Bifidobacterium longum and prebiotic interventions restore early-life high-fat/high-sugar diet-induced alterations in feeding behavior in adult mice.

An unhealthy diet disrupts feeding behavior and the gut microbiota, but whether early-life dietary effects persist, or can be restored later in life, remains unclear. We investigated whether microbiota-targeted interventions (FOS + GOS or Bifidobacterium longum APC1472) could restore early-life high-fat/high-sugar (HFHS) diet-induced feeding alterations in adult female and male mice. HFHS exposure exclusively in early-life induced persistent, sex-specific feeding alterations in adult mice, despite normalized body weight. Early-life HFHS diet reduced hypothalamic cells expressing feeding-related markers (POMC, GHSR, PNOC, NOD2) in adult mice. Females were more vulnerable, with reduced LEPR(+) cells and disrupted arginine/tryptophan metabolism, while males showed impaired peptidoglycan sensing and steroid metabolism. We show that microbiota interventions restore these effects via distinct mechanisms. FOS + GOS induced extensive microbiome compositional shifts and sex-specific restoration of gut-brain pathways, while B. longum APC1472 induced greater behavioral restoration with minimal microbiome compositional changes. These findings highlight sex-specific vulnerabilities and mechanism-dependent therapeutic potential of microbiota-based interventions after exposure to early-life unhealthy diets.