C. Cuesta-Marti, Eduardo Ponce España, Friederike Uhlig, Iris Stoltenborg, Luiza Adela Wasiewska, Lamiah Kareem, Dara Hedayatpour, Loreto Olavarría-Ramírez, Cristina Rosell-Cardona, Thomaz F. S. Bastiaanssen, G. Tofani, Benjamín Valderrama, Klára Vlčková, Suzanne L. Dickson, Aonghus Lavelle, Catherine Stanton, R. Paul Ross, John F. Cryan, Timothy G. Dinan, Gerard Clarke, Siobhain M. O’Mahony, Harriët Schellekens
Abstract 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.