Early postnatal antibiotic-associated gut microbiota alterations might promote long-term lipid metabolism via brown adipose tissue metabolic programming

The Developmental Origins of Health and Disease theory describes early life as a critical window for long-term metabolic health. Accumulating evidence has identified the gut microbiota as a key mediator of early-life metabolic programming. This study utilized antibiotic intervention in neonatal mice to investigate the long-term effects of early postnatal gut microbiota perturbations on adult lipid metabolism and examined the underlying mechanisms involving both thermogenic adipose tissue programming and microbiota structural remodeling. We found that early postnatal antibiotic exposure significantly disrupted the normal developmental assembly of the gut microbiota. Surprisingly, these alterations were associated with partial attenuation of high‑fat diet‑induced lipid metabolic disturbances in adulthood, an effect that was more pronounced in male mice than in female mice. Mechanistically, the observed metabolic improvement appeared to be associated with brown adipose tissue (BAT) thermogenic activation rather than with white adipose tissue browning or persistent gut microbiota restructuring. Early postnatal antibiotic exposure-associated gut microbiota alterations were linked to enhanced BAT development, potentially via interleukin-6 signaling and M2 macrophage polarization, suggestive of a metabolic programming effect that enhanced adaptive thermogenesis and improved long-term lipid homeostasis. These findings indicate that the gut microbiota might represent a modifiable factor influencing adipose tissue development, highlighting the potential of targeting the microbiota–BAT interplay in early life for obesity prevention strategies.