Early-life gut dysbiosis programs divergent metabolic trajectories in a sex-dependent manner

Previous studies have established that long-term antibiotic (ABX) exposure disrupts gut microbiota, leading to adiposity, insulin resistance, and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the metabolic effects of short-term ABX treatment in early life, along with the underlying mechanism, remain unclear. This study reveals that short-term ABX exposure during early life induces sex-specific metabolic programming in mice. Immature males exhibited reduced gonadal white adipose tissue (gWAT) mass, predisposing them to exacerbated hepatic steatosis under high-fat diet (HFD) challenge. Females displayed protected liver metabolism. We identified dimethylarsinous acid (DMAIII) as a key microbiota-dependent metabolite that inversely correlated with both gWAT mass and specific bacterial abundances, including Muribaculum gordoncarteri and Ligilactobacillus apodemi in male mice. Critically, timely fecal microbiota transplantation (FMT) reversed these metabolic alterations in males. Our findings demonstrate that transient early-life microbiota disruption programs lasting, sex-divergent metabolic outcomes, highlighting the therapeutic potential of microbiota-targeted interventions during developmental windows.