic use was associated with increased biological age and a higher risk of diarrhea in middle-aged and older adults, supporting a link between antibiotic exposure and impaired gut health and aging processes. Using zebrafish and intestinal epithelial cell models, we demonstrate that low-dose ENR exposure impairs intestinal function, characterized by increased permeability, reduced mucus secretion, tight junction disruption, and chronic inflammation. Multi-omics profiling revealed that ENR induced gut microbial dysbiosis, reduced metabolic diversity, and intestinal hypoxia. Mitochondrial dysfunction, particularly impaired oxidative phosphorylation, was identified as the key driver of epithelial damage. Remarkably, treatment with pyrroloquinoline quinone, a mitochondrial-targeted antioxidant, reversed ENR-induced mitochondrial injury, restored intestinal integrity, reduced inflammation, and partially normalized the microbiome. Stratified analyses in the human cohort showed that higher gut microbiota-related diet quality and antioxidant capacity mitigated antibiotic-associated aging and diarrhea risk. These findings highlight mitochondrial protection and microbiota optimization as promising therapeutic strategies.