An energetic framework for gut microbiome-mediated obesity induced by early-life exposure to antibiotics

Early-life antibiotic (ELA) exposure has garnered attention for its potential role in modulating obesity risk, although outcomes from mouse experiments and human epidemiological studies often vary based on dosage and sex. Low-dose (subtherapeutic) antibiotics can enhance energy availability through moderate alterations in gut microbiome profile, while high-dose (therapeutic) antibiotics substantially deplete the gut microbiota, thereby contributing to short-term negative energy balance. In this perspective, we propose a framework to understand how these distinct impacts of antibiotics on the gut microbiome during critical developmental windows shape long-term obesity risk through their influence on host energy balance. Using this framework, we then propose several hypotheses to explain variation in ELA-induced obesity outcomes across males and females. We conclude by discussing the evolutionary implications of ELAs, positing that the response of the gut microbiome to ELAs may signal energy availability and environmental volatility, influencing metabolic programming and adaptive traits across generations.